RU2792010C2 - Methods and compositions to improve cognitive functions - Google Patents

Abstract

FIELD: medicine, therapy, neurology, psychiatry.

SUBSTANCE: group of inventions is intended for the treatment of a cognitive impairment associated with a central nervous system (CNS) disorder in a subject. A specified CNS disorder is mild cognitive impairment causing memory loss, dementia, Alzheimer’s disease (AD), AD’s prodrome, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS) or anticancer therapy-associated cognitive impairment. Brivaracetam or a pharmaceutically acceptable salt thereof is administered in an amount of 0.7-180 mg per day to treat said cognitive impairment in a subject in need thereof or at risk of its occurrence. Also provided is a pharmaceutical composition for oral administration once a day containing 0.7-180 mg of brivaracetam or a pharmaceutically acceptable salt thereof.

EFFECT: improvement or normalization of cognitive functions in a subject with a CNS disorder, and prevention or slowing of the progression of said CNS disorder accompanied by cognitive impairment.

7 cl, 18 dwg, 6 tab, 3 ex

Description

This application claims the priority and benefit of U.S. Provisional Application No. 61/441,251, filed Feb. 9, 2011, the contents and description of which are incorporated herein by reference in their entirety.

The field of technology to which the invention belongs

The present invention relates to methods and compositions for the treatment of central nervous system (CNS) disorders accompanied by cognitive impairment. In particular, the present invention relates to the use of synaptic vesicle 2A (SV2A) glycoprotein inhibitors, either alone or in combination with valproate, in the treatment of central nervous system (CNS) disorders that are accompanied by cognitive impairment in a patient in need of such treatment or at risk of developing such disorders, including, without limitation, in the treatment of patients who have or are at risk of developing age-related cognitive impairment, mild cognitive impairment (MCI), moderate cognitive impairment causing memory loss (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis, and anticancer therapy-associated cognitive impairment.

State of the art

Cognitive abilities may decline as a normal consequence of aging or as a consequence of a CNS disorder.

A significant portion of the older population experiences cognitive decline that is greater than the cognitive decline that occurs with normal aging. This age-related cognitive loss is clinically characterized by progressive memory loss, deterioration in the thought process, reduced levels of intellectual activity, and loss of the ability to associate words or concepts. Mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), or disorders classified in a similar clinical group are among those disorders that are associated with similar age-related cognitive decline. It is estimated that there are more than 16 million people with AAMI in the US alone (Barker et al, 1995), and MCI is estimated to affect 5.5-7 million people in the US over the age of 65 (Plassman et al., 2008). ).

Other central nervous system (CNS) disorders such as dementia, Alzheimer's disease (AD), prodromal Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis, and anticancer therapy-associated cognitive impairment are also associated with cognitive decline .

Thus, there is a need to effectively treat disorders of the central nervous system (CNS) accompanied by cognitive impairment and to improve cognitive functions in patients diagnosed with age-related cognitive impairment, MCI causing memory loss MCI, AAMI, ARCD, dementia, AD, prodromal phase Alzheimer's disease, PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS), anticancer therapy-associated cognitive impairment, and similar central nervous system (CNS) disorders with cognitive impairment, or there is a need to treat patients at risk of developing such violations.

The essence of the invention

According to a first aspect of the present invention, there is provided a method for treating or improving cognitive function, a method for delaying or slowing the progression of cognitive impairment, or a method for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment, or is at risk for such a disorder, the method comprising the step of administering to said subject a therapeutically effective amount of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In some related aspect of the embodiments of the present invention, these methods improve or normalize cognitive function in the specified subject. In some related aspect embodiments of the present invention, these methods delay or slow the progression of cognitive impairment in the specified subject. In some related aspect embodiments of the present invention, these methods reduce the rate of cognitive decline in the specified subject. In certain related aspect embodiments of the present invention, said methods prevent or slow the progression of said CNS cognitive impairment disorder in said subject. In other related embodiments of the present invention, these methods alleviate, reduce the intensity of symptoms or slow the progression of one or more symptoms associated with the specified CNS disorder, which is accompanied by cognitive impairment, in the specified subject.

In certain related embodiments of the present invention, the CNS cognitive impairment disorder is an age-related cognitive impairment, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one related aspect of the embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In certain related embodiments of the present invention, the CNS disorder with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or cognitive impairment. associated with anticancer therapy. In one aspect-related embodiment of the present invention, the subject suffering from such a CNS disorder or cognitive impairment is a human patient.

An SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is suitable for use in the methods and compositions according to this aspect of the present invention includes those described, for example, in US Patent Application 12/580464, International PCT/US2009/005647, US Patent Application 61/105847, US Patent Application 61/152631 and US Patent Application 61/175536. However, any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be used in the methods and compositions according to this aspect of the present invention. In other embodiments, implementation of the present invention, the SV2A inhibitor is selected from the group of SV2A inhibitors specified in international patent applications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Patent Nos. 7,465,549; 7244747; 5334720; 4696943; 4696942; U.S. patent application numbers 20090312333; 20090018148; 20080081832; 2006258704; and UK Patent Nos. 1039113 and 1309692, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs. In other embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives or analogs thereof, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In other embodiments, the SV2A inhibitor is brivaracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In other embodiments, the SV2A inhibitor is seletracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In other related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, may be administered at dosages as described, for example, in US Patent Application 12/580464, International Patent Application PCT/US2009 /005647, US Patent Application 61/105847, US Patent Application 61/152631, US Patent Application 61/175536 and US Patent Application 61/441251. In other related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered every 12 or 24 hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 2.0 to 4.0 mg/kg, or about 2 0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3 mg/ kg, or about 0.3 to 0.4 mg/kg, or about 0.001-5 mg/kg, or about 0.001-0.5 mg/kg, or about 0.01-0.5 mg/kg.

According to a second aspect of the present invention, there is provided a method for treating or improving cognitive function, a method for delaying or slowing the progression of a cognitive impairment, or a method for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment, or is at risk for such a disorder, the method comprising the step of administering to said subject a therapeutically effective amount of an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof. In some related aspect of the embodiments of the present invention, these methods improve or normalize cognitive function in the specified subject. In some related aspect embodiments of the present invention, these methods delay or slow the progression of cognitive impairment in the specified subject. In some related aspect embodiments of the present invention, these methods reduce the rate of cognitive decline in the specified subject. In certain related aspect embodiments of the present invention, said methods prevent or slow the progression of said CNS cognitive impairment disorder in said subject. In other related embodiments of the present invention, these methods alleviate, reduce the intensity of symptoms or slow the progression of one or more symptoms associated with the specified CNS disorder, which is accompanied by cognitive impairment, in the specified subject.

In certain related embodiments of the present invention, said SV2A inhibitor and/or valproate is administered at doses that are sub-therapeutic as compared to the doses at which said compounds are therapeutically effective when each agent is administered in the absence of the other.

In certain related embodiments of the present invention, the CNS cognitive impairment disorder is an age-related cognitive impairment such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one related aspect of the embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In some related embodiments of the present invention, the CNS disorder associated with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient.

An SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is suitable for use in the methods and compositions according to this aspect of the present invention includes those described, for example, in US Patent Application 12/580464, International PCT/US2009/005647, US Patent Application 61/105847, US Patent Application 61/152631, US Patent Application 61/175536 and US Patent Application 61/441251. However, any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be used in the methods and compositions according to this aspect of the present invention. In other embodiments, implementation of the present invention, the SV2A inhibitor is selected from the group of SV2A inhibitors specified in international patent applications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Patent Nos. 7,465,549; 7244747; 5334720; 4696943; 4696942; U.S. patent application numbers 20090312333; 20090018148; 20080081832; 2006258704; and British Patent Nos. 1039113 and 1309692, or from their pharmaceutically acceptable salts, hydrates, solvates or polymorphs. In other embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives or analogs thereof, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In other embodiments, the SV2A inhibitor is brivaracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In other embodiments, the SV2A inhibitor is seletracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In other related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, when administered in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, may be administered at the dosages disclosed. , for example, in US Patent Application 12/580464, International Patent Application PCT/US2009/005647, US Patent Application 61/105847, US Patent Application 61/152631, US Patent Application 61/175536 and US Patent Application 61 /441251. In other related embodiments of the present invention, said SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, which is administered in combination with valproate or an analogue, derivative or pharmaceutically acceptable salt thereof, is administered every 12 or 24 hours. with a daily dose of about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.1 mg/kg to 5 mg/kg, or about 0.05 mg/kg to 0 .5 mg/kg.

In certain related embodiments of the present invention, valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, when administered in combination with an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered at a daily dose such that the total content of valproate in the blood plasma of the subject was maintained at a level of from 0.5 to 5 μg/ml.

In other related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, are administered simultaneously or sequentially, or as a single composition, or in in the form of separate compositions in one package. In other related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, are administered via various routes. As used herein, the term "combination" includes the administration of any of these drugs or the use of any route of administration.

According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt thereof. In some related embodiments of the present invention, said SV2A inhibitor is present in an amount of 0.07-60 mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg or 3-60 mg. In other related embodiments of the present invention, said SV2A inhibitor is present in an amount of 0.05-35 mg.

According to a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof. In certain related embodiments of the present invention, said SV2A inhibitor, or a pharmaceutically acceptable salt thereof, is present in an amount of 0.05-35 mg, 0.07-60 mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-15 mg, 5-30 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg or 0.07-50 mg, or 3-60 mg. In other related embodiments of the present invention, the amount of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg , less than 50 mg, less than 35 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0 .05 mg.

According to a fifth aspect of the present invention, there is provided a method for treating or improving cognitive function, a method for delaying or slowing the progression of cognitive impairment, or a method for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment, or is at risk for such a disorder, the method comprising the step of administering to said subject a therapeutically effective amount of levetiracetam or a pharmaceutically acceptable salt thereof. In some related aspect of the embodiments of the present invention, these methods improve or normalize cognitive function in the specified subject. In some related aspect embodiments of the present invention, these methods delay or slow the progression of cognitive impairment in the specified subject. In some related aspect embodiments of the present invention, these methods reduce the rate of cognitive decline in the specified subject. In certain related aspect embodiments of the present invention, said methods prevent or slow the progression of said CNS cognitive impairment disorder in said subject. In other related embodiments of the present invention, these methods alleviate, reduce the intensity of symptoms or slow the progression of one or more symptoms associated with the specified CNS disorder, which is accompanied by cognitive impairment, in the specified subject.

In some related embodiments of the present invention, the CNS cognitive impairment disorder is an age-related cognitive impairment, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one related aspect of the embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In some related embodiments of the present invention, the CNS disorder associated with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient.

In some related embodiments of the present invention, levetiracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered every 12 or 24 hours at a daily dose of about 1 to 2 mg/kg, or about 0.1 to 2 .5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 2.0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg, or about 2.0 to 4.0 mg/kg, or about 0.1 to 5 mg/kg, or about 70 to 140 mg, or about 7 to 180 mg, or about 25-180 mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200 to 300 mg, or about 140 to 200 mg, or about 7-350 mg.

In some related embodiments of the present invention, levetiracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered once every 12 or 24 hours with a daily dose in accordance with one of the daily dosage intervals indicated as "+", which are given in table 1 or table 2.

According to a sixth aspect of the present invention, there is provided a method for treating or improving cognitive function, a method for delaying or slowing the progression of cognitive impairment, or a method for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment, or is at risk for such a disorder, the method comprising the step of administering to said subject a therapeutically effective amount of brivaracetam or a pharmaceutically acceptable salt thereof. In some related aspect of the embodiments of the present invention, these methods improve or normalize cognitive function in the specified subject. In some related aspect embodiments of the present invention, these methods delay or slow the progression of cognitive impairment in the specified subject. In some related aspect embodiments of the present invention, these methods reduce the rate of cognitive decline in the specified subject. In certain related aspect embodiments of the present invention, said methods prevent or slow the progression of said CNS cognitive impairment disorder in said subject. In other related embodiments of the present invention, these methods alleviate, reduce the intensity of symptoms or slow the progression of one or more symptoms associated with the specified CNS disorder, which is accompanied by cognitive impairment, in the specified subject.

In certain related embodiments of the present invention, the CNS cognitive impairment disorder is an age-related cognitive impairment, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one related aspect of the embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In some related embodiments of the present invention, the CNS disorder associated with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient.

In certain related embodiments of the present invention, brivaracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered every 12 or 24 hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0 .01 to 2.5 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.2 to 0.4 mg/kg kg, or about 7 to 15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg.

In some related embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.1 mg; 0.5 mg; 0.75 mg; 1.0 mg; 1.5 mg or 2.0 mg, but not more than with a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg. In other embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0. 01 mg/kg, 0.015 mg/kg, 0.02 mg/kg or 0.03 mg/kg, but not more than with a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg /kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg or 0.04 mg/kg.

In certain related embodiments of the present invention, brivaracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered once every 12 or 24 hours at a daily dose in accordance with one of the daily dosage intervals designated as "+", which are listed in Table 3 or Table 4. For example, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof can be administered once every 12 or 24 hours with a daily dose of 0.1-35 mg, 0.5-35 mg, 0.75 -35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1- 15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0, 01-0.5 mg/kg, 0.015-0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg , 0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0 .05 mg/kg or 0.0015-0.04 mg/kg.

According to a seventh aspect of the present invention, there is provided a method for treating or improving cognitive function, a method for delaying or slowing the progression of cognitive impairment, or a method for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment, or is at risk for such a disorder, the method comprising the step of administering to said subject a therapeutically effective amount of seletracetam or a pharmaceutically acceptable salt thereof. In some related aspect of the embodiments of the present invention, these methods improve or normalize cognitive function in the specified subject. In some related aspect embodiments of the present invention, these methods delay or slow the progression of cognitive impairment in the specified subject. In some related aspect embodiments of the present invention, these methods reduce the rate of cognitive decline in the specified subject. In certain related aspect embodiments of the present invention, said methods prevent or slow the progression of said CNS cognitive impairment disorder in said subject. In other related embodiments of the present invention, these methods alleviate, reduce the intensity of symptoms or slow the progression of one or more symptoms associated with the specified CNS disorder, which is accompanied by cognitive impairment, in the specified subject.

In certain related embodiments of the present invention, the CNS cognitive impairment disorder is an age-related cognitive impairment, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one related aspect of the embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In some related embodiments of the present invention, the CNS disorder associated with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, post-traumatic stress disorder (PTSD), schizophrenia, or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient.

In some related embodiments of the present invention, seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.1 mg, 0.5 mg, 0. 75 mg, 1.0 mg, 1.5 mg or 2.0 mg, but not more than a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg . In other embodiments of the present invention, seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.0015 mg/kg; 0.0075 mg/kg; 0.01 mg/kg; 0.015 mg/kg; 0.02 mg/kg or 0.03 mg/kg, but not more than with a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg or 0.04 mg/kg.

In some related embodiments of the present invention, seletracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered once every 12 or 24 hours at a daily dose in accordance with one of the daily dosage intervals, designated as "+", which are listed in Table 5 or Table 6. For example, seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof can be administered once every 12 or 24 hours with a daily dose of 0.1-35 mg, 0.5-35 mg, 0.75 -35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1- 15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0, 01-0.5 mg/kg, 0.015-0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg , 0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0 .05 mg/kg or 0.0015-0.04 mg/kg.

Brief description of the drawings

Fig. 1 shows increased mRNA expression of the gene encoding SV2A in the dentate gyrus of the hippocampus in age-affected (AI) rats compared to young (Y) and normal adult (AU) rats. Normalized signal values of the Affymetrix GeneChip Probe Set (Y-axis) as a measure of mRNA expression are presented for different rats depending on learning scores as a measure of cognitive impairment.

In FIG. 2 shows the effect of levetiracetam administration on spatial memory retention in six aging-impaired (AI) rats in the Morris water maze (MWM) test. Three treatment conditions were used: administration of vehicle as control, administration of levetiracetam (5 mg/kg/day) and administration of levetiracetam (10 mg/kg/day). AI rats were trained for two consecutive days and once a day before testing were subjected to a single treatment. After 24 hours, AI rats were tested. The time that rat AI, after 24 hours of exposure to various conditions and two days of training, spent swimming in a given sector or in a given ring zone in memory retention tests was used as a measure of spatial memory retention. The specified sector is the sector of the labyrinth (which was a round pool), where the rescue site was located during the preparation of the tests. The predetermined annular zone refers to the exact location of the rescue site during the preparation for the test.

In FIG. 3 shows the effect of levetiracetam administration on spatial memory retention in ten age-impaired (AI) rats in a radial eight-arm maze (RAM) test. Six treatment conditions were used: vehicle control administration, levetiracetam (1.25 mg/kg), levetiracetam (2.5 mg/kg), levetiracetam (5 mg/kg), levetiracetam (10 mg/kg), and levetiracetam ( 20 mg/kg). In the RAM task, a one-hour delay was applied between presentation of a subset of sleeves (5 sleeves available and 3 sleeves blocked) and completion of the eight sleeve retrieval and transfer task (eight sleeves available). 30-40 minutes prior to testing, rats were pre-treated with a single drug or control treatment. The number of errors made by the rats after the delay was used as a measure of spatial memory retention. Errors were defined as cases where rats entered a sleeve from which food had already been removed in the pre-hold test component, or when, in a post-hold session, rats revisited a sleeve that they had already visited. Paired t-tests are used to compare error rates between different doses of levetiracetam and vehicle control.

In FIG. 4 shows the effect of separate administration of levetiracetam or valproate on spatial memory retention in ten age-impaired (AI) rats in the Radial Eight-arm Maze (RAM) test.

In FIG. 5 shows the effect of administration of levetiracetam or in combination with valproate on the retention of spatial memory in ten age-impaired (AI) rats in the radial eight-arm maze (RAM) test.

In FIG. 6 is an isobologram of levetiracetam dose versus valproate dose. The diagonal straight line is an additivity line with the minimum effective dose of valproate and levetiracetam recorded on each axis when they were evaluated separately.

In FIG. 7 shows the design of experiments on the study of levetiracetam in humans.

In FIG. 8A shows the mean activity of the left CA3 aMCI of placebo-treated patients and subjects in the age-matched placebo-treated controls during the presentation of baits as stimuli correctly identified by the patient as "similar".

In FIG. 8B shows the mean activity in the left CA3 of aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) during the presentation of baits as stimuli correctly identified by the patient as "similar".

Fig. 8C is a table of the data shown in FIG. 8A and 8B.

In FIG. 9A shows mean activity in the left entorhinal cortex of patients in the age-matched placebo control group and aMCI of placebo patients during the presentation of baits as stimuli correctly identified by the patient as "similar".

In FIG. 9B shows mean activity in the left entorhinal cortex of the same aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) during the presentation of baits as stimuli correctly identified by the patient as "similar".

Fig. 9C is a table of the data shown in FIG. 9A and 9B.

In FIG. 10A is an example of a sequence of images that were shown to patients in the 3-alternative preselection sampling method described in Example 2.

In FIG. 10B shows an example of a pair of identical images ("bait").

In FIG. 11 shows the difference between aMCI (placebo) patients and age-matched control (placebo) subjects when they performed the 3-alternative preselection sampling test as described in Example 2. Each bar indicates the proportion of patient responses (old, similar, or new) when they are shown a picture of a lure.

In FIG. 12 shows the difference between the same aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the 3-alternative pre-set sampling test as described in Example 2. Each bar represents the proportion responses of patients (old, similar or new) when they are shown a picture of a decoy.

Fig. 13 is a table of the data shown in FIG. 11 and 12.

In FIG. 14A shows the difference between age-matched control (placebo) subjects and aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the Buschke Selective Memory Test - Delayed Recall.

Fig. 14B is a table of the data shown in FIG. 14A.

In FIG. 15A shows the difference between control (placebo) subjects and aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the Benton visual retention test.

Fig. 15B is a table of the data shown in FIG. 15A.

In FIG. 16A shows the difference between control (placebo) subjects and aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the verbal pair association test - Recognition.

Fig. 16B is a table of the data shown in FIG. 16A.

In FIG. 17A shows the difference between control (placebo) subjects and aMCI patients treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the Verbal Pair Association Test - Delayed Recall.

Fig. 17B is a table of the data shown in FIG. 17A.

Fig. 18A is a table explaining the patient selection process for the human study of levetiracetam as described in Example 2.

Fig. 18B is a table showing the characteristics of patients selected for the human study of levetiracetam as described in Example 2.

Detailed description of the invention

Unless otherwise defined in the present description, the scientific and technical terms that are used in this description have meanings that are fully understood by specialists in this field of technology. As a rule, the nomenclature used in connection with cell and tissue cultures and the methods of molecular biology, cytology and biology of malignant tumors, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and chemistry of protein and nucleic acids described in the present description is well known and widely used in the art.

The methods and techniques that are used in the present invention, as a rule, are performed, unless otherwise indicated, in accordance with conventional methods well known in the art, and in accordance with the way described in various general and more specific references, which given and discussed in this description. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., N.Y. (1999); Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

As used herein, chemical terms are used in accordance with their common usage in the art, such as in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above and any other publications, patents and published patent applications mentioned in the present description are expressly incorporated herein by reference. In the event of conflict, the present description, including the specific definitions given therein, shall prevail.

As used herein, the word "comprise" or its derivatives such as "comprises" or "comprising" is to be understood to include the specified integer (or components) or groups of integers (or components), but does not exclude any other integer ( or component) or groups of integers (or components).

The singular forms include the plural unless the context clearly indicates otherwise.

The term "including" is used to mean "including but not limiting". "Including" and "including but not limited to" are used interchangeably.

The term "agent" is used in this description to refer to a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), biological macromolecules (for example, nucleic acids, antibodies, including parts thereof, as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or part thereof, eg a peptide, lipid, carbohydrate) or extracts from biological substances such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is well known, as well as those whose structure is not known. The SV2A inhibitory activity of such agents may make them useful as "therapeutic agents" in the methods and compositions of the present invention.

The terms "patient", "subject" or "individual" are used interchangeably and refer to either a human or non-human animal. The terms used include mammals such as humans, primates, farm animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice). and rats).

The terms "cognition" or "cognitive status" refer to any higher-order intellectual process or brain state, respectively, that is involved in learning and/or memory, including, but not limited to, attention, information gathering, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision making, inhibition response control, attention shift, delayed reinforcement learning, reversal learning, temporal integration of voluntary behavior, and self-interest. environment and yourself.

In humans, cognition can be measured, without limitation, by, for example, the Clinical Overall Impression Rating Scale (CIBIC-plus scale); Mini-Scale Mental Status Assessment (MMSE); the Neuropsychiatric Status Inventory (NPI); dementia clinical rating scale (CDR); the Computerized Neuropsychological Test Battery (CANTAB) developed at Cambridge; Sandoz Geriatric Clinical Assessment Scale (SCAG); the Buschke selective memory test (Buschke and Fuld, 1974); subtest of verbal pair associations; logical memory subtest; an image reproduction subtest; the Wechsler Memory Scale (WMS-R) (Wechsler, 1997); Benton visual retention test; or the method of 3-alternative sampling according to a predetermined criterion. See Folstein et al., J. Psychiatric. Res. 12:189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J. Geriatr. Psychiatry Neurol . 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994.

In animal model systems, cognition can be determined by various conventional methods known in the art, including using the Morris water maze (MWM), the Barnes circular maze located on the elevation of the radial maze, the T maze, or any other maze in which animals use spatial information. Other tests known in the art can also be used to assess cognitive function, such as tasks for recognizing novel objects and smells.

Cognitive function can also be assessed using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or any other imaging technique that evaluates brain function. In animals, cognitive functions can also be determined by electrophysiological methods.

The term "activation" of cognitive functions refers to the effect on impaired cognitive functions so that they more closely resemble those of a normal, non-disturbed subject. Cognitive functions may be activated to any appreciable degree, but in humans, preferably, cognitive functions are activated to a sufficient degree to allow the impaired subject to carry out daily activities with the same skill level as a normal, non-disabled subject in normal life.

In some cases, "activating" cognitive function in a subject suffering from age-related cognitive impairment refers to affecting impaired cognitive functions to more closely resemble those of a normal, unimpaired subject of the same age or that of a young adult. Cognitive functions may be activated to any appreciable degree, but in humans, preferably, cognitive functions are activated to a sufficient degree to allow the impaired subject to carry out daily activities with the same skill level as a normal, non-disabled subject of the same age in normal life. or a young adult.

The term "preservation" of cognition refers to the effect on normal or impaired cognitive functions so that they do not deteriorate or fall below the level that was observed in the subject at the first description or first diagnosis, or to the effect to delay such cognitive decline. .

"Improvement" of cognitive functions includes activation of cognitive functions and/or preservation of cognitive function in a subject.

The term "cognitive impairment" refers to a subject's cognitive functions that are not as reliable as expected for a normal, non-impaired subject. In some instances, cognition is reduced by about 5%, about 10%, about 30%, or more, compared to what would be expected in a normal, non-impaired subject. In some cases, "cognitive impairment" in subjects suffering from age-related cognitive impairment refers to a subject's cognitive functions that are not as reliable as one would expect for a normal, non-impaired subject of the same age, or not as reliable as those of a young person. an adult (i.e. subjects with an average score for a given age when conducting cognitive tests).

The term "age-related cognitive impairment" refers to cognitive impairment in elderly subjects, when their cognitive functions are not as reliable as would be expected in healthy subjects of the same age or as would be expected in young adult subjects. In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more, compared to the cognitive functions that would be expected for a healthy subject of the same age. In some cases, cognitive function is the same as expected for a healthy subject of the same age, but reduced by about 5%, about 10%, about 30%, about 50% or more, compared with the cognitive function expected for a young adult subject. Age-related cognitive impairment may be associated with mild cognitive impairment (MCI) (including memory-loss-causing mild cognitive impairment and non-memory-losing mild cognitive impairment), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

"Cognitive impairment" associated with AD, or related to AD, or occurring in AD, refers to a subject's cognitive functions that are not as reliable as would be expected for subjects who have not been diagnosed with AD using conventional methods and standards.

"Moderate cognitive impairment" or "MCI" refers to a condition characterized by an isolated memory impairment, not accompanied by other cognitive impairment, and which is characterized by relatively normal functional abilities. One of the criteria for the clinical characterization of MCI defines the following characteristics: (1) memory complaints (as reported by the patient, informant, or clinician), (2) elementary self-care activities (ADL), (3) normal general cognitive function, (4) abnormal memory for age (defined as a score of more than 1.5 standard deviations below the mean for age) and (5) absence of dementia scores (defined according to DSM-IV guidelines). Petersen et al., Srch. Neurol., 56: 303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease", Oxford University Press, NY (2003).

The diagnosis of MCI usually entails an objective assessment of cognitive impairment, which can be obtained using reliable neuropsychological tests, including the Mini Mental Status Assessment (MMSE), the Cambridge-developed computerized battery of neuropsychological tests, and individual tests such as the Ray Test for Auditory Learning. (AVLT), the Wechsler Corrected Memory Scale (WMS-R) logical memory subtest, and the New York University (NYU) short message recall test. See Folstein et al., J. Psychiatric. Res. 12:189-98 (1975); Robbins et al., Dementia 5: 266-81 (1994); Kluger et al., J. Geriatric. Psychiatry Neurol. 12:168-79 (1999).

The term "age-related memory impairment (AAMI)" refers to memory impairment due to aging. A patient may be considered suffering from AAMI if he or she is at least 50 years of age and meets all of the following criteria: a) the patient has experienced a decline in memory quality, b) the patient performs worse on standard memory tests compared to younger adults, c) excluded all other apparent causes of memory decline other than changes due to natural aging (in other words, memory impairment cannot be explained by other causes such as a recent heart attack or head injury, depression, adverse drug reactions, Alzheimer's disease, etc.).

The term "age-related cognitive decline (ARCD)" refers to the decline in memory and cognition that is a normal consequence of aging in humans (eg, Craik & Salthouse, 1992). This is also true for virtually all mammalian species. Age-related cognitive decline refers to older people with objective memory impairment compared to their younger years, but their cognitive function is normal relative to their peers (Crook et al., 1986). Age-appropriate memory impairment is a less derogatory label that emphasizes that these changes are due to normal development (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smithh et al., 1991), and rarely develop into overt dementia (Youngjohn & Crook, 1993). The DSM-IV (1994) compiles the ARCD diagnostic classification codes.

Alzheimer's disease (AD) is characterized by early memory impairment. Later symptoms include clouding of consciousness, disorientation, confusion, behavioral changes, speech problems, and motor defects. Histologically, AD is characterized by the presence of beta-amyloid plaques and tau protein tangles.

Vascular dementia is caused by strokes. The symptoms overlap with those of AD, but without the emphasis on memory impairment.

Dementia with Lewy bodies is characterized by abnormal deposits of alpha-synuclein that form inside neurons in the brain. Cognitive impairment may be similar to AD, including impairments to memory and the ability to associate words or concepts, as well as behavioral changes.

Frontotemporal dementia is characterized by gliosis, loss of nerve cells, superficial spongiform degeneration in the frontal cortex and/or anterior temporal lobe, and Pick bodies. Symptoms include personality and behavioral changes, including decreased communication skills and the ability to express/perceive language.

The term "post-traumatic stress disorder (PTSD)" refers to an anxiety disorder characterized by an immediate or delayed response to a distressing event, characterized by re-experiencing trauma, mental numbness or avoidance of trauma-related stimuli, and increased arousal. Re-experiencing the phenomenon includes intrusive memories, vivid memories of past traumatic experiences, nightmares, and psychological or physiological distress in response to the trauma reminder. These responses are worrisome and can have a significant impact, both chronic and acute, on the patient's quality of life and physical and mental health. PTSD is also associated with cognitive impairment, and older people with PTSD show more cognitive decline than controls.

The term "schizophrenia" refers to a debilitating chronic disorder characterized by a variety of psychopathologies, including positive symptoms such as aberrant or distorted mental images (eg, hallucinations, delusions), negative symptoms characterized by decreased motivation and adaptive goal-directed action. (eg, anhedonia, emotional dullness, lack of will), and cognitive impairment. Because brain disorders are thought to underlie the variety of psychopathologies in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairment in patients.

"Amyotrophic Lateral Sclerosis", also known as ALS, refers to a progressive, fatal, neurodegenerative disease characterized by the degradation of the anterior horn cells of the spinal cord, the nerve cells in the central nervous system that control the movement of voluntarily contracting muscles. ALS is also characterized by neuronal degradation in the entorhinal cortex and hippocampus, memory impairment, and neuronal overexcitation in various brain regions such as the cerebral cortex.

The term "anticancer therapy-associated cognitive impairment" refers to a cognitive impairment that develops in patients who are undergoing antitumor therapy such as chemotherapy and radiotherapy. Cytotoxicity and other adverse brain side effects of cancer treatment lead to cognitive impairments in functions such as memory, learning ability, and concentration.

The term "treatment" of a condition or patient refers to measures taken to obtain beneficial or desired results, including clinical results. Beneficial or desirable clinical results include, but are not limited to, improving cognitive function, delaying or slowing the progression of cognitive impairment, reducing the rate of cognitive decline, preventing or slowing the progression of a disease or disorder, or alleviating, reducing symptoms, or slowing the progression of one or more symptoms. associated with disorders of the central nervous system (CNS) that are accompanied by cognitive impairment, such as age-related cognitive impairment, mild cognitive impairment (MCI), memory loss-inducing mild cognitive impairment, dementia, Alzheimer's disease (AD), prodromal phase of Alzheimer's disease, PTSD , schizophrenia, amyotrophic lateral sclerosis (ALS), or cognitive impairment associated with anticancer therapy. Treatment of age-related cognitive impairment further includes slowing the transformation of age-related cognitive impairment (including, but not limited to, MCI, ARCD and AAMI) to dementia (particularly AD).

The term "treatment of cognitive impairment" refers to measures taken to improve cognitive function in a patient with cognitive impairment such that the patient's performance on one or more cognitive tests is measurably improved or further cognitive decline is prevented. Preferably, the cognitive function of the patient after treatment for cognitive impairment more closely resembles that of a healthy, non-impaired subject. Treatment of cognitive impairment in humans can markedly improve cognition, but preferably improves it sufficiently to allow the impaired patient to carry out daily activities with the same skill level as a healthy, non-disabled subject in normal life. In some cases, the term "treatment of cognitive impairment" refers to measures taken to improve cognitive function in a patient with cognitive impairment, such that the patient's performance on one or more cognitive tests is measurably improved or further cognitive decline is prevented. Preferably, the cognitive function of the patient after treatment for cognitive impairment more closely resembles that of a healthy, non-impaired subject. In some cases, the term "treatment of cognitive impairment" in a patient with age-related cognitive impairment refers to measures taken to improve cognitive function in a patient with cognitive impairment, so that the patient's cognitive function after treatment for cognitive impairment more closely resembles that of a healthy, non-impaired subject. or the function of a young adult subject. In some cases, the term "treatment of cognitive impairment" in a patient refers to measures taken to delay or slow the progression of cognitive impairment in a patient with cognitive impairment. In some cases, the term "treatment of cognitive impairment" in a patient refers to measures taken in order to reduce the rate of cognitive decline in a patient with cognitive impairment.

"Administration" or "administration" of a substance, compound, or agent to a patient can be accomplished using one of a variety of methods known to those skilled in the art. For example, a compound or agent can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, through the eyes, sublingually, orally (by swallowing), intranasally (by inhalation), intraspinally, intracerebral, and transdermally (by absorption, for example, through skin channels). The compound or agent, respectively, may also be administered via rechargeable or biodegradable polymeric devices or other devices, such as patches and pump packs, or as formulations that provide a sustained, slow, or controlled release of the compound or agent. The introduction can also be carried out, for example, once, multiple times and/or over a certain period or over longer periods of time. In accordance with some aspects of the present invention, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing the drug itself. For example, as used herein, a physician who prescribes self-administration of a drug to a patient, or prescribes another person to administer a drug to a patient, and/or provides a prescription for a drug to a patient, prescribes drug administration to the patient.

Suitable routes of administration of the substance, compound or agent to the patient will also depend on, for example, the age of the subject, whether the subject is active or inactive at the time of drug administration, whether the subject has cognitive impairment at the time of administration, and will also depend on the degree of impairment. and on the chemical and biological properties of the compound or agent (eg, solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments of the present invention, the compound or agent is administered orally, for example, administered to a subject by ingestion, or intravenously, in particular, administered to a subject by injection. In some embodiments, the orally administered compound or agent is a sustained release formulation or a slow release formulation, or the drug is administered using a device designed for such slow or sustained release.

As used herein, administration of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and valproate or an analog, derivative or pharmaceutically acceptable salt thereof "in combination" or "together" includes simultaneous administration and/or administration at different times, e.g. , consistent introduction. It also includes administration as a single preparation or as separate formulations in the same package.

The term "simultaneous administration" as used herein means that the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, are administered at a time interval of no more than about 15 minutes, and at some embodiments of the present invention, with an interval of no more than about 10 minutes. When the drugs are administered simultaneously, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and valproate or an analog, derivative or pharmaceutically acceptable salt thereof may be contained in the same dosage unit (e.g., unit dosage form). containing both an SV2A inhibitor and valproate), or as discrete doses (for example, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is contained in a single dosage form, and valproate or its analogue, derivative or pharmaceutically acceptable salt is contained in a different dosage form).

The term "sequential administration" as used herein means that the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, are administered at a time interval of greater than about 15 minutes, and at some embodiments of the present invention, at intervals greater than about one hour, or up to 12 hours. Either an SV2A inhibitor or valproate can be administered first. When administered sequentially, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, may be contained in discrete dosage forms, optionally in the same container or package.

A "therapeutically effective amount" of a drug or agent is the amount of the drug or agent that, when administered to a subject, produces the intended therapeutic effect, such as improving cognitive function or delaying or slowing the progression of cognitive impairment, or reducing the rate of cognitive decline in a patient, such as a patient with a CNS disorder accompanied by cognitive impairment. The full therapeutic effect is not necessarily achieved by the administration of a single dose, and can only be achieved after a series of doses. Thus, a therapeutically effective amount may be administered in one or more doses. The exact effective amount required for a subject will depend, for example, on the subject's size, health and age, the nature and severity of the cognitive impairment, and the therapy or combination of therapeutic modalities chosen to be administered, and the route of administration. One skilled in the art can readily determine the effective amount for a particular situation by routine experimentation.

"Sub-therapeutic amount" means an amount of an agent or compound of the present invention administered that is less than a therapeutic amount, i.e. less than the amount normally used when said agent or said compound is administered alone (ie, alone and in the absence of other therapeutic agents or compounds) for the treatment of cognitive impairment disorders.

The term "analogue" in the present description refers to a compound that is functionally similar to another chemical, but not identical with it in chemical structure. For example, an analog is sufficiently similar to the parent or parent compound such that it can replace the parent compound in therapeutic applications despite minor structural differences.

The term "derivative" as used herein refers to a chemical modification of a compound. Chemical modifications of the compound may include, for example, substitution of a hydrogen atom with an alkyl, acyl, or amino group. Many other modifications are also possible.

The term "prodrug" is recognized in the art and encompasses compounds or agents that, under physiological conditions, are converted to an SV2A inhibitor or valproate. The general way to obtain a prodrug is to select chemical functional groups that are hydrolyzed or metabolized under physiological conditions with the formation of the desired compound or agent. In other embodiments, the implementation of the present invention, the prodrug is converted into an SV2A inhibitor or valproate due to the enzymatic activity of the host animal.

The term "pharmaceutically acceptable salt" as used herein means an agent or compound of the invention which is a therapeutically active, non-toxic salt of said compounds with a base and an acid. An acid addition salt form of a compound which exists in the free base form can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric, nitric , phosphoric acid, and the like; or an organic acid such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic , pamoic acid, and the like. See, for example, WO 01/062726.

Description of the methods of the present invention

The methods of this invention include the administration of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof. The methods of this invention also include the administration of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, in combination with the administration of valproate, or a pharmaceutically acceptable salt thereof. SV2A inhibitor agents or compounds or valproate and their pharmaceutically acceptable salts also include hydrates, solvates, polymorphs and prodrugs of these agents, compounds and salts.

Methods for assessing cognitive impairment

Animal models are an important resource for the development and evaluation of treatments for CNS disorders accompanied by cognitive impairment. The features that characterize cognitive impairment in animal models generally extend to cognitive impairment in humans. Thus, efficacy in such an animal model is expected to be able to predict efficacy in humans. The degree of cognitive impairment in an animal model for a CNS disorder, as well as the effectiveness of a treatment method for said CNS disorder, can be tested and validated using various cognitive tests.

Behavioral tasks that are performed in the radial maze (RAM) is one example of a cognitive test, in particular an example of a spatial memory test (Chappell et al. Neuropharmacology 37: 481-487, 1998). The RAM device consists, in particular, of eight equally spaced sleeves. Arms of the maze extend from each face of the polyhedron at the center of the platform. The chamber with food is located at the end of each sleeve, far from the center. Food is used as a reward. Barriers may be installed to prevent entry into any of the sleeves. Numerous additional maze signals can also be installed that surround the device. After the training and training steps have been completed, the subjects' spatial memory can be tested in RAM under control compound or test compound conditions. As part of the test, prior to testing, subjects are pre-treated with vehicle as a control compound or one of the dose ranges of the test compound. At the beginning of each test, part of the sleeves of the eight-arm labyrinth is blocked. Subjects are allowed to obtain food from unblocked sleeves, access to which is permitted during this initial "information phase" of the study. Subjects are then removed from the maze for a delay period (e.g., the delay can be 60 seconds, 15 minutes, one hour, two hours, six hours, 24 hours or more) between the information phase and the subsequent "retention test" during which the barriers from the labyrinth are removed, thus providing access to all eight arms. After the delay period, subjects are placed back on the central platform (barriers to the previously blocked sleeves are removed) and allowed to receive the remaining food rewards during this memory retention test phase of the trial. The identity and configuration of the blocked sleeves varies depending on the tests. Track the number of "mistakes" that subjects make during the test for memory retention, as one of the phases of the test. A test error occurs when subjects enter a sleeve from which food was already taken during the pre-delay component of the trial, or if a subject in a session after a delay revisits a sleeve that they have already visited. Fewer errors will mean better spatial memory. The number of errors made by the test subject under different treatment regimens with the test compound can then be compared with the effectiveness of the test compound in treating CNS disorders accompanied by cognitive impairment.

Another cognitive test that can be used to evaluate the effect of a test compound on cognitive impairment in an animal model of CNS disorder is the Morris water maze. The water maze is a pool surrounded by a new set of pictures placed next to the maze. The preparatory technique for the water maze may be based on a modified water maze task that has been shown to be dependent on the hippocampus (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Subject is trained to find rescue on an underwater platform hidden below the surface of the pool. During preparatory attempts, the subject is released into the maze (pool) from random starting positions around the perimeter of the pool. The starting position changes from attempt to attempt. If the subject does not find an exit to the platform within a certain time limit, the experimenter guides and places the subject on the platform to "teach" him the location of the platform. After a delay period following the last training attempt, a memory retention test is given in the absence of a rescue platform in order to evaluate spatial memory. The subject's preference levels for the location of the rescue platform (currently missing), which is determined, for example, by the time spent in a given area, or by the number of mouse crossings of a given area, indicates better spatial memory, i.e. indicates the cure of cognitive impairment. The preference for the location of the rescue platform under different treatment conditions can then be compared to determine the efficacy of the test compound in the treatment of CNS disorders accompanied by cognitive impairment.

Various tests are known in the art for assessing cognitive function in humans, for example, and without limitation, the overall clinical impression scale (CIBIC-plus scale); Mini Mental Status Assessment (MMSE); Neuropsychiatric Assessment Questionnaire (NPI); dementia clinical rating scale (CDR); the Computerized Neuropsychological Test Battery (CANTAB) developed at Cambridge; Sandoz Geriatric Clinical Assessment Scale (SCAG), Buschke Selective Memory Test (Buschke and Fuld, 1974); subtest of verbal pair associations; logical memory subtest; Wechsler Memory Scale (WMS-R) Image Reproduction Subtest (Wechsler, 1997); or Benton's visual retention test. See Folstein et al., J. Psychiatric. Res. 12:189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J. Geriatr. Psychiatry Neurol . 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. Another example of a cognitive test for humans is the 3-alternative sampling task against a predetermined criterion. In this test, subjects are shown color photographs of ordinary objects, consisting of a mixture of three types of image pairs: similar pairs, identical pairs, and unrelated film cuts. The second pairs of similar objects are called "bait". These pairs of images are completely randomized and presented individually as a series of images. Subjects are instructed to evaluate whether the objects they see are new, old, or similar. A response "similar" to the presented bait-irritants indicates successful memory retrieval by the subject. In contrast, referring to the stimulus bait as "old" or "new" means that proper memory retrieval is not occurring.

In addition to assessing cognitive functions, the progression of age-related cognitive impairment and dementia, as well as the transformation of age-related cognitive impairment into dementia, can be monitored by assessing surrogate changes in the subject's brain. Surrogate changes include, but are not limited to, changes in regional brain volume, perforant pathway degradation, and changes seen in brain function using resting fMRI (R-fMRI) and positron emission tomography using the radiopharmaceutical fluorodeoxyglucose (EDG-PET). Examples of regional brain volumes that are useful for monitoring the progression of age-related cognitive impairment and dementia include a decrease in hippocampal volume and a decrease in volume or thickness of the entorhinal cortex. These volumes can be measured in the subject, for example, using MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). It has been shown that the perforant pathway of degradation, as well as cognitive decline, is associated with age. For example, older adults with more perforant pathways tend to perform worse on hippocampus-dependent tests of memory efficiency. The perforating pathway of degradation can be monitored in subjects using ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting fMRI (R-fMRI) involves imaging the brain during rest and recording spontaneous low-frequency (<0.1 Hz) high-amplitude fMRI signal changes that correlate with functionally related regions. Source-dependent functional connectivity, independent component analysis, and/or signal frequency range analysis are used to reveal functional associations between brain regions, in particular those brain regions that become more or less connected with age, as well as the degree of cognitive impairment and/or dementia. FDG-PET uses fluorodeoxyglucose (FDG) uptake as a measure of regional metabolic activity in the brain. Reduced FDG uptake in locations such as the posterior cingulate cortex, temporoparietal cortex, and prefrontal association cortex has been shown to be associated with the degree of cognitive impairment and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

Age-related cognitive impairment

The present invention provides methods and compositions for the treatment of age-related cognitive impairment or the risk of its development, which use an SV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvate or polymorphic modification, either alone or in combination with valproate or its analogue, derivative or pharmaceutically acceptable salt. In some embodiments, the implementation of the present invention, the treatment includes improving cognitive functions in patients with age-related cognitive impairment. In some embodiments, implementation of the present invention, the treatment includes slowing or delaying the progression of age-related cognitive impairment. In some embodiments of the present invention, the treatment includes reducing the rate of cognitive decline associated with age-related cognitive impairment. In some embodiments, the implementation of the present invention, the treatment includes preventing or slowing the progression of age-related cognitive impairment. In some embodiments, the implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the progression of one or more symptoms associated with age-related cognitive impairment. In some embodiments of the present invention, the treatment of age-related cognitive impairment includes slowing the transformation of age-related cognitive impairment (including, but not limited to, MCI, ARCD and AAMI) into dementia (eg, AD). These methods and compositions can be used in human patients in a clinical setting in the treatment of age-related cognitive impairment in cases such as MCI, ARCD and AAMI, or if they are at risk of developing. The composition dose and dosing interval used in the method of the invention as described herein are safe and effective in the indicated applications.

In some embodiments, implementation of the present invention, the subject to be treated using the methods and compositions of the present invention, there is an age-related cognitive impairment, or he is at risk of developing such a violation. In some embodiments of the present invention, age-related cognitive impairment includes, without limitation, age-related memory impairment (AAMI), mild cognitive impairment (MCI), and age-related cognitive decline (ARCD).

Animal models are an important resource for developing and evaluating treatments for these age-related cognitive impairments. The features that characterize age-related cognitive impairment in animal models generally extend to age-related cognitive impairment in humans. Thus, efficacy in similar animal models is expected to be able to predict efficacy in humans.

Various animal models of age-related cognitive impairment are known in the art. For example, extensive behavioral studies have identified a natural form of cognitive impairment in outbred aged rats of the Long Evans genetic line (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In a behavioral assessment in the Morris Water Maze (MWM), rats recognize and remember the location of the escape platform based on the configuration of the spatial cues surrounding the maze. The cognitive basis of test performance is tested in pilot trials by determining the movement of the animal in space in search of the location of the rescue platform. Elderly rats in the study population do not have difficulty swimming to the visible platform, but age-related impairments are found when the platform is masked and spatial information is required. Task performance in individual aged rats in the Long Evans outbred rat model varies considerably. For example, some of these rats perform the task on a par with young adults. However, approximately 40-50% of rats fall outside the range of juvenile ability. This variability among older rats reflects robust individual differences. Thus, among the elderly population, some animals are cognitively impaired and are referred to as age-related impaired (AI), while other animals are not impaired and are referred to as age-associated (AU). See, for example, Colombo et al, Proc. Natl. Acad. sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 5 691-708, (1989); Gallagher et al., Behav. neurosci. 107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. sci. 93: 9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); Nicolle et al., J. Neurosci. 19: 9604-9610, (1999); international patent publication WO 2007/019312; and international patent publication WO 2004/048551. Such an animal model of age-related cognitive impairment can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive impairment.

The effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive impairment can be assessed using various cognitive tests, including the Morris water maze and the radial arm maze described above.

Dementia

The present invention also provides methods and compositions for the treatment of dementia using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In some embodiments, implementation of the present invention, the treatment includes improving cognitive function in patients with dementia. In some embodiments, implementation of the present invention, the treatment includes slowing or delaying the progression of dementia. In some embodiments, implementation of the present invention, the treatment includes reducing the rate of cognitive decline caused by dementia. In some embodiments, implementation of the present invention, the treatment includes preventing or slowing the progression of dementia. In some embodiments, the implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the development of one or more symptoms caused by dementia. In some embodiments, the symptom to be treated is a cognitive impairment. In some embodiments, implementation of the present invention dementia is Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies or frontotemporal dementia. These methods and compositions can be used in human patients in a clinical setting in the treatment of dementia. The composition dose and dosing interval used in the method of the invention as described herein are safe and effective in the indicated applications.

Animal models are an important resource for developing and evaluating treatments for dementia. The features that characterize dementia in animal models generally extend to dementia in humans. Thus, efficacy in similar animal models is expected to be able to predict efficacy in humans. Various animal models are known in the art such as PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg and APP + PS1 transgenic mice. Sankaranarayanan, Curr. top. Medicinal Chem . 6:609-627, 2006; Kobayashi et al., Genes Brain Behav . 4:173-196. 2005; Ashe and Zahns, Neuron. 66: 631-45, 2010. Similar animal models of dementia can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of dementia.

The effectiveness of the methods and compositions of the present invention in the treatment of dementia or cognitive impairment caused by dementia can be assessed in animal models of dementia, as well as in human patients suffering from dementia, using, as described above, various cognitive tests known in the art. .

Post Traumatic Stress Disorder

The present invention also provides methods and compositions for the treatment of post-traumatic stress disorder (PTSD) using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In some embodiments, the implementation of the present invention, the treatment includes improving cognitive function in patients with PTSD. In some embodiments, the implementation of the present invention, the treatment includes slowing or delaying the progression of PTSD. In some embodiments, implementation of the present invention, the treatment includes reducing the rate of cognitive decline associated with PTSD. In some embodiments, the implementation of the present invention, the treatment includes preventing or slowing the progression of PTSD. In some embodiments, implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the development of one or more symptoms associated with PTSD. In some embodiments, the symptom to be treated is a cognitive impairment. These methods and compositions can be used in human patients in a clinical setting in the treatment of PTSD. The composition dose and dosing range used in the method of the present invention as described herein are safe and effective in the indicated applications.

In PTSD patients (and to a lesser extent in trauma patients without PTSD), the hippocampus has a smaller volume (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch. Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with cognitive impairment. Older people with PTSD have more cognitive decline than controls (Yehuda et al, Bio. Psych. 60: 714-721, 2006) and are more likely to develop dementia (Yaffe et al., Arch Gen Psych 678: 608-613, 2010).

Animal models are an important resource for developing and evaluating treatments for PTSD. The features that characterize PTSD in animal models tend to extend to PTSD in humans. Thus, efficacy in similar animal models is expected to be able to predict efficacy in humans. Various animal models of PTSD are known in the art.

One rat model of PTSD is time dependent arousal (TDS). TDS involves exposing an animal to a highly stressful event followed by exposure to a situational indicator of the previous stress. Below is an example of TDS. The rats are placed in a paw fixer and then placed in a swimming pool and made to swim for a certain period of time, for example, for 20 minutes. Thereafter, each rat is immediately exposed to a gaseous anesthetic until they pass out, and finally dried. Animals are left alone for a few days, for example, one week. The rats are then subjected to a "re-stress" session that includes the initial stressor, such as a swimming session in a swimming pool (Liberzon et al., Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al., Psychopharmacology 175:494-502 , 2004). TDS results in increased acoustic startle response (ASR) in rats comparable to the abnormal acoustic startle response that is a known symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). Similar animal models of PTSD can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of PTSD.

As indicated above, the effectiveness of the methods and compositions of the present invention in the treatment of PTSD or PTSD-related cognitive impairment can be assessed in animal models of PTSD, as well as in humans with PTSD, using various cognitive tests known in the art.

Schizophrenia

The present invention also provides methods and compositions for the treatment of schizophrenia using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In some embodiments, implementation of the present invention, the treatment includes improving cognitive functions in patients with schizophrenia. In some embodiments, the implementation of the present invention, the treatment includes slowing or delaying the progression of schizophrenia. In some embodiments, implementation of the present invention, the treatment includes reducing the rate of cognitive decline associated with schizophrenia. In some embodiments, the implementation of the present invention, the treatment includes preventing or slowing the progression of schizophrenia. In some embodiments, implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the development of one or more symptoms associated with schizophrenia. In some embodiments, the symptom to be treated is a cognitive impairment. These methods and compositions can be used in human patients in a clinical setting in the treatment of schizophrenia. The composition dose and dosing range used in the method of the present invention as described herein are safe and effective in the indicated applications.

Cognitive impairment is also associated with schizophrenia. They precede the onset of psychosis and are present in unaffected close relatives. Cognitive impairment associated with schizophrenia is a good predictor of functional outcome and is a key feature of the disorder. Cognitive signs in schizophrenia reflect dysfunction in frontal cortex and hippocampal circuits. Patients with schizophrenia also have hippocampal pathologies such as shrinkage of the hippocampus, shrinkage of neurons, and their inappropriate hyperactivity. In patients with schizophrenia, excitatory and inhibitory imbalances in these brain regions have also been documented, suggesting that drugs that target inhibitory mechanisms may be of therapeutic value. See, for example, Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych. Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63, 2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009; Young et al. Pharmacol. Ther. 122:150-202, 2009.

Animal models are an important resource for developing and evaluating treatments for schizophrenia. The features that characterize schizophrenia in animal models tend to extend to schizophrenia in humans. Thus, efficacy in similar animal models is expected to be able to predict efficacy in humans. Various animal models of schizophrenia are known in the art.

One animal model for schizophrenia is long-term methionine treatment. Methionine-treated mice show underexpression of GAD67 in the frontal lobe and hippocampus, similar to that found in the brains of schizophrenic patients after their death. Methionine-treated mice also show prepulse startle inhibition and social interaction deficits (Tremonlizzo et al., PNAS , 99: 17095-17100, 2002). Another animal model for schizophrenia is the treatment of rats with methyloxymethanol acetate (MAM). Pregnant female rats were administered MAM (20 mg/kg, ip) on the 17th gestational day. MAM treatment ultimately induces in the offspring a pathological process resulting in a schizophrenia-like phenotype, including anatomical changes, behavioral disturbances, and altered neuronal information processing. More specifically, in rats treated with MAM, there is a decrease in the density of parvalbumin-positive GABA-ergic interneurons in parts of the prefrontal cortex and hippocampus. In behavioral tests, MAM-treated rats show a decrease in latent inhibition. Latent inhibition is a behavioral phenomenon in which there is a decrease in learning to a stimulus previously used to produce an effect, with any consequences. This tendency to ignore a previously used mild stimulus and reduce association formation with a similar stimulus is thought to be intended to prevent sensory overload. Low latent inhibition indicates psychosis. Latent inhibition can be tested in rats as follows. Rats are divided into two groups. One group is pre-exposed to a sound signal for several tests. The other group is not exposed to the sound signal. Both groups are then subjected to an auditory conditioned fading procedure, in which the same sound signal is given simultaneously with a painful stimulus, such as an electric shock to the legs. After that, both groups are exposed to a sound signal and the change in the motor activity of rats is monitored during the sound signal. After conditioned reflex freezing, the rats react to the sound signal by greatly reducing their motor activity. However, the group that is exposed to the sound signal before the conditioned freezing procedure shows a strong latent inhibition: the suppression of motor activity in response to the sound signal is reduced. In contrast, MAM-treated rats show disruption of latent inhibition. Thus, exposure to a sound signal that precedes the conditioned freezing procedure does not have a significant effect on the suppression of conditioned freezing (see Lodge et al., J. Neurosci., 29:2344-2354, 2009) Similar animal models of schizophrenia can be used to evaluate the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia.

As indicated above, the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia, or cognitive impairment associated with schizophrenia, can also be assessed in animal models of schizophrenia, as well as in humans suffering from schizophrenia, using various cognitive tests known in the art. .

Amyotrophic Lateral Sclerosis (ALS)

The present invention also provides methods and compositions for the treatment of ALS using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In some embodiments, implementation of the present invention, the treatment includes improving cognitive functions in patients with ALS. In some embodiments, the implementation of the present invention, the treatment includes slowing or delaying the progression of ALS. In some embodiments, implementation of the present invention, the treatment includes reducing the rate of cognitive decline associated with ALS. In some embodiments, implementation of the present invention, the treatment includes preventing or slowing down the progression of ALS. In some embodiments, implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the development of one or more symptoms associated with ALS. In some embodiments, the symptom to be treated is a cognitive impairment. These methods and compositions can be used in human patients in a clinical setting in the treatment of ALS. The composition dose and dosing interval used in the method of the invention as described herein are safe and effective in the indicated applications.

In addition to cell degeneration of the anterior horn of the spinal cord, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory impairment, and neuronal hyperexcitability in various areas of the brain such as the cerebral cortex.

As indicated above, the effectiveness of the methods and compositions of the present invention for the treatment of ALS or cognitive impairment associated with ALS can also be assessed in animal models of ALS, and in patients with ALS can be assessed using various cognitive tests known in the art.

Cognitive Impairments Associated with Anticancer Therapy

The present invention also provides methods and compositions for the treatment of cognitive impairment that is associated with antitumor therapy using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or its analogue, derivative or pharmaceutically acceptable acceptable salt. In some embodiments, implementation of the present invention, the treatment includes improving cognitive function in patients with cognitive impairment associated with anticancer therapy. In some embodiments, implementation of the present invention, the treatment includes slowing or delaying the progression of cognitive impairment associated with anticancer therapy. In some embodiments, the implementation of the present invention, the treatment includes reducing the rate of cognitive decline associated with cognitive impairment caused by anticancer therapy. In some embodiments, the implementation of the present invention, the treatment includes preventing or slowing the progression of cognitive impairment associated with anticancer therapy. In some embodiments, the implementation of the present invention, the treatment includes alleviating, reducing the intensity of symptoms or slowing the development of one or more symptoms related to cognitive impairment, which is associated with anticancer therapy. These methods and compositions can be used in human patients in a clinical setting in the treatment of cognitive impairment associated with anticancer therapy. The composition dose and dosing range used in the method of the present invention as described herein are safe and effective in the indicated applications.

Therapies that are used in the treatment of cancer, including chemotherapy, radiation therapy, or combinations thereof, can cause cognitive impairment in patients for functions such as memory, learning ability, and concentration. Cytotoxicity and other adverse brain side effects of cancer treatment are responsible for this form of cognitive impairment, which can persist for decades. (Dietrich et al., Oncologist 13:1285-95, 2008; Soussain et al., Lancet 374:1639-51, 2009).

Cognitive impairment after cancer therapy reflects dysfunctions in frontal cortex and hippocampal circuits that are essential for normal cognitive function. In animal models, exposure to chemotherapy or radiotherapy adversely affects the ability to perform cognitive tests that are particularly dependent on these brain systems, in particular the hippocampus (Kim et al., J. Radial Res. 49:517-526, 2008; Yang et al ., Neurobiol Learning and Mem 93:487-494, 2010). Thus, drugs targeting these cortical and hippocampal systems may be neuroprotective in patients undergoing cancer therapy and may be effective in treating symptoms of cognitive impairment that may persist after interventions used as cancer therapy.

Animal models serve as an important resource for the development and evaluation of treatments for cognitive impairment associated with anticancer therapy. Features that are characteristic of anticancer therapy-associated cognitive impairment in animal models generally extend to anticancer therapy-associated cognitive impairment in humans. Thus, the performance of such animal models is expected to be able to predict efficacy in humans. Various animal models of cognitive impairment associated with anticancer therapy are known in the art.

Examples of animal models of cognitive impairment associated with antitumor therapy include treatment of animals with antitumor agents such as cyclophosphamide (CYP) or radiation, such as ⁶⁰ Co gamma rays. (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Cognitive performance in animal models of cancer therapy associated cognitive impairment can then be tested in cognitive tests to evaluate the effectiveness of the methods and compositions of the present invention in treating cancer therapy associated cognitive impairment. As indicated above, the effectiveness of the methods and compositions of the present invention in treating cancer therapy-related cognitive impairment, as well as the treatment of people with cancer therapy-related cognitive impairment, can be assessed using various cognitive tests that are known in the art.

SV2A inhibitor

"Synaptic vesicle proteins-2 (SV2)" is a family of synaptic vesicle proteins that includes three members, designated SV2A, SV2B and SV2C. SV2A is the most abundant member of the family and is expressed ubiquitously in the brain. These proteins are integral membrane proteins and have a low level of homology (20-30%) with respect to a family of twelve transmembrane transport proteins of bacteria and fungi that transport sugar, citrate and xenobiotics (Bajjalieh et al., Science, 257: 1271-1273 ( 1992)). The SV2 protein family is present in the brain and endocrine cells, and is also present in all synaptic and endocrine vesicles. SV2 proteins have been reported to play a role in normal synaptic function and in the primed vesicle maturation step that converts vesicles to a Ca( ²⁺ ) and synaptotagmin-responsive state (Sudhof et al., 2009). Functionally, SV2 proteins have been reported to enhance synaptic fluxes and increase the likelihood of mediator release by maintaining the size of an easily released set of vesicles (Custer et al., 2006).

The term "SV2A inhibitor" refers to any agent, substance, or compound that binds to SV2A and reduces synaptic function by reducing the secretion of presynaptic vesicles (see, for example, Noyer et al., 1995; Fuks et al., 2003; Lynch et al., 2004; Gillard et al., 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al., 2007; Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission," Epilepsia , 2012 Jan. 31; and Example 8 in WO 2001/62726, each of which is specifically incorporated herein by reference). A substance or compound or agent is an inhibitor of SV2A, even if it does not itself bind to SV2A, provided that it causes binding or interferes with the ability of another compound or agent to bind to SV2A or reduce synaptic function by decrease in the secretion of presynaptic vesicles. As used herein, SV2A inhibitors include pharmaceutically acceptable salts of said inhibitors. They also include hydrates, polymorphs, prodrugs, salts and solvates of these inhibitors.

Among the SV2A inhibitors or their pharmaceutically acceptable salts, hydrates, solvates and polymorphs that are suitable for use in the methods and compositions of the present invention, there may be those described, for example, in US patent application 12/580464, international patent application PCT/ US2009/005647, US Patent Application 61/105847, US Patent Application 61/152631 and US Patent Application 61/175536. However, any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be used in the methods and compositions of the present invention. In some embodiments of the present invention, the SV2A inhibitor is selected from the group of SV2A inhibitors specified in international patent applications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726, US Patent Nos. 7465549, 7244747, 5334720, 4696943, 4696942, US Patent Applications Nos. 20090312333; 20090018148, 20080081832, 2006258704; and UK Patent Nos. 1039113 and 1309692, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs. Other SV2A inhibitors may also be used in this invention. The authors of the present invention also indicate methods for obtaining these compounds, which are contained in the above documents. Other synthetic methods may also be used. These methods are well known to those skilled in the art.

In some embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives or analogs thereof, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or prodrugs thereof.

In some embodiments, the SV2A inhibitor is levetiracetam, or salts, solvates, hydrates, polymorphs, or prodrugs thereof. According to the International Union of Pure and Applied Chemistry (IUPAC), levetiracetam is a compound with the chemical name (2S)-2-(2-oxopyrrolidin-1-yl)butanamide). Levetiracetam is a widely used antiepileptic drug. Levetiracetam binds to a specific site in the CNS: the synaptic vesicle protein 2A (SV2A) (See, for example, Noyer et al. 1995; Fuks et al., 2003; Lynch et al., 2004; Gillard et al., 2006) and, has been further shown to directly inhibit synaptic activity and neurotransmission by inhibiting presynaptic neurotransmitter secretion (Yang et al., 2007).

SV2A inhibitors useful in the methods and compositions of the present invention are:

i) International patent application WO 2001/062726:

A compound having formula I or a pharmaceutically acceptable salt thereof

,

,

where X represents a group -CA ¹ NR ⁵ R ⁶ or -CA ¹ OR ⁷ or CA ¹ R ⁸ or CN;

And ¹ and A ² independently of each other represent an atom of oxygen, sulfur or-NR ⁹ ;

R ¹ denotes a hydrogen atom, alkyl, aryl or-CH ² -R ^1a where R ^1a denotes aryl, heterocycle, halogen atom, hydroxy, amino, nitro or cyano;

R ² , R ³ and R ⁴ may be the same or different and each independently represents a hydrogen atom, a halogen atom, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl , alkynyl, ester, ether, aryl, heterocycle, or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative, or sulfinyl derivative;

R ^2a , R ^3a and R ^4a are the same or different and each independently represents a hydrogen atom, a halogen atom, alkyl, alkenyl, alkynyl or aryl;

R ⁵ , R ⁶ , R ⁷ and R ⁹ are the same or different, and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or hydroxy derivative; And

R ⁸ denotes a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle or its thio derivative;

under the proviso that at least one of R ² , R ³ , R ⁴ , R ^2a , R ^3a and R ^4a is other than a hydrogen atom; and that when a compound is a mixture of all possible isomers, X is -CONR ⁵ R ⁶ , A ² is an oxygen atom, and R ¹ is a hydrogen atom, methyl, ethyl, or propyl, then the pyrrolidine ring substitution is other than mono-, di - or trimethyl or mono-ethyl; and that when R ¹ , R ² , R ⁴ , R ^2a , R ^3a and R ^4a are each a hydrogen atom, A ² is an oxygen atom, and X is CONR ⁵ R ⁶ , then R ³ is other than carboxy, an ester , amido, substituted oxopyrrolidine, hydroxy, hydroxy derivative, amino, amino derivative, methyl, naphthyl, phenyl, optionally substituted with hydroxy derivatives or substituted in the para position with a halogen atom.

In the definitions below, unless otherwise indicated, R ¹¹ and R ¹² may be the same or different, and each independently denotes amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or oxy derivative, thio derivative , acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative, each of which is optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from lower alkyl or other groups, which are described below as substituents for alkyl.

The term "oxy derivative" as used herein includes the -OR ¹¹ groups, where R ¹¹ is as defined above, with the exception of "hydroxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, hydroxyether, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, or heterocyclooxy, such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyrioxy. , methylenedioxy, carbonate.

The term "thio derivative" as used herein includes the -SR ¹¹ groups, where R ¹¹ is as defined above, with the exception of "thio derivative". Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

The term "amino derivative" as used herein includes the groups -NHR ¹¹ or -NR ¹¹ R ¹² where R ¹¹ and R ¹² are as defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

The term "acyl derivative" as used herein means a radical derived from a carboxylic acid and is thus defined as including groups of the formula R ¹¹ -CO-, where R ¹¹ is as defined above and may also be a hydrogen atom. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term "sulfonyl derivative" as used herein includes a group of the formula -SO ₂ -R ¹¹ , where R ¹¹ is as defined above, with the exception of "sulfonyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term "sulfinyl derivative" as used herein includes a group of formula -SO-R ¹¹ , where R ¹¹ is as defined above, with the exception of "sulfinyl derivative". Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term "alkyl" as used herein includes saturated monovalent hydrocarbon radicals containing straight, branched or cyclic fragments or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl ( in these two preferred cases, unless otherwise noted, "lower alkyl"). Alkyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester , ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyether, oxyamido, heterocycle, vinyl, C1-5-alkoxy, C6-10-aryloxy and C6-10-aryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl and 2,2,2-trimethylethyl, each of which is optionally substituted with at least one substituent selected from the group consisting of a halogen atom , hydroxy, thiol, amino, nitro and cyano such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl .

The term "alkenyl" as used herein includes both branched and unbranched, unsaturated hydrocarbon radicals which contain at least one double bond, such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2- dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like, and which are optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, and heterocycle, such as mono- and dihalogenvinyl, where the halogen atom is a fluorine, chlorine or bromine atom.

The term "alkynyl" as used herein includes a monovalent branched or straight hydrocarbon radical which contains at least one carbon-carbon triple bond, e.g. ethynyl, 2-propynyl (= propargyl) and the like, and which may be substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, and a heterocycle such as haloethynyl.

Where they represent bridging groups, alkyl, alkenyl and alkynyl are straight or branched chain groups, C1-12, preferably C1-C4 alkylene or C2-C12, preferably C2-4 alkenylene or alkynylene moieties, respectively.

Groups in which branched derivatives are defined for convenience by a prefix such as "n", "sec", "iso", etc. (for example, "n-propyl", "sec-butyl"), unless otherwise indicated, have a straight form.

The term "aryl" as used herein includes an organic radical which is derived from an aromatic hydrocarbon having 1-3 rings and containing 6-30 carbon atoms by removing one hydrogen atom, such as phenyl and naphthyl, each of which is optionally substituted from 1 to 5 substituents independently selected from halo, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyether, oxyamido, aryl, C1-6 alkoxy, C6-10 aryloxy, C1-6 alkyl, C1-6 haloalkyl. Aryl radicals are preferably monocyclic and contain 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each optionally substituted with 1 to 5 substituents independently selected from halo, nitro, amino, azido, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C1 -6-haloalkyl and phenyl.

The term "halogen atom" as used herein includes Cl, Br, F, I.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "thiol" as used herein means a group of the formula -SH.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "nitrooxy" as used herein refers to a group of the formula -ONO ₂ .

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "carboxy" as used herein refers to a group of the formula -COOH.

The term "sulfonic acid" as used herein means a group of the formula -SO ₃ H.

The term "sulfonamide" as used herein refers to a group of the formula -SO ₂ NH ₂ .

The term "ester" as used herein includes a group of the formula -COO-R ¹¹ where R ¹¹ is as defined above, excluding the hydroxy derivative, thio derivative, or amine derivative.

The term "ether" includes a group selected from C1-50 straight or branched alkyl, or C2-50 straight or branched alkenyl or alkynyl, or a combination thereof, interrupted by one or more oxygen atoms.

The term "amido" includes a group of formula -CONH ₂ or -CONHR ¹¹ or -CONR ¹¹ R ¹² where R ¹¹ and R ¹² are defined above.

The term "heterocycle" is defined herein as including an aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S, and/or N atom that interrupts the carbocyclic ring structure, wherein optionally, one of the carbon atoms of the carbocyclic ring structure may be substituted with a carbonyl. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolyl, purinolyl , carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranil, benzofuranyl, benzoxepinyl, isoxazolyl, oxazolyl, thianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, pyrimidinyl , phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracinyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted with alkyl or as described above for alkyl groups. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxopyrrolidinyl, sugar residues (e.g., glucose, pentose, hexose, ribose, fructose, which may also be substituted) or which may be optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from lower alkyl, or other groups as described above for alkyl groups. The term "heterocycle" also includes bicyclic, tricyclic, tetracyclic, and spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another a monocyclic heterocyclic moiety, or a group in which a monocyclic heterocyclic ring is bridged by an alkylene group such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl .

It should be understood that in the above definitions, when a substituent such as R ² , R ³ , R ⁴ , R ^2a , R ^3a , R ^4a , R ⁵ , R ⁶ , R ⁷ , R ⁸ attached to the rest molecules through a heteroatom or carbonyl, C1-12 straight or branched chain, preferably C1-4 alkylene or C2-12, preferably C2-4 alkenylene or alkynylene bridging group may optionally be located between the heteroatom or carbonyl and the point of attachment to the rest molecule.

Preferred examples of X are -COOR ⁷ or -CONR ⁵ R ⁶ where R ⁵ , R ⁶ and R ⁷ are preferably hydrogen, C1-4 alkyl, phenyl or alkylphenyl.

Preferably, X is carboxy or -CONR ⁵ R ⁶ , where R ⁵ and R ⁶ are preferably hydrogen, C1-4 alkyl, phenyl or alkylphenyl, in particular -CONH ₂ .

Preferably, A ¹ and A ² each represents an oxygen atom.

Preferably, R ¹ represents a hydrogen atom, alkyl, in particular C1-12 alkyl, in particular lower alkyl or aryl, in particular phenyl.

Examples of preferred R ¹ groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, each of which is optionally attached via a methylene bridge group or is substituted by at least one a halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

The most preferred value for R ¹ is ethyl.

Preferably, R ² and R ^2a independently represent a hydrogen atom, a halogen atom or alkyl, in particular lower alkyl.

Examples of preferred groups R ² and R ^2a are independently hydrogen atom, halogen atom or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same groups substituted with at least , one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

In particular, at least one and most preferably both R ² and R ^2a represent a hydrogen atom.

Preferably R ^3a , R ⁴ and R ^4a independently represent a hydrogen atom, alkyl, in particular methyl or ethyl, or aryl, in particular phenyl or aralkyl, in particular benzyl.

Examples of preferred groups R ^3a , R ⁴ and R ^4a are independently hydrogen atom, halogen atom or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same groups substituted, at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

In particular, at least one and most preferably both R ⁴ and R ^4a represent a hydrogen atom.

R ^3a especially represents a hydrogen atom or alkyl, in particular lower alkyl, and most preferably a hydrogen atom.

Preferably, R ³ is a hydrogen atom, C1-12 alkyl, in particular C1-6 alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and which are attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group, and optionally via a C1-4 alkylene bridge, in particular methylene; C2-6-alkenyl or C2-6-alkynyl, in particular C2-3-alkenyl or C2-3-alkynyl, each of which is optionally substituted with one or more halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or piperazinyl groups, each of which is optionally substituted with one or more substituents selected from a halogen atom, C1- 6-alkyl and phenyl, and attached to the cycle directly or through a carbonyl group or a C 1-4 alkylene bridge, in particular methylene; naphthyl or phenyl, phenylalkyl or phenylalkenyl, each of which is optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azido, phenyl and nitro, each attached to the ring directly or via an hydroxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally via a C1-4 alkylene bridge, in particular methylene.

Further preferably, R ³ is C1-6 alkyl optionally substituted with one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl, nitrooxy; C2-3-alkenyl or C2-3-alkynyl, each of which is optionally substituted with one or more halogen or acetyl atoms; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl each optionally substituted with one or more substituents selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, amino, azido, phenyl, and nitro, and each is attached to the cycle either directly or via a sulfonyloxy, and optionally additionally via a C1-4 alkylene bridge, in particular methylene.

Other examples of preferred R ³ groups include hydrogen atom, halogen atom or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same groups substituted with at least one atom halogen such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

In particular, R ³ is C1-4 alkyl optionally substituted with one or more substituents selected from halo, thiocyanato or azido; C2-5-alkenyl or C2-5-alkynyl, each of which is optionally substituted with one or more halogen atoms; thienyl; or phenyl optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 haloalkyl, or azido.

Further examples of preferred R ³ groups are C1-6 alkyl, C2-6 haloalkenyl.

Preferably, R ⁵ and R ⁶ independently represent a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, in particular hydrogen or methyl.

In particular, at least one, and most preferably both R ⁵ and R ⁶ is a hydrogen atom.

Preferably R ⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl, or the same groups substituted with at least one halogen atom, such as trifluoromethyl, chlorophenyl.

Preferably, R ⁷ represents a hydrogen atom, methyl or ethyl, in particular a hydrogen atom.

Preferably R ⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same groups substituted with at least one halogen atom, such as trifluoromethyl, chlorobenzyl.

Preferably R ⁸ is hydrogen or methyl.

Combinations of one or more of these preferred groups are particularly preferred.

A specific group of compounds of formula I (compounds 1A) includes compounds in which,

And ² means an oxygen atom;

X is -CONR ⁵ R ⁶ or -COOR ⁷ or -CO-R ⁸ or CN;

R ¹ denotes a hydrogen atom or alkyl, aryl, halogen atom, hydroxy, amino, nitro, cyano;

R ² , R ³ , R ⁴ are the same or different, and each independently represents a hydrogen atom or a halogen atom, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, thio derivative, alkyl, alkoxy, hydroxyester, hydroxyamido, aryl, hydroxy derivative, heterocycle, vinyl, and R ³ may further be C2-5 alkenyl, C2-5 alkynyl, or azido, each of which is optional substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; or phenylsulfonyloxy, wherein any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino and/or phenyl; most preferably is methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

R ^2a , R ^3a and R ^4a represent a hydrogen atom;

R ⁵ , R ⁶ , R ⁷ are the same or different, and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or hydroxy derivative; And

R ⁸ denotes a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle, alkylthio or thio derivative.

Among compounds 1A, R ¹ is preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; most preferably methyl, ethyl or n-propyl.

R ² and R ⁴ preferably independently represent a hydrogen atom, or a halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and most preferably represents a hydrogen atom.

Preferably, R ³ is C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, cyclopropyl, azido, each optionally substituted with one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl ; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, wherein any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino and/or phenyl; most preferably is methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

X is preferably -COOH or -COOMe or -COOEt or -CONH ₂ ; most preferably, -CONH ₂ .

Another specific group of compounds of formula I (compounds 1B) includes compounds in which,

X is -CA ¹ XH ₂ , -CA ¹ NHCH ₃ or -CA ¹ N(CH ₃ ) ₂ ;

R ¹ is alkyl or phenyl;

R ³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanate, ether, carboxyl, amido, aryl, heterocycle, or

R ³ is CH ₂ R ¹⁰ where R ¹⁰ is hydrogen, cycloalkyl, oxyether, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl ;

R ^3a is hydrogen, alkyl or aryl (especially provided that when R ^3a is hydrogen, R ³ is other than methyl);

or R ³ and R ^3a form cycloalkyl;

and R ² , R ^2a , R ⁴ and R ^4a each represents a hydrogen atom.

In compounds of formula I,

R ¹ is preferably alkyl, in particular C1-12 alkyl, in particular C1-6 alkyl and most preferably ethyl;

R ² , R ^2a , R ^3a and R ^4a preferably represent a hydrogen atom;

preferably R ³ is selected from hydrogen, C1-12 alkyl, preferably C1-6 alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally a C1-4 alkylene bridge, in particular methylene; C2-6-alkenyl or C2-6-alkynyl, especially C2-3-alkenyl or C2-3-alkynyl, each of which is optionally substituted with one or more halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, C1-6 -alkyl and phenyl, and attached to the ring directly or through a carbonyl group or a C1-C4 alkylene bridge, in particular methylene; naphthyl; or phenyl, phenylalkyl, or phenylalkenyl, each optionally substituted with one or more substituents selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylthio, amino, azido, phenyl and nitro, and attached to the ring directly or via an hydroxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally via a C1-4 alkylene bridge, in particular methylene;

R ^3a preferably denotes a hydrogen atom or C1-4-alkyl;

R ⁴ and R ^4a are preferably independently hydrogen, C1-4 alkyl, phenyl or benzyl.

Another group of compounds of formula I (compounds 1C) includes those compounds in racemic form in which, when X is -CONR ⁵ R ⁶ and R ¹ is hydrogen, methyl, ethyl or propyl, the substitution on the pyrrolidine ring is other than mono-, di- or trimethyl or monoethyl.

Another group of compounds of formula I (compounds 1D) includes those compounds in racemic form in which when X is -CONR ⁵ R ⁶ and R ¹ is a hydrogen atom or C 1-6 alkyl, C 2-6 alkenyl, or C2-6 alkynyl or cycloalkyl, each of which is unsubstituted, then the substitution in the ring is different from alkyl, alkenyl, or alkynyl, each of which is unsubstituted.

Another specific group of compounds of formula I (compounds 1E) includes those in which,

X is -CA ¹ NH ₂ ;

R ¹ is H;

R ³ is azidomethyl, iodomethyl, ethyl optionally substituted with 1 to 5 halogen atoms, n-propyl optionally substituted with 1 to 5 halogen atoms, vinyl optionally substituted with one or two methyl and/or 1 to 3 halogen atoms, acetylene , optionally substituted with C1-4 alkyl, phenyl, or a halogen atom;

R ^3a is a hydrogen atom or a halogen atom, preferably a fluorine atom;

and R ² , R ^2a , R ⁴ and R ^4a each represents a hydrogen atom;

as their racemates or in enantiomerically enriched form, preferably as pure enantiomers.

Another specific group of compounds of formula I (compounds 1F) includes compounds in which,

X is -CA ¹ NH ₂ ;

R ¹ is H;

R ³ is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl optionally substituted with azido, oxynitro, 1 to 6 halogen atoms;

R ^3a is a hydrogen atom or a halogen atom, preferably a fluorine atom;

and R ² , R ^2a , R ⁴ and R ^4a each represents a hydrogen atom; as their racemates or in enantiomerically enriched form, preferably as pure enantiomers.

Within all of the above limits, when the carbon atom to which R ¹ is attached is asymmetric, it preferably has the "S" configuration.

In some embodiments of the present invention, compounds suitable for use in the methods and compositions of the present invention are selected from the group that includes:

(2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl 4-methylbenzenesulfonate;

(2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;

2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl nitrate;

(2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;

2-{2-oxo-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;

(2S)-2-(4-[1,1'-biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide;

(2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;

2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-ethynyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl}butanamide;

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

(2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[(4S)-4-(2,2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;

3-cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms thereof and mixtures thereof or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, compounds suitable for use in the methods and compositions of the present invention are selected from the group that includes:

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

ii) International patent application WO 2002/094787:

,

,

where n is 0 or 1, with R ¹ not present when n=0 and R ¹ present when n=1;

A ¹ represents an oxygen or sulfur atom;

X is -CONR ⁷ R ⁸ , -COOR ⁹ , -CO-R ¹⁰ or CN;

R ¹ if present, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each independently represents a hydrogen atom, a halogen atom, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle or hydroxy derivative, thio derivative, amine derivative, acyl derivative, sulfonyl or sulfinyl derivative,

with the proviso that at least one of the substituents R selected from R ¹ , when present, R ² , R ³ , R ⁴ or R ⁵ , is not a hydrogen atom;

R ⁶ denotes a hydrogen atom, alkyl, aryl or -CH ² -R ^6a where R ^6a represents aryl, heterocycle, halogen atom, hydroxy, amino, nitro or cyano;

R ⁷ , R ⁸ and R ⁹ are the same or different and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ¹⁰ denotes a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle or thio derivative;

their pharmaceutically acceptable salts, geometric isomers (including cis and trans isomers, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one of the R ¹ -R ⁵ substituents is other than a hydrogen atom. Some unsubstituted compounds are disclosed in US Pat. In particular, these compounds block the ability of Ras to convert normal cells into cancer cells and therefore can be included in several chemotherapeutic compositions for the treatment of malignant tumors.

US Pat. No. 5,516,759 relates to ring-unsubstituted 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivatives present at the N-terminus of dodecapentides with LHRH (lutropin releasing hormone) antagonistic activity. Such LHRH antagonists are useful in the treatment of various conditions in which sex steroid suppression plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, and others.

In the definitions below, unless otherwise indicated, R ¹¹ and R ¹² are the same or different, and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle, or oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, sulfinyl derivative, each of which is optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from lower alkyl or other groups, as described below as substituents for alkyl.

The term "oxy derivative" as used herein includes the -OR ¹¹ groups, where R ¹¹ is as defined above, with the exception of "hydroxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, hydroxyether, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, or heterocyclooxy, such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy. , methylenedioxy, carbonate.

The term "thio derivative" as used herein includes the -SR ¹¹ groups, where R ¹¹ is as defined above, with the exception of "thio derivative". Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

The term "amino derivative" as used herein includes the groups -NHR ¹¹ or -NR ¹¹ R ¹² where R ¹¹ and R ¹² are as defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl and arylamino or mixed amino.

The term "acyl derivative" as used herein means a radical derived from a carboxylic acid and is thus defined as including groups of the formula R ¹¹ -CO-, where R ¹¹ is as defined above and may also be a hydrogen atom. Preferred are acyl derivatives of the formula -COR ¹¹ wherein R ¹¹ is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkenyl, heterocycle and aryl. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term "sulfonyl derivative" as used herein includes a group of the formula -SO ₂ -R ¹¹ , where R ¹¹ is as defined above, with the exception of "sulfonyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term "sulfinyl derivative" as used herein includes a group of formula -SO-R ¹¹ , where R ¹¹ is as defined above, with the exception of "sulfinyl derivative". Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term "alkyl" as used herein is defined as including saturated monovalent hydrocarbon radicals which have linear, branched or cyclic moieties or combinations thereof and typically contain 1-20 carbon atoms, most commonly 1 to 12 carbon atoms, preferably 1-7 carbon atoms. carbon for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise noted, "lower alkyl"), each of which is optionally substituted, preferably with 1 to 5 substituents independently selected from the group which includes halogen atom, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, hydroxyester, oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy (preferably C6-10) and aryl (preferably C6-10).

Preferred are alkyl groups containing from 1 to 7 carbon atoms, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7 cycloalkyl, each optionally substituted with one or more hydroxy, halogen, lower alkyl and/or azido.

The most preferred alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, iodomethyl , azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term "lower alkyl" in this description, unless otherwise indicated, means C ₁ -C ₇ saturated linear, branched or cyclic hydrocarbon. Non-limiting examples are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, optionally substituted with any suitable group, including , but not limited to, one or more fragments selected from the groups as described above for alkyl groups. Preferably, the lower alkyl is methyl.

The term "alkenyl" as used herein includes both branched and straight, unsaturated hydrocarbon radicals having at least one double bond and optionally substituted with at least one substituent selected from the group consisting of a halogen atom, hydroxy , thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl, and heterocycle.

Preferred alkenyl groups are C2-C12 alkenyls, in particular C2-6 alkenyls such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, etc., which are optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl optionally substituted with one or more halogen and/or lower alkyl, in particular 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term "alkynyl" as used herein includes a monovalent branched or straight hydrocarbon radical containing at least one carbon-carbon triple bond, eg ethynyl, 2-propynyl (= propargyl) and the like. and optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, alkylthio, alkyl, and acyl.

Preferred alkynyl groups are C2-12 alkynyl, in particular C2-6 alkynyl optionally substituted with one or more substituents selected from halo, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyl, or alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl optionally substituted with a lower alkyl and/or halogen atom, and in particular 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl are straight or branched chains, C1-12, preferably C1-4 alkylene or C2-C12, preferably C2-4 alkenylene or C2-4 alkynylene moieties, respectively.

Groups in which branched derivatives are defined for convenience by a prefix such as "n", "sec", "iso", etc. (for example, "n-propyl", "sec-butyl"), unless otherwise indicated, have a straight form.

The term "aryl" as used herein includes an organic radical which is derived from an aromatic hydrocarbon consisting of at least one cycle, most commonly 1 to 3 cycles, and generally containing 6-30 carbon atoms, by removing one atom hydrogen, such as phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, simple ester, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio, oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl . Aryl radicals are preferably monocyclic or bicyclic and contain 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each optionally substituted with one or more substituents independently selected from halo, nitro, amino, azido, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl, sulfonyl, and phenyl.

Preferred aryl is phenyl optionally substituted with one or more halogen, lower alkyl, azido or nitro, eg 3-chlorophenyl, 3-azidophenyl.

The term "halogen atom" as used herein includes Cl, Br, F, I.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "thiol" in this description, denotes a group of formula -SH.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "nitrooxy" as used herein refers to a group of the formula -ONO ₂ .

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "carboxy" in this description means a group of the formula -COOH.

The term "sulfonic acid" as used herein means a group of the formula -SO ₃ H.

The term "sulfonamide" as used herein refers to a group of the formula -SO ₂ NH ₂ .

The term "ester" as used herein includes a group of the formula -COO-R ¹¹ where R ¹¹ is as defined above, excluding the hydroxy derivative, thio derivative, or amine derivative. Esters of formula -COOR ¹¹ are preferred, wherein R ¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R ¹¹ is lower alkyl, in particular methyl.

The term "ether" is defined as including a group selected from C1-C50 straight or branched alkyl, or C2-50 straight or branched alkenyl or alkynyl groups, or a combination thereof, and which is interrupted by one or more oxygen atoms.

The term "amido" is defined as including a group of the formula -CONH ₂ or -CONHR ¹¹ or -CONR ¹¹ R ¹² where R ¹¹ and R ¹² are as defined above.

The term "heterocycle" as used herein includes an aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S, and/or N atom that interrupts the carbocyclic structure, optionally one of the carbon atoms the carbocyclic ring structure may be substituted with a carbonyl group, said moiety being optionally substituted with any suitable group including, but not limited to, one or more substituents selected from lower alkyl or other groups as described above for alkyl groups. Non-limiting examples of heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isoxazolyl, oxazolyl, thianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1- оксидопиридил, фенантридинил, акридинил, пиримидинил, фенантролинил, фенотиазинил, фуразанил, бензодиоксолил, изохроманил, индолинил, ксантенил, гипоксантинил, птеридинил, 5-азацитидинил, 5-азаурацинил, триазолопиридинил, имидазолопиридинил, пирролопиримидинил, пиразолопиримидинил, тетрагидрофуранил, тетрагидропиранил, пиперидинил, пиперидил, piperazinil, imidazolidinil, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-ox opyrrolidinyl, sugar residues (eg glucose, pentose, hexose, ribose, fructose, which may also be substituted) optionally substituted with alkyl or as described above for alkyl groups. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle, or a monocyclic heterocyclic group has a bridged alkylene group, for example quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

The heterocycle is preferably selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl.

More preferably, the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl, and in particular from 2- and 3-thienyl optionally substituted with one or more halogen atoms, acyl such as formyl, cyano and/or lower alkyl such as methyl.

It should be understood that in the above definitions, when a substituent such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is attached to the rest of the molecule via a heteroatom or carbonyl, then a C1-12 straight or branched chain bridging group, preferably a C1-4 alkylene or C2-12, preferably a C2-4 alkenylene or C2-4 alkynylene bridging group may optionally be located between the heteroatom or carbonyl and the point of attachment to the rest of the molecule.

The term "R Deputy" independently refers to R ¹ , R ² , R ³ , R ⁴ or R ⁵ .

In accordance with a preferred embodiment of the present invention, the compound of formula I is a compound as defined above, wherein n is 0. The compound is a 6-membered ring structure (2-thioxo or 2-oxo-piperidinyl derivative), where R ¹ is not present because n=0, and is represented by formula (IA).

According to a further preferred embodiment of the present invention, the compound of formula I is a compound as defined above, wherein n is 1. The compound is a 7-membered ring structure (2-thioxo or 2-oxo-azepanyl derivative) where R ¹ is present because n=1 and is represented by formula (IB).

According to a more preferred embodiment of the present invention, said compound is a compound as defined above, wherein n=0, R ³ and/or R ⁴ are other than a hydrogen atom, and R ² and R ⁵ represent a hydrogen atom.

In accordance with yet another more preferred embodiment of the present invention, said compound is a compound as defined above, wherein n=1, R ² , R ³ and/or R ⁴ are other than a hydrogen atom, and wherein R ¹ and R ⁵ are a hydrogen atom.

According to an even more preferred embodiment of the present invention, said compound is a compound as defined above wherein only one substituent R is selected from R ³ or R ⁴ when n=0, or from R ² , R ³ or R ⁴ when n=1 is other than a hydrogen atom, and the remaining substituents R are a hydrogen atom. The authors of the present invention in this case mean mono-substituted 2-thioxo-piperidinyl and 2-oxo-piperidinyl or 2-thioxo-azepanyl and 2-oxo-azepanyl derivatives.

According to another preferred embodiment of the present invention, the compounds of formula I are those as defined above, wherein A ¹ is an oxygen atom. The authors of the present invention in this case have in mind 2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another preferred embodiment of the present invention, the compounds of formula I are those as defined above, wherein X is CONR ⁷ R ⁸ , in particular CONH ₂ . The authors of the present invention in this case have in mind the amide derivatives of 2-oxo(or thioxo)-piperidinyl or 2-oxo(or thioxo)-azepanil.

According to another preferred embodiment of the present invention, the compounds of formula I are those as defined above, wherein R ⁶ is hydrogen, C1-4 alkyl, or CH ₂ -R ^6a , where R ^6a is a heterocycle. Most preferably, R ⁶ is C1-4 alkyl, in particular ethyl. When R ⁶ is ethyl, we mean 2-(2-oxo(or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo(or thioxo)-1-azepanyl)butanamide derivatives .

According to another preferred embodiment of the present invention, the compounds of formula I are those as defined above, wherein the carbon atom to which R ⁶ is attached is in the S configuration. When R ⁶ is ethyl, A is an oxygen atom, and X is -CONR ⁷ R ⁸ , we mean (2S)-2-(2-oxo-1-piperidinyl)butanamide or (2S )-2-(2-oxo-1-azepanyl)butanamide derivatives.

According to another preferred embodiment of this invention, the compounds of formula I are compounds as defined above, wherein R ² when n=1, R ³ and R ⁴ are the same or different, and each independently represents a hydrogen atom, a halogen atom, nitro, nitrooxy, cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ¹ when present, R ² when n=0, and R ⁵ represent a hydrogen atom;

R ⁶ denotes a hydrogen atom, alkyl, aryl or -CH ₂ -R ^6a where R ^6a represents aryl, heterocycle, halogen atom, hydroxy, amino, nitro or cyano.

In accordance with said preferred embodiment of the present invention, the compound is generally such that when R ⁶ is benzyl, X is —COOCH ₃ and n=1, R ² is other than methyl when R ³ and R ⁴ are both an atom hydrogen, and R ⁴ is other than methyl when R ² and R ³ both represent a hydrogen atom.

In accordance with another preferred embodiment of the present invention, the compound is defined above, where R ² when n=1, R ³ and R ⁴ may be the same or different, and each independently represents a hydrogen atom; cyano; carboxy; amido;

C1-12-alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cycloalkyl, acyl, aryl and heterocycle;

C2-12-alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

C2-12 alkynyl, each of which is optionally substituted with one or more substituents selected from halo, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl; an acyl derivative of formula -CO-R ¹¹ wherein R ¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;

an ester of the formula -CO-OR ¹¹ where R ¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and aryl;

a heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom , alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;

aryl, each optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azido, sulfonyl, aryl and nitro.

In accordance with another preferred embodiment of the present invention, the compound is defined above, where R ² when n=1, R ³ and R ⁴ may be the same or different, and each independently represents a hydrogen atom;

C1-7 alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

C2-6 alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each optionally substituted with one or more substituents selected from C1-6 alkyl, halogenated alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl and nitro.

In accordance with another preferred embodiment of the present invention, the compound is defined above, wherein at least one of the R substituents is selected from the group R ² , R ³ and R ⁴ when n=1, or from the group R ³ and R ⁴ when n=0 is independently C1-4alkyl or C3-7cycloalkyl optionally substituted with one or more halogen, hydroxy, lower alkyl and/or azido.

In accordance with another preferred embodiment of the present invention, the compound is defined above, wherein at least one of the R substituents is selected from the group R ² , R ³ and R ⁴ when n=1, or from the group R ³ and R ⁴ when n=0 is independently vinyl optionally substituted with one or more halogen and/or lower alkyl.

In accordance with another preferred embodiment of the present invention, the compound is defined above, wherein at least one of the R substituents is selected from the group R ² , R ³ and R ⁴ when n=1, or from the group R ³ and R ⁴ when n=0 is independently ethynyl, propynyl or butynyl optionally substituted with one or more halogen and/or lower alkyl.

In accordance with another preferred embodiment of the present invention, the compound is defined above, wherein at least one of the R substituents is selected from the group R ² , R ³ and R ⁴ when n=1, or from the group R ³ and R ⁴ when n=0 is independently phenyl optionally substituted with one or more halogen, lower alkyl, azido and/or nitro.

In accordance with another preferred embodiment of the present invention, the compound is defined above, wherein at least one of the R substituents is selected from the group R ² , R ³ and R ⁴ when n=1, or from the group R ³ and R ⁴ when n=0 is independently 2- or 3-thienyl optionally substituted with one or more halo, acyl, cyano and/or lower alkyl.

In accordance with the most preferred embodiment of this invention, the compound is defined above, where at least one of the substituents R selected from the group R ³ , R ⁴ and R ² when n=1, or from the group R ³ and R ⁴ when n=0 is hydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl, 3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl, 2,2- difluoropropyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

In accordance with another preferred embodiment of the present invention, the compound is defined above, where R ¹ , R ² , R ⁴ and R ⁵ denote a hydrogen atom.

In accordance with an even more preferred embodiment of the present invention, the compound is defined above, where R ¹ , R ² , R ³ and R ⁵ denote a hydrogen atom.

In accordance with an even more preferred embodiment of the present invention, the compound is as defined above, wherein n=1 and R ¹ , R ³ , R ⁴ and R ⁵ represent a hydrogen atom.

Within all of the above limits, when the carbon atom to which R ⁶ is attached is asymmetric, it preferably has the "S" configuration.

Specific examples of compounds suitable for use in the methods and compositions of this invention, as defined above, are selected from the group consisting of:

2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-propyl-1-piperidinyl)butanamide,

2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,

2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,

2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,

2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,

2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,

2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,

2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-propyl-1-piperidinyl)butanamide,

2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,

2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,

2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,

2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-propyl-1-azepanyl)butanamide,

2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-phenyl-1-azepanyl]butanamide,

2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,

2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,

2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-6-propyl-1-azepanyl)butanamide,

2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-6-phenyl-1-azepanyl)butanamide,

2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,

2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,

2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,

2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-propyl-1-azepanyl)butanamide,

2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-phenyl-1-azepanyl)butanamide,

2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,

2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,

2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

In some embodiments of the present invention, the compounds suitable for use in the methods and compositions of the present invention are selected from the group that includes:

(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,

(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

iii) International patent application WO 2004/087658:

A compound having formula I, or a pharmaceutically acceptable salt or stereoisomeric forms thereof,

,

,

Where

R ¹ denotes a hydrogen atom,

R ² means a hydrogen atom or C1-20-alkyl,

R ³ denotes a hydrogen atom, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl, aromatic or non-aromatic heterocycle, C1-20-alkoxy or a group of the formula: -WR ⁸ , R ^3a denotes a hydrogen atom, C1-20-alkyl or a group of the formula:

or NR ³ R ^3a is a group of the formula:

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom; nitro; a halogen atom; azido; cyano; -S-C1-4-alkyl; -SO-C1-4-alkyl; -SO ₂ -C1-4-alkyl; -SONH ₂ , C1-20 alkyl, unsubstituted or substituted with a halogen atom; or C1-20 alkoxy, unsubstituted or substituted with a halogen atom,

R ⁶ is a hydrogen atom, C1-20 alkyl or a halogen atom,

R ⁷ is a hydrogen atom, C1-20 alkyl or a halogen atom,

W is C1-12-alkylene, -NH- or -NHC(=O)-,

X is O, S or NH,

Y is O, S, -CR ¹² R ¹³ -, -NR ¹⁴ - or -C(=O)-,

R ⁸ is aryl or heterocycle,

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C1-4 alkyl, halogen, hydroxy or methoxycarbonyl,

or R ¹⁰ and R ^10a together form C3-6-alkylene;

R ¹² denotes a hydrogen atom, C1-4-alkyl, a halogen atom or hydroxy,

R ¹³ denotes a hydrogen atom,

or CR ¹² R ¹³ is dioxolanyl,

R ¹⁴ is aryl, heterocycle or a group of formula -VR ¹⁵ ,

V is C _1-22 -alkylene,

R ¹⁵ is aryl or heterocycle,

m takes a value from 1 to 4,

n is 0 or 1,

and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen when R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

According to another aspect, the compound is a compound having formula I, or a pharmaceutically acceptable salt or stereoisomeric forms thereof,

,

,

Where

R ¹ denotes a hydrogen atom,

R ² denotes a hydrogen atom or C1-20-alkyl,

R ³ denotes a hydrogen atom, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl, aromatic or non-aromatic heterocycle, C1-20-alkoxy or a group of formula -WR ⁸ ,

R ^3a is a hydrogen atom, C1-20 alkyl, or a group of the formula:

or NR ³ R ^3a is a group of the formula:

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom; nitro; a halogen atom; C1-20 alkyl, unsubstituted or substituted with a halogen atom; or C1-20 alkoxy, unsubstituted or substituted with a halogen atom,

R ⁶ is a hydrogen atom, C1-20 alkyl or a halogen atom,

R ⁷ is a hydrogen atom, C1-20 alkyl or a halogen atom,

W is C1-12-alkylene, -NH- or -NHC(=O)-,

X is O, S or NH,

Y is O, S, -CR ¹² R ¹³ -, -NR ¹⁴ - or -C(=O)-,

R ⁸ is aryl or heterocycle,

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C1-4 alkyl, halogen, hydroxy or methoxycarbonyl,

or R ¹⁰ and R ^10a together form C3-6-alkylene,

R ¹² denotes a hydrogen atom, C1-4-alkyl, a halogen atom or hydroxy,

R ¹³ denotes a hydrogen atom,

or CR ¹² R ¹³ is dioxolanyl,

R ¹⁴ is aryl, heterocycle or a group of formula -VR ¹⁵ ,

V is C1-12 alkylene,

R ¹⁵ is aryl or heterocycle,

m takes values from 1 to 4,

n is 0 or 1,

and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen when R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

The term "alkyl", as used herein, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties, or combinations thereof, and containing 1-20 carbon atoms, preferably 1-6 carbon atoms, and more preferably 1-4 carbon atoms for non-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. The alkyl moieties may optionally be substituted with 1 to 5 substituents independently selected from halo, hydroxy, alkoxy, alkoxycarbonyl, ester, or alkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3 -trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3-(dimethylamino)propyl.

The term "cycloalkyl" as used herein refers to a monovalent group of 3 to 18 carbon atoms, preferably 4 to 8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon, which may be substituted by any suitable group, including but not limited to one or more substituents selected from the group described above for alkyl groups. A preferred cycloalkyl group is cycloheptyl.

The term "alkylene" as used herein means a divalent alkyl group having straight or branched moieties, which contains 1-12 carbon atoms, preferably 1-6 carbon atoms, and which is optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from the group described above for alkyl groups. Preferred alkylene groups are methylene, ethylene, hydroxyethylene, trimethylene and propylene.

The term "cycloalkenyl" as used herein means a cyclic unsaturated hydrocarbon radical having at least one double bond and containing 4-20 carbon atoms, preferably 5-8 carbon atoms, which may be substituted by any suitable group, including but not limited to this without limitation, one or more substituents selected from the group described above for alkyl groups. A preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex-3-en-1-yl.

The term "aryl" as used herein includes an organic radical which is derived from an aromatic hydrocarbon having 1-3 rings and containing 6-30 carbon atoms by removing one hydrogen atom, such as phenyl and naphthyl, each of which is optionally substituted from 1 to 5 substituents independently selected from halogen, hydroxy, nitro, C1-6alkyl, C1-6alkoxy, C1-6alkylsulfonyl, trifluoromethylthio, or pyridinylalkyl. Aryl radicals are preferably phenyl radicals. Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4 -dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl or 4-bromophenyl.

The term "halogen atom" as used herein includes Cl, Br, F, I.

The term "nitro" in this description is a group of the formula -NO ₂ .

The term "hydroxy" as used herein means a group of the formula -OH.

The term "alkoxy" as used herein is a group of the formula -OR ^b , where R ^b is an alkyl group as defined above.

The term "ester" as used herein means a group of the formula -COOR ^c , where R ^c is an alkyl group or an aryl group as defined above.

The term "alkoxycarbonyl" as used herein means a group of the formula -COOR ^d , where R ^d is an alkyl group as defined above.

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "alkylamino" as used herein means a group of the formula -NHR ^e or -NR ^e R ^f , where R ^e and R ^f are an alkyl group as defined above.

The term alkylsulfonyl as used herein denotes a group of the formula -SO ₂ -R ⁸ where R ⁸ is C1-4 alkyl.

The term "heterocycle" as used herein includes an aromatic or non-aromatic cycloalkyl or cycloalkenyl residue, as defined above, having at least one O, S and/or N atom that interrupts the carbocyclic ring structure and optionally one of the carbon atoms. carbocyclic ring structure may be substituted with a carbonyl.

Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl , triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolisinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, purinyl, carbazolyl, thieno(2,3-b) furanyl, thianthrenyl, cinnoxazolinyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, , phenothiazinyl, isochromanyl and xanthenyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, thiol, amino, nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl , C1-6 haloalkyl, formyl or ester. More preferred aromatic heterocycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxolanyl, 1-ro-5-oxospiro(4. -oxopyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl, 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro , cyano, azido, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C1-6 haloalkyl, formyl, or ester. More preferred non-aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1- yl, tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanyl. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, cycloalkyl ring, cycloalkenyl ring or other monocyclic heterocyclic ring, or in which a monocyclic heterocyclic group is attached by an alkylene bridge group, for example quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl and 8-azabicyclo(3.2.1)octanyl.

The term "pyridinylalkyl" as used herein is a group of the formula -R ^h -pyridinyl, in which R ^h is C1-4 alkylene.

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "cyano" as used herein refers to a group of the formula -CN.

In general, R ² is a hydrogen atom or C 1-4 alkyl.

Preferably, R ² represents a hydrogen atom, methyl or ethyl. More preferably, R ² represents a hydrogen atom or methyl.

In general, R ³ means a hydrogen atom; C1-6alkyl, unsubstituted or substituted with 1 to 5 substituents selected from halo, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; C5-7-cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl unsubstituted or substituted with 1 to 5 substituents selected from halogen, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio, or pyridinylalkyl; pyridinyl, unsubstituted or substituted with methoxy; triazolyl; C1-4-alkoxy; or a group of formula -WR ⁸ where:

In general, W is C1-4 alkylene, unsubstituted or substituted with halogen, hydroxy, C1-4 alkyl, or alkoxy; -NH- or -NHC(=O)-; And

R ⁸ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from halo, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimidazolyl.

Preferably, R ³ is a hydrogen atom, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl , 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridine- 2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl) thio]benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridine- 3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol- 1-yl)propyl, 2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl)propyl, 2-(2-methylpiperidin-1- yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino More preferably, R ³ is contains a hydrogen atom.

In general, R ^3a is a hydrogen atom, C1-4-alkyl, or a group of the formula

,

,

where m takes values from 1 to 4.

Preferably R ^3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl. More preferably R ^3a is a hydrogen atom.

In another embodiment, NR ³ R ^3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a formula group:

,

,

in which R ¹⁴ denotes pyridinyl; phenyl, unsubstituted or substituted halogen atom, hydroxy, C1-4 alkyl; or a group of formula -VR ₁₅ where V is an unsubstituted C1-4 alkylene and R ¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR ³ R ^3a is 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4 -(2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3 -thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

In general, R ⁵ is hydrogen, nitro, halogen, C1-4 alkyl, unsubstituted or substituted with halogen, or C 1-4 alkoxy, unsubstituted or substituted halogen.

Preferably R ⁵ is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen. More preferably R ⁵ is a halogen atom or trifluoromethyl.

In general, R ⁶ is a hydrogen atom, C1-6 alkyl or a halogen atom.

Preferably R ⁶ is hydrogen, methyl or Cl. More preferably R ⁶ is a hydrogen atom.

In general, R ⁷ denotes a hydrogen atom, methyl or a halogen atom.

Preferably R ⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R ⁷ is a hydrogen atom, Br or F.

Especially preferred are combinations of one or more of these groups of compounds.

In a preferred embodiment of the invention, the compound is a compound which has formula I, or a pharmaceutically acceptable salt thereof, or stereoisomers of the form,

,

,

where R ¹ denotes a hydrogen atom,

R ² denotes a hydrogen atom or C1-4-alkyl,

R ³ is hydrogen, C1-6 alkyl, unsubstituted or substituted with 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; C5-7-cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio, or pyridinylalkyl; pyridinyl, unsubstituted or substituted with methoxy; triazolyl; C1-4-alkoxy; or a group of formula -WR ⁸ ,

R ^3a is a hydrogen atom, C1-4 alkyl, or a group of the formula

,

,

or NR ³ R _3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, 4-oxooctahydro-1(2H)-quinolinyl; or formula group

R ⁴ denotes a hydrogen atom,

R ³ denotes a hydrogen atom; nitro; a halogen atom; C1-4-alkyl, unsubstituted or substituted halogen atom; or C1-4-alkoxy, unsubstituted or substituted halogen atom,

R ⁶ is a hydrogen atom, C1-6-allyl or a halogen atom,

R ⁷ denotes a hydrogen atom, methyl or a halogen atom,

W is C1-4 alkylene, unsubstituted or substituted halogen, hydroxy, C1-4 alkyl or alkoxy; -NH-; or -NHC(=O)-;

R ⁸ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from halo, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimidazolyl,

R ¹⁴ is pyridinyl; phenyl, unsubstituted or substituted with halogen, hydroxy, C1-4 alkyl; or a group of formula -VR ¹⁵ ,

V is an unsubstituted C1-4-alkylene,

R ¹⁵ means phenyl or morpholinyl,

m takes values from 1 to 4,

and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen when R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

In a more preferred embodiment of the invention, the compound is of formula I, or is a pharmaceutically acceptable salt or stereoisomeric forms thereof,

,

,

Where

R ¹ denotes a hydrogen atom,

R ² denotes a hydrogen atom, methyl or ethyl,

R ³ denotes a hydrogen atom, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3 -ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2- ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio] benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridine-3- yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1- yl)propyl, 2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2-methylpiperidin-1-yl) ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino,

R ^3a is a hydrogen atom, methyl or tetrahydrofuran-2-ylmethyl, or NR ³ R ^3a , 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4- hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4- yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4- oxooctahydro-1(2H)-quinolinyl,

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro or a halogen atom,

R ⁶ denotes a hydrogen atom, methyl or Cl,

R ⁷ denotes a hydrogen atom, methyl, Br, F or Cl,

and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen when R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

More preferably, R ² is a hydrogen atom or methyl, R ³ is a hydrogen atom, R ^3a is a hydrogen atom, R ⁵ is a halogen atom or trifluoromethyl, R ⁶ is a hydrogen atom, and R ⁷ is a hydrogen atom, Br or F.

Within the above limits, when R ² is C1-C20 alkyl, the carbon atom to which R ² is attached preferably has the "S" configuration.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl)acetamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(7-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; (+)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; (-)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (+)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (-)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (-)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetamide; 5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl)ethyl-1,3-dihydro-2H-indol-2-one; 5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide; 5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-isonicotinoylacetoxyhydrazide; 5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydroquinolin-4(1H)-one; N'-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetoxyhydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide; N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide; 5-chloro-1-{2-oxo-2[4-(2-phenylethyl)piperazin-1-yl]ethyl}-1,3-dihydro-2H-indol-2-one; ethyl {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]amino}acetate; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamide; N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamide; 5-chloro-1-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide; methyl 3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl]acetyl]-1,3-thiazolidine-4-carboxylate; 5-chloro-1-[2-( 2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro -1H-indol-1-yl)-N'-(4,5-dihydro-1H-imidazol-2-yl)acetoxyhydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indole -1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N- [2-(2-chlorophenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl] acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide; 2-(5-chloro-2- oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl]acetamide; 2- (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide;2-(5-chloro-2 -oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1- yl)-N-(3,4-dihydro-1H-isochromen-1-ylmethyl)acetamide;N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro -1H-indole-1 -yl)acetamide; N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide; 5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide; 5-chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; and 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide and 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro- 1H-indol-1-yl)acetamide.

In another embodiment, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide; and (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide.

iv) US Patent No. 7244747:

A compound having formula I or a pharmaceutically acceptable salt thereof

where R ¹ denotes a hydrogen atom, C _1-20 -alkyl, C _3-8 cycloalkyl, halogen atom, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R ² is hydrogen, C _1-20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl;

R ³ is hydrogen, C _1-20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl;

or R ² and R ³ can form the following 1H-benzimidazole ring together with the imidazole ring

R ⁴ is hydrogen, C _1-20 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy, or heterocycle;

R ^4a denotes a hydrogen atom or C _1-20 alkyl;

or R ⁴ and R ^4a may together form C _3-8 cycloalkyl;

R ⁵ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ together with the 2-oxo-1-pyrrolidine ring may form the following 1,3-dihydro-2H-indol-2-one ring.

R ⁶ denotes a hydrogen atom or C _1-20 alkyl;

R ⁷ denotes a hydrogen atom;

or R ⁶ and R ⁷ are linked to each other and form C _3-6 cycloalkyl;

R ⁸ denotes a hydrogen atom, a halogen atom, nitro, cyano, C _1-20 alkyl or alkoxy;

R ⁹ is hydrogen, C _1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹⁰ is hydrogen, C _1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹¹ denotes a hydrogen atom, a halogen atom, nitro, cyano, C _1-20 alkyl or alkoxy;

R ¹² denotes a hydrogen atom or a halogen atom;

R ¹³ is hydrogen, nitro, halogen, heterocycle, amino, aryl, C _1-20 alkyl, unsubstituted or substituted halogen, or alkoxy, unsubstituted or substituted halogen;

R ¹⁴ denotes a hydrogen atom, C _1-20 alkyl or a halogen atom;

R ¹⁵ denotes a hydrogen atom, C _1-20 alkyl or a halogen atom;

with the proviso that R ⁴ is other than a hydrogen atom when it represents a group of formula

.

.

An asterisk * indicates the place of attachment of the substituents.

In a preferred embodiment of this invention, the compounds are of formula I and include their tautomers, geometric isomers (including cis and trans Z- and E-isomers), enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers) or pharmaceutically acceptable salt,

,

,

where R ¹ denotes a hydrogen atom, C _1-20 alkyl, C _3-8 cycloalkyl, halogen atom, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle;

R ² is hydrogen, C _1-20 alkyl, halogen, cyano, ester, carbamate or amido;

R ³ denotes a hydrogen atom, cyano, C _1-20 alkyl, a halogen atom or an ester;

or R ² and R ³ can, together with the imidazole ring, form the following 1H-benzimidazole ring

;

;

R ⁴ denotes a hydrogen atom, C _1-20 alkyl, C _2-12 alkenyl or aryl;

R ^4a represents a hydrogen atom;

R ⁵ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ may, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

R ⁶ denotes a hydrogen atom or C _1-20 alkyl;

R ⁷ denotes a hydrogen atom; or R ⁶ and R ⁷ are linked to each other and form C _3-6 cycloalkyl;

R ⁸ denotes a hydrogen atom;

R ⁹ denotes a hydrogen atom, C _1-20 alkyl, halogen atom or alkoxy;

R ¹⁰ denotes a hydrogen atom, C _1-20 alkyl, a halogen atom or cyano;

R ¹¹ denotes a hydrogen atom;

R ¹² denotes a hydrogen atom or a halogen atom;

R ¹³ denotes a hydrogen atom, a halogen atom, a heterocycle or C _1-20 alkyl;

R ¹⁴ denotes a hydrogen atom;

R ¹⁵ denotes a hydrogen atom;

provided that R ⁴ is other than a hydrogen atom, when

is a group of formula

The term "alkyl" as used herein means saturated monovalent hydrocarbon radicals having a straight (straight) or branched or cyclic structure, or combinations thereof, and containing 1-20 carbon atoms, preferably 1-10 carbon atoms; more preferably, the alkyl groups contain 1-3 carbon atoms. Alkyl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. Typically in this specification, alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, ( 4-chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, azidomethyl or trifluoromethyl. The most preferred alkyl groups are methyl or n-propyl.

The term "cycloalkyl", as used herein, means a monovalent group containing from 3 to 8 carbon atoms, usually containing 3-6 carbon atoms, which is derived from a saturated cyclic hydrocarbon and may be substituted by any suitable group, including, but not limited to one or more substituents selected from the group described above for alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

The term "alkenyl" as used herein refers to straight, branched or cyclic unsaturated hydrocarbon radicals, or combinations thereof, which have at least one carbon-carbon double bond containing 2-12 carbon atoms, preferably containing 2-4 carbon atoms. Alkenyl groups are optionally substituted with any suitable group including, but not limited to, one or more substituents selected from the group described above for alkyl groups. Typically, the alkenyl group is ethenyl (vinyl) optionally substituted with 1 to 3 halogen atoms. In this case, the preferred alkenyl group is 2,2-difluorovinyl.

The term "alkynyl" as used herein means straight, branched or cyclic hydrocarbon radicals, or combinations thereof, which have at least one carbon-carbon triple bond containing 2-12 carbon atoms, preferably containing 2-6 carbon atoms and optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from the group described above for alkyl groups. Typically, the alkenyl group is a haloalkynyl group (haloalkynyl group).

Groups that are defined by prefixes such as "second", "iso", "tert", etc. (eg "isopropyl", "sec-butyl") are branched derivatives.

The term "aryl" is defined herein as phenyl optionally substituted with 1 to 4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C _1-3 alkyl or azido, preferably halogen or azido. Usually in this case, aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4 -trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferably, the aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. The most preferred aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5 -trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term "heterocycle" is defined herein as including an aromatic or non-aromatic cycloalkyl moiety, as defined above, having at least one O, S and/or N atom that interrupts the carbocyclic ring structure. Heterocyclic ring fragments may be substituted with alkyl groups or halogen atoms, and optionally one of the carbon atoms in the carbocyclic ring structure may be substituted with a carbonyl. Usually heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl, 1-methyl-1H-pyrrole -2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazole -4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 4-methyl -1H-imidazol-5-yl or 2-methyl-1,3-thiazol-4-yl. Preferred heterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrole -2-yl, 1H-pyrrol-2-yl.

The term "halogen atom" as used herein includes chlorine, bromine, fluorine and iodine. Typically, halogen atoms are chlorine, bromine and fluorine. Preferred halogen atoms are fluorine, bromine and chlorine.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "alkoxy" as used herein means a group of the formula -OR ^a , where R ^a is an alkyl group as defined above. The preferred alkoxy group is methoxy.

The term "aryloxy" as used herein means a group of the formula -OR ^b , where R ^b is an aryl group as defined above. A preferred aryloxy group is phenoxy.

The term "ester" as used herein means a group of the formula -COOR ^c , where R ^c is an alkyl group or an aryl group as defined above. A preferred ester group is methoxycarbonyl.

The term "amido" as used herein refers to a group of the formula -CONH ₂ .

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "amino derivative" as used herein means an alkylamino group or an arylamino group, where the meanings of the terms "alkyl" and "aryl" are defined above.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "guanidine" as used herein refers to a group of the formula -NHC(=NH)NH ₂ .

The term "alkylthio" as used herein means a group of the formula -SR ^d , where R ^d is an alkyl group as defined above. A preferred alkylthio group is methylthio.

The term "alkylsulfonyl" as used herein means a group of the formula -S(=O) ₂ R ^e , where R ^e is an alkyl group as defined above. A preferred alkylsulfonyl group is methylsulfonyl.

The term "alkylsulfinyl" as used herein means a group of the formula -S(=O)R ^f , where R ^f is an alkyl group as defined above. A preferred alkylsulfinyl group is methylsulfinyl.

The term "arylthio" as used herein means a group of the formula -SR ^g , where R ^g is an aryl group as defined above.

The term "arylsulfonyl" as used herein means a group of formula -S(=O) ₂ R ^h , where R ^h is an aryl group as defined above.

The term "arylsulfinyl", as used herein, denotes a group of the formula -S(=O)R ⁱ , where R ⁱ is an aryl group as defined above.

The term "carbamate" as used herein means a group of the formula -N(H)C(O)OR ^j , where R ^j is alkyl or aryl, as defined above. Typically, the carbamate groups are (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. A preferred carbamate group is (benzyloxycarbonyl)amino.

The term "alkanoylamino" as used herein means a group of the formula -NHC(=O)R ^k , where R ^k is an alkyl group as defined above.

The term "(arylcarbonyl)amino" as used herein means a group of the formula -NHC(=O)R ^m , where R ^m is an aryl group as defined above. The preferred (arylcarbonyl)amino is benzoylamino.

Usually R ¹ denotes a hydrogen atom; C _1-10 alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy; C _3-6 -cycloalkyl; a halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; a heterocycle unsubstituted or substituted with alkyl groups; or guanidine. Preferably R ¹ is a hydrogen atom; methyl; ethyl; iso-propyl; n-propyl; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl, chlorine atom; bromine atom; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably R ¹ is a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; a chlorine atom or 1H-pyrrol-2-yl. Most preferably R ¹ is a hydrogen atom; methyl; methylthio; nitro; cyano; amino or chlorine atom.

Usually R ² denotes a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; a halogen atom; ester; cyano, alkyl carbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably R ² is a hydrogen atom; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; [(benzyloxy)carbonyl]amino; a chlorine or cyano atom. More preferably R ² is a hydrogen atom; a chlorine or cyano atom.

Usually R ³ denotes a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with hydroxy; a halogen atom; ester or cyano. Preferably R ³ is a hydrogen atom; hydroxymethyl; a chlorine atom; cyano. More preferably R ³ is hydrogen or cyano. Most preferably R ³ is a hydrogen atom.

Usually R ⁴ denotes a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with halogen atoms; C _2-4 alkenyl substituted with halogen atoms or a phenyl group which is unsubstituted or substituted with azido and/or halogen atoms. Preferably R ⁴ is a hydrogen atom; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. More preferably R ⁴ is a hydrogen atom; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably R ⁴ is n-propyl; 2,2-difluorovinyl; phenyl, 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

Usually R ^4a represents a hydrogen atom.

Usually R ⁵ denotes a hydrogen atom.

Usually R ⁶ denotes a hydrogen atom or C _1-10 alkyl, unsubstituted or substituted with hydroxy or azido. Preferably R ⁶ is hydrogen or azidomethyl. More preferably R ⁶ is a hydrogen atom.

Usually R ⁷ denotes a hydrogen atom.

In other preferred embodiments of the invention, R ⁶ and R ⁷ are linked to each other to form cyclopropyl.

In other preferred embodiments, R ² and R ³ together with the imidazole ring may form the following 1H-benzimidazole ring

Usually R ⁸ denotes a hydrogen atom.

Usually R ⁹ denotes a hydrogen atom; a halogen atom; C _1-3 alkyl or alkoxy. Preferably R ⁹ is a hydrogen atom; methyl; chlorine or methoxy. More preferably R ⁹ is a hydrogen atom.

Usually R ¹⁰ denotes a hydrogen atom; a halogen atom; cyano; C1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy. Preferably R ¹⁰ is methyl, hydrogen atom, trifluoromethyl, fluorine atom, cyano or methoxy. More preferably R ¹⁰ is hydrogen, trifluoromethyl, fluorine or cyano.

Usually R ¹¹ denotes a hydrogen atom.

In other preferred embodiments of the invention, R ⁴ , R ^4a and R ⁵ can, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

Usually R ¹² denotes a hydrogen atom or a halogen atom. Preferably R ¹² is a hydrogen atom, a chlorine atom or a fluorine atom. More preferably R ¹² is a hydrogen atom.

Usually R ¹³ denotes a hydrogen atom; C _1-3 alkyl; a halogen atom; or a thiazolyl unsubstituted or substituted with alkyl groups, such as methylthiazolyl. Preferably R ¹³ is a hydrogen atom; a chlorine atom; bromine atom or methyl. Most preferably R ¹³ is a chlorine atom; bromine atom or methyl.

Usually R ¹⁴ denotes a hydrogen atom.

Usually R ¹⁵ denotes a hydrogen atom.

Most preferred are combinations of one or more of these functional groups.

Generally, among the embodiments of this invention, the compounds of formula I or their pharmaceutically acceptable salts are compounds in which

R ¹ is selected from a hydrogen atom; C _1-10 alkyl, unsubstituted or substituted with a halogen atom, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C _3-6 cycloalkyl; a halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; a heterocycle unsubstituted or substituted with an alkyl group; or guanidine;

R ² is selected from a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; a halogen atom; ester; cyano; alkylcarbamate; or [(N-methoxy-N-methyl)amino]carbonyl.

R ³ is selected from hydrogen, C _1-4 alkyl, unsubstituted or substituted with hydroxy; a halogen atom; ester or cyano;

R ⁴ is selected from a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with halogen atoms; C _2-4 alkenyl substituted with halogen atoms, or a phenyl group unsubstituted or substituted with azido and/or halogen atoms;

R ^4a represents a hydrogen atom;

R ⁵ denotes a hydrogen atom;

R ⁶ is selected from hydrogen or C _1-10 alkyl, unsubstituted or substituted with hydroxy, or azido;

R ⁷ denotes a hydrogen atom;

or R ⁶ and R ⁷ may be linked together to form cyclopropyl;

or R ² and R ³ can, together with the imidazole ring, form the following 1H-benzimidazole ring

R ⁸ denotes a hydrogen atom;

R ⁹ is selected from hydrogen atom, halogen atom, C _1-3 alkyl, alkoxy;

R ¹⁰ is selected from a hydrogen atom; a halogen atom; cyano or C _1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy;

R ¹¹ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ may, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

R ¹² is selected from a hydrogen atom or a halogen atom;

R ¹³ is selected from a hydrogen atom; C _1-3 alkyl; a halogen atom; thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl;

R ¹⁴ denotes a hydrogen atom;

R ¹⁵ denotes a hydrogen atom;

provided that R ⁴ is other than a hydrogen atom, when

is a group of formula

In a preferred embodiment of the invention, the compounds of formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R ¹ is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, trifluoromethyl, 2,2,2-trifluoroethyl , hydroxymethyl, chloromethyl, cyanomethyl, 2-(methylthio)ethyl, chlorine atom, bromine atom, nitro, cyano, amino, aminocarbonyl, methoxycarbonyl, methylthio, methylsulfinyl, methylsulfonyl, phenyl, 2-furyl, 3-furyl; 1H-pyrrol-2-yl, 1-methyl-1H-pyrrol-2-yl, 2-thienyl, 1H-pyrazol-3-yl, 1,2,3-thiadiazol-4-yl or 1H-imidazol-2- silt;

R ² is selected from hydrogen, methyl, hydroxymethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (benzyloxycarbonyl)amino, chlorine or cyano;

R ³ is selected from hydrogen, hydroxymethyl, chlorine, cyano;

or R ² and R ³ together with the imidazole ring can form the following 1H-benzimidazole ring

R ⁸ denotes a hydrogen atom;

R ⁹ is selected from a hydrogen atom; methyl; a chlorine atom; methoxy;

R ¹⁰ is selected from methyl; a hydrogen atom; trifluoromethyl; a fluorine atom; cyano; or methoxy;

R ¹¹ denotes a hydrogen atom;

R ⁴ is selected from hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 3-chloro -4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl, or 3- azido-2,4,6-trifluorophenyl.

R ^4a represents a hydrogen atom;

R ⁵ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ may, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

R ¹² is selected from a hydrogen atom, a chlorine atom, a fluorine atom;

R ¹³ is selected from hydrogen atom, chlorine atom, bromine atom, methyl;

R ¹⁴ denotes a hydrogen atom;

R ¹⁵ denotes a hydrogen atom;

R ⁶ is selected from hydrogen, azidomethyl;

R ⁷ denotes a hydrogen atom;

or R ⁶ and R ⁷ are linked to each other to form cyclopropyl;

provided that R ⁴ is other than a hydrogen atom, when

is a group of formula

In a more preferred embodiment of the present invention, the compounds of formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R ¹ is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, methylthio, nitro, cyano, amino, chlorine or 1H-pyrrol-2-yl;

R ² is selected from hydrogen atom, chlorine atom, cyano;

R ³ is selected from hydrogen, cyano;

or R ² and R ³ together with the imidazole ring can form the following 1H-benzimidazole ring

R ⁸ denotes a hydrogen atom;

R ⁹ denotes a hydrogen atom;

R ¹⁰ is selected from hydrogen, trifluoromethyl, fluorine, cyano;

R ¹¹ denotes a hydrogen atom;

R ⁴ is selected from hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 3-chloro -4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl;

R ^4a represents a hydrogen atom;

R ⁵ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ may, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

,

,

Where

R ¹² denotes a hydrogen atom;

R ¹³ is selected from methyl, chlorine atom, bromine atom;

R ¹⁴ denotes a hydrogen atom;

R ¹⁵ denotes a hydrogen atom;

R ⁶ denotes a hydrogen atom;

R ⁷ denotes a hydrogen atom;

provided that R4 is other than a hydrogen atom, when

is a group of formula

In the most preferred embodiment of this invention, the compounds of formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R ¹ is selected from hydrogen, methyl, methylthio, nitro, cyano, amino, chlorine;

R ² is selected from hydrogen atom, chlorine atom, cyano;

R ³ denotes a hydrogen atom;

R ⁴ is selected from n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl;

R ^4a represents a hydrogen atom;

R ⁵ denotes a hydrogen atom;

or R ⁴ , R ^4a and R ⁵ may, together with the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring

R ¹² denotes a hydrogen atom;

R ¹³ is selected from chlorine atom, bromine atom, methyl;

R ¹⁴ denotes a hydrogen atom;

R ¹⁵ denotes a hydrogen atom;

R ⁶ denotes a hydrogen atom;

R ⁷ denotes a hydrogen atom.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-t-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide, 4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2- He; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; methyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,54-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; benzyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamate; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl]methyl]propanamide; 1-(1H-benzimidazole -1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2 -propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl- 1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidine -2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl] methyl}-4-propylpyrrolidin-2-one;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetonitrile;1-[(5-methoxy-1H -benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5 ,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4 -propylpyrrolidin-2-one;1-[(6- chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl]methyl]-4-propylpyrrolidin-2-one; 1-{[6-methyl-2-(1H-pyrrol-2-yl) -1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one ; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-{[2-[2-(methylthio)ethyl]-5-( trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2 -one; 1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 2-cyclopropyl-1-[( 2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazole-3 -yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro -2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl} -4-propylpyrrolidin-2-one, 1-[(2-cyclopro pyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile; 1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(2-oxo-2,3-dihydro-1H-indol-1-yl]methyl]-1H-imidazole-5-carbonitrile; and 1-[(5-chloro-2-oxo-2,3- dihydro-1H-indol-1-yl]methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1 -ylmethyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)- 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl]-1-(1H-imidazol-1-ylmethyl]pyrrolidin-2- he; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4- propylpyrrolidin-2-one, 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one, 4-propyl-1-[(2-propyl-1H-imidazol-1 -yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(-)-1-(1H-imidazol-1-ylmethyl) -4-propylpyrrolidin-2-one, 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 4-(3-chlorophenyl)-1-(1H-imidazole) -1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl]pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl]pyrrolidin-2- it;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1- ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2, 3,4-trifluorophenyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl]pyrrolidin-2-one, 1-(1H-imidazol-1- ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl] pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl]pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino- 1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one, 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidine -2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4 -(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyr olidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group that includes: 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group that includes: (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazole- 1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

v) International patent application WO 2007/065595:

Compounds having formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers) or their pharmaceutically acceptable salts,

Where

R ¹ denotes a hydrogen atom or C _1-6 alkyl;

R ² denotes a hydrogen atom or C _1-4 alkyl;

R ³ is a group of formula -CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle;

R ⁵ is C2-4 alkyl;

R ⁶ is C2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ is C1-4 alkyl.

Typically, when R ³ is a benzyl group, then R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl.

Typically, when R ³ is a group of formula -CHR ⁵ R ⁶ , then R ⁴ is C _1-8 alkyl optionally substituted with C _3-6 cycloalkyl, aryl, or heterocycle.

The term "alkyl" as used herein means a group which is a saturated monovalent hydrocarbon radical having linear (straight) or branched fragments, or combinations thereof, and containing 1-8 carbon atoms, preferably 1-6 carbon atoms; more preferably, alkyl groups have 1-4 carbon atoms. The alkyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl groups may optionally be substituted with cycloalkyl as defined below. Preferred alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, isobutyl, n-pentyl, 3- pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, ( 3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3 -nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. The most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

The term "cycloalkyl" as used herein means a monovalent group which contains 3 to 8, preferably 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or several fragments selected from the group described for alkyl groups. A preferred cycloalkyl group is cyclohexyl.

The term "aryl" as used herein means a phenyl group optionally substituted with 1 to 4 substituents independently selected from halogen, amino, nitro, alkoxy, or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term "phenyl" as used herein refers to an aromatic hydrocarbon group of the formula -C ₆ H ₅ .

The term "benzyl group" in this description means a group of the formula -CH ₂ -aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-aminobenzyl. The most preferred alkyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

The term "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The preferred halogen atom is a bromine atom.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "ethynyl" as used herein refers to a group of the formula -C≡CH.

The term "alkoxy" as used herein means a group of the formula -OR ^a , where R ^a is an alkyl group as defined above. The preferred alkoxy group is methoxy.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "amido" as used herein refers to a group of the formula -C(=O)NH ₂ .

The term "acyl" as used herein means a group of the formula -C(=O)R ^b , where R ^b is an alkyl group as defined above. The preferred acyl group is acetyl (-C(=O)Me).

The term "alkoxycarbonyl (or ester)" as used herein means a group of the formula -COOR ^c , where R ^c is an alkyl group; with the proviso that R ^c is not alkyl substituted at the alpha position with hydroxy. A preferred alkoxycarbonyl group is ethoxycarbonyl.

The term "heterocycle" as used herein means a 5-membered ring containing one or two heteroatoms selected from an O or N atom. The heterocycle may be substituted with one or two C _1-4 alkyls or nitro. Preferred heterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). The most preferred heterocycle is (5-nitro-2-furyl).

In general, R ¹ is a hydrogen atom or C _1-6 alkyl. Usually R ¹ denotes a hydrogen atom or C 1-6 alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. Preferably R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferably R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl. Most preferably R ¹ is a hydrogen atom.

In general, R ² is a hydrogen atom or C _1-4 alkyl. Usually R ² denotes a hydrogen atom or unsubstituted C _1-4 alkyl. Preferably, R ² denotes a hydrogen atom, methyl or n-butyl. More preferably R ² is methyl.

In general, R ³ is a group of formula -CHR ⁵ R ⁶ or a benzyl group. Preferably R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl. Most preferably R ³ is 1-(ethoxycarbonyl)propyl.

In general, R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl, or heterocycle. Typically, R ⁴ is C _1-8 alkyl optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. Preferably, R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-( aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferably, R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro- 2-furyl)methyl or 1-(ethoxycarbonyl)propyl. Most preferably R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

In general, R ⁵ is C _2-4 alkyl. Usually R ⁵ denotes unsubstituted C _2-4 alkyl. Preferably R ⁵ is ethyl.

In general, R ⁶ is C _2-4 alkyl, amido or —COOR ⁷ . Typically R ⁶ is unsubstituted C _2-4 alkyl, amido or —COOR ⁷ . Preferably R ⁶ is ethyl, amido or ethoxycarbonyl. Most preferably R ⁶ is ethoxycarbonyl.

In general, R ⁷ is C _1-4 alkyl. Typically R ⁷ is unsubstituted C _1-4 alkyl. Preferably R ⁷ is ethyl.

In some embodiments of this invention, the compounds are those compounds having formula I, and their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or their pharmaceutically acceptable salts,

,

,

Where

R ¹ denotes a hydrogen atom, C _1-6 alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl;

R ² denotes a hydrogen atom or unsubstituted C _1-4 alkyl;

R ³ is a group of formula -CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl;

R ⁵ is unsubstituted C _2-4 alkyl;

R ⁶ is unsubstituted C _2-4 alkyl, amido or —COOR ⁷ ;

R ⁷ is unsubstituted C _1-4 alkyl;

provided that when R ¹ is hydrogen, R ² is methyl, R ³ is —CHR ⁵ R ⁶ , R ⁶ is ethoxycarbonyl and R ⁵ is ethyl, then R ⁴ is other than n-propyl, isopropyl, n-pentyl , n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2-phenylethyl.

In the above embodiment of the invention, preferably when R ³ is a benzyl group, then R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl.

In the above embodiment of the invention, preferably when R ³ is a group of formula -CHR ⁵ R ⁶ , then R ⁴ is C _1-8 alkyl optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

In a preferred embodiment of the invention,

R ¹ denotes a hydrogen atom, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl;

R ² denotes a hydrogen atom, methyl or n-butyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, iso-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-( aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R ¹ is hydrogen, R ² is methyl, and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than n-pentyl, 3-bromobenzyl or 2-phenylethyl.

In the above embodiment of the present invention, preferably when R ³ is 3-bromobenzyl, then R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl.

In the above embodiment of the present invention, preferably, when R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment of the invention,

R ¹ denotes a hydrogen atom, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R ² is methyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl )methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R ¹ is hydrogen, R ² is methyl, and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 3-bromobenzyl.

In the above embodiment of the invention, preferably when R ³ is 3-bromobenzyl then R ⁴ is 1-(ethoxycarbonyl)propyl.

In the above embodiment of the present invention, preferably, when R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1-(ethoxycarbonyl)propyl.

In the most preferred embodiment of this invention,

R ¹ denotes a hydrogen atom;

R ² is methyl;

R ³ is 1-(ethoxycarbonyl)propyl;

and R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Another embodiment of this invention includes compounds in which R ² is methyl, R ³ is a group of formula -CHR ⁵ R ⁶ where R ⁵ is C _2-4 alkyl and R ⁶ is amido or -COOR ⁷ , and R ⁷ is methyl or ethyl.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group that includes: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3, 6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8 -yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate ; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl} thio)butanoate; ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl]butanoate; and ethyl 2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group that includes: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3, 6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate ; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl} thio)butanoate; ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; and ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, compounds suitable for use in the methods and compositions of this invention are selected from the group consisting of: ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2, 3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; and ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio )butanoate.

In some embodiments, the compounds of the invention are compounds having formula II, their enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or their pharmaceutically acceptable salts:

,

,

where R ¹ denotes a hydrogen atom or C _1-6 alkyl;

R ² denotes a hydrogen atom or C _1-4 alkyl;

R ³ is a group of the formula CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ denotes a hydrogen atom or C _1-4 alkyl;

R ⁶ is C _1-4 alkyl, amido or —COOR ⁷ ;

R7 is C _1-4 alkyl.

In the embodiment of the present invention described above, in some cases where R ³ is a benzyl group, R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl.

In the above embodiment of the present invention, in some cases where R ³ is a group of formula -CHR ⁵ R ⁶ , R ⁴ is C _1-8 alkyl optionally substituted with C _3-6 cycloalkyl, aryl, or heterocycle.

In some embodiments, the compounds of the invention are compounds having formula II, their enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or their pharmaceutically acceptable salts:

,

,

Where

R ¹ denotes a hydrogen atom or C _1-6 alkyl;

R ² denotes a hydrogen atom or C _1-4 alkyl;

R ³ is a group of the formula CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ denotes a hydrogen atom or C _1-4 alkyl;

R ⁶ is C _1-4 alkyl, amido or —COOR ⁷ ;

R7 is C _1-4 alkyl.

In some embodiments, the compounds of the invention are compounds of formula II selected from ethyl 2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8- yl)thio]butanoate; 7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purine-2,6-dione; ethyl 2-[(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate; ethyl 2-[(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; and ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}propanoate.

In some embodiments, the compounds of the invention are compounds having formula I, their enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or their pharmaceutically acceptable salts:

,

,

Where

R ¹ denotes a hydrogen atom or C _1-6 alkyl;

R ² denotes a hydrogen atom or C _1-4 alkyl;

R ³ is a group of the formula CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ is C _2-4 alkyl;

R ⁶ is C _2-4 alkyl, amido or —COOR ⁷ ;

R7 is C _1-4 alkyl.

In another embodiment, the compounds of the invention are compounds having formula II, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers) or their pharmaceutically acceptable salts:

,

,

Where

R ¹ denotes a hydrogen atom or C _1-6 alkyl;

R ² denotes a hydrogen atom or C _1-4 alkyl;

R ³ is a group of the formula CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ denotes a hydrogen atom or C _1-4 alkyl;

R ⁶ is C _1-4 alkyl, amido or —COOR ⁷ ;

R7 is C _1-4 alkyl.

vi) International Patent Publication WO 2010/144712

In one embodiment of the present invention, a chemical composition is disclosed that includes a LEV derivative of formula 1 or formula 2

The variables n in formula 2, and the variables L, X and Y in formulas 1 and 2, are defined as follows: a) n is an integer that takes values from 0 to 8; b) L is included in the group consisting of CH ₂ , CO, NHCO, NHCOO, CONH, NH, O or S and combinations thereof; c) X is a terminal group, an aromatic group, an aryl group, or a saturated, unsaturated, substituted, unsubstituted straight or branched chain aliphatic group containing from 1 to 10 carbon atoms and/or heteroatoms in the chain, the heteroatoms in the heterochain being selected from a group that includes an oxygen, nitrogen, sulfur or phosphorus atom, as well as combinations thereof; and d) Y is optional and, if present, represents one of the functional groups selected from the group consisting of alcohol, amine, amide, carboxylic acid, aldehyde, ester, iminoester, isocyanate, isothiocyanate, anhydride, thiol, thiolacetone, diazonium , NHS, CO-NHS, O-NHS, maleimido, or e) Y is Yi-Z, where Yi is selected from the group that includes COO, CO, O, CONH, NHCO or NH and Z is an operating group.

In one embodiment of the method according to the invention, the operational group Z is selected from the group that includes detectable labels, antigenic carriers, condensing agents, end groups, proteins, lipoproteins, glycoproteins, polypeptides, polysaccharides, nucleic acids, polynucleotides, teichoic acids, radioactive isotopes, enzymes , enzyme fragments, enzyme donor fragments, enzyme acceptor fragments, enzyme substrates, enzyme inhibitors, coenzymes, fluorescent fragments, phosphorescent fragments, anti-Stokes activating agents, chemiluminescent fragments, luminescent fragments, dyes, sensitizers, particles, microparticles, magnetic particles, solid carriers, liposomes, ligands, receptors, haptens for radioisotope research and combinations thereof.

vii) International patent publication WO 2010/002869

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z is independently selected from hydrogen and deuterium; R1 is an n-propyl group which contains from zero to seven deuterium atoms; R2 is an ethyl group that contains zero to five deuterium atoms, and when each R contains zero deuterium atoms, then at least one Z is deuterium.

In one embodiment, the present invention provides compounds of formula I, where R1 is selected from CD ₃ CH ₂ CH ₂ -, CD ₃ CD ₂ CH ₂ -, CD ₃ CH ₂ CD ₂ -, CH ₃ CH ₂ CD ₂ -, CH ₃ CD ₂ CD ₂ -, CD ₃ CD ₂ CD ₂ - or CH ₃ CH ₂ CH ₂ -. In a more specific embodiment of the invention, R1 is CD ₃ CD ₂ CD ₂ - or CD ₃ CD ₂ CH ₂ -. In accordance with one aspect of these embodiments of the present invention, Z1 and Z2 both represent a hydrogen atom. According to another aspect of said embodiments of the present invention, Z1 and Z2 are both deuterium.

In another embodiment, R ² is selected from CH ₃ CH ₂ -, CD ₃ CH ₂ -, CH ₃ CD ₂ - or CD ₃ CD ₂ -. In a more specific embodiment of the invention, R2 is selected from CH ₃ CH ₂ - or CD ₃ CD ₂ -. In accordance with one aspect of these embodiments of the invention, Z1 and Z2 both represent a hydrogen atom. In accordance with another aspect of these embodiments of the invention, Z1 and Z2 are both deuterium.

R and Z are variables, the values of which are described above, and can be chosen and taken together, allowing for more specific embodiments of the present invention. For example, in one embodiment of this invention, R1 is CD ₃ CH ₂ CH ₂ -, CD ₃ CD 2 CH 2 -, CD 3 CH _{2 CD 2} -, CH ₃ CH ₂ CD _{2 -} , _{CH 3 CD 2} CD ₂ -, CD ₃ CD ₂ CD ₂ - or CH ₃ CH ₂ CH ₂ -; a R2 is selected from CH ₃ CH ₂ -, CD ₃ CH ₂ -, CH ₃ CD ₂ - or CD ₃ CD ₂ -. According to one aspect of said embodiment of the invention, R ² is CH ₃ CH ₂ - or CD ₃ CD ₂ -.

In another embodiment of the invention, R1 is CD ₃ CD ₂ CD ₂ - or CD ₃ CD ₂ CH ₂ - and R2 is selected from CH ₃ CH ₂ -, CD ₃ CH ₂ -, CH ₃ CD ₂ - or CD ₃ CD ₂ -. According to one aspect of said embodiment, R2 is CH ₃ CH ₂ - or CD ₃ CD ₂ -.

Examples of specific compounds of this invention include the following compounds:

viii) 20090312333

The compounds of this invention are those covered by formula (I), their diastereomers and mixtures thereof, or a pharmaceutically acceptable salt thereof.

(I)

R1 is a hydrogen atom, a substituted or unsubstituted C1-12 alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted (3-8)-membered heterocycle.

R2 represents a hydrogen atom. Alternatively, R1 and R2 may be combined with each other to form a C3-6 cycloalkyl.

R3 means either

(a) a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its carbon atoms, said heterocycle being selected from the group consisting of:

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-7-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl;

or R3 stands for

b) a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its N atoms, said heterocycle being selected from the group consisting of:

1H-1,2,3-benzotriazol-1-yl;

1H-imidazo[4,5-b]pyridin-1-yl;

3H-imidazo[4,5-b]pyridin-3-yl;

7H-imidazo[4,5-c]pyridazin-7-yl;

1H-indol-1-yl;

2,3-dihydro-1H-indol-1-yl;

9H-purin-9-yl;

1H-pyrazolo[3,4-b]pyridin-1-yl;

2H-pyrazolo[3,4-b]pyridin-2-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

3,4-dihydroquinolin-1(2H)-yl;

8H-isothiazolo[5,4-b]indol-8-yl;

1H-1,2,4-triazol-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group consisting of or which includes a hydrogen atom; C1-12 alkyl, optionally substituted halogen, C1-4 alkoxy, C1-4 alkylthio, azido, nitrooxy, or aryl; C2-12 alkenyl, an optionally substituted halogen atom; C2-12 alkynyl, an optionally substituted halogen atom; azido; alkoxycarbonylamino; arylsulfonyloxy substituted or unsubstituted with aryl; or (3-8)-membered substituted or unsubstituted heterocycle.

In a particular embodiment of this invention, R4 is a hydrogen atom; or R4 is C1-12 alkyl or C1-6 alkyl, optionally substituted halogen, C1-4 alkoxy, C1-4 alkylthio, azido or nitrooxy; or R4 is C2-12 alkenyl or C1-6 alkenyl, an optionally substituted halogen atom; or R4 is C2-12 alkynyl or C1-6 alkynyl, optionally substituted with a halogen atom; or R4 is alkoxycarbonylamino.

R5 denotes a hydrogen atom.

Alternatively, R4 together with R5 and the 2-oxo-1-pyrrolidine ring can form a 1,3-dihydro-2H-indol-2-one ring with the following structure:

An asterisk * indicates the place of attachment of the substituents.

R6 represents a hydrogen atom or a halogen atom.

R7 in formula (I) is selected from the group consisting of or which includes a hydrogen atom; nitro; a halogen atom; heterocycle; amino; aryl; C1-12 alkyl optionally substituted with at least one halogen atom; or C1-12 alkoxy optionally substituted with at least one halogen atom.

R8 in formula (I) is selected from or includes a hydrogen atom, C1-12 alkyl optionally substituted with a halogen atom, or a halogen atom.

R9 in formula (I) is selected from or includes a hydrogen atom, C1-12 alkyl optionally substituted with a halogen atom, or a halogen atom.

Another aspect of this invention relates to compounds of formula (I), in which:

R1 and R2 both represent a hydrogen atom.

R3 is:

(a) a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its carbon atoms, which is selected from the group consisting of:

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-7-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl.

Alternatively, R3 stands for:

(b) a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its N atoms, which is selected from the group consisting of:

1H-1,2,3-benzotriazol-1-yl;

1H-imidazo[4,5-b]pyridin-1-yl;

3H-imidazo[4,5-b]pyridin-3-yl;

7H-imidazo[4,5-c]pyridazin-7-yl;

1H-indol-1-yl;

2,3-dihydro-1H-indol-1-yl;

9H-purin-9-yl;

1H-pyrazolo[3,4-b]pyridin-1-yl;

2H-pyrazolo[3,4-b]pyridin-2-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

3,4-dihydroquinolin-1(2H)-yl;

8H-isothiazolo[5,4-b]indol-8-yl;

1H-1,2,4-triazol-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group consisting of or which includes a hydrogen atom; C1-12 alkyl optionally substituted with halo or C1-4 alkoxy; C2-12 alkenyl optionally substituted with a halogen atom; C2-12 alkynyl optionally substituted with a halogen atom.

In yet another specific embodiment of this invention, R4 is n-propyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-difluorovinyl.

In another specific embodiment of this invention, R4 is phenyl, 2,3,5-trifluorophenyl or 3-chloro-4-fluorophenyl.

R5 denotes a hydrogen atom.

Another embodiment of this invention includes compounds of formula (I) wherein R4 together with R5a forms a 1,3-dihydro-2H-indol-2-one ring

The asterisk * denotes the site of attachment of the heteroaryl alkylene substituent, and where

R6 represents a hydrogen atom;

R7 represents a chlorine atom;

R8 is a hydrogen atom;

R9 denotes a hydrogen atom.

Another embodiment of this invention includes compounds of formula (I) wherein R3 is a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its carbon atoms and selected from the group consisting of:

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl.

In yet another specific embodiment of this invention, R3 is a heterocycle linked to the rest of the molecule through one of its carbon atoms, which is selected from the group consisting of:

imidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-pyrazol-4-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1,3-thiazol-5-yl.

Said heterocycles are optionally substituted with e.g. , 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

In yet another specific embodiment of this invention, R3 is a heterocycle, is linked to the rest of the molecule through one of its carbon atoms, and is selected from the group consisting of: 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl , 6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl, 6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl, 6 -chlorimidazo[2,1-b][1,3]thiazol-5-yl, 2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1H-imidazole -4-yl, 5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl, 4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1 -methyl-1H-imidazol-5-yl, 4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl .

Another embodiment of the present invention includes compounds of formula (I) wherein R3 is a heterocycle linked to the rest of the molecule through one of its carbon atoms and is substituted or unsubstituted imidazo[1,2-a]pyridin-3-yl.

Said imidazo[1,2-a]pyridin-3-yl is optionally substituted with, for example, methyl, cyclopropyl, bromine atom, chlorine atom, fluorine atom, iodine atom.

In yet another specific embodiment of this invention, R3 is a heterocycle linked to the rest of the molecule through one of its carbon atoms and selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1 ,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

Another embodiment of this invention includes compounds of formula (I) wherein R3 is a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its nitrogen atoms, which is selected from the group consisting of:

3H-imidazo[4,5-b]pyridin-3-yl;

1H-indol-1-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

Yet another specific embodiment of this invention includes compounds of formula (I) wherein R3 is a heterocycle linked to the rest of the molecule through one of its nitrogen atoms, which is selected from the group consisting of:

3H-imidazo[4,5-b]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

Said heterocycles may be optionally substituted with trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In yet another specific embodiment of this invention, R3 is a heterocycle linked to the rest of the molecule through one of its carbon atoms, which is selected from the group consisting of: 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridine -3-yl, 6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2,5-dichloro -1H-pyrrol-1-yl, 2-chloro-5-methoxy-1H-benzimidazol-1-yl, 5-bromo-2-chloro-1H-benzimidazol-1-yl or 2,5-dichloro-1H-benzimidazole -1-yl.

Another embodiment of the present invention includes compounds of formula (I), where R1, R2 and R5 represent a hydrogen atom.

R4 is C1-6 alkyl optionally substituted with a halogen atom, C2-6 alkenyl optionally substituted with a halogen atom, or C2-12 alkynyl optionally substituted with a halogen atom.

R3 is selected from the group that includes:

imidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-pyrazol-4-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1,3-thiazol-5-yl;

and optionally substituted with methyl, n-propyl, trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino, cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl , cyano, phenyl, benzyl or 3-thienyl.

Another embodiment of the present invention includes compounds of formula (I), where R1, R2 and R5 represent a hydrogen atom.

R4 is C1-6 alkyl optionally substituted with a halogen atom, C2-6 alkenyl optionally substituted with a halogen atom, or C2-12 alkynyl optionally substituted with a halogen atom.

R3 is selected from the group that includes:

3H-imidazo[4,5-b]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl;

optionally substituted with trifluoromethyl, cyclopropyl, bromine atom, chlorine atom, fluorine atom, methoxy or cyano.

Another embodiment of the present invention includes compounds of formula (I), diastereomers thereof and mixtures thereof, or a pharmaceutically acceptable salt thereof.

R1, R2 and R5 represent a hydrogen atom.

R3 is a substituted or unsubstituted heterocycle linked to the rest of the molecule through one of its carbon atoms, said heterocycle being selected from the group consisting of:

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-7-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl.

Most preferred are imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyrimidin-3-yl, imidazo[1,2-b]pyridazin-3-yl, 1H-imidazol-4 -yl, 1H-imidazol-5-yl.

R4 is a substituted or unsubstituted phenyl group.

Another embodiment of this invention includes compounds of formula (I), where R1 denotes a hydrogen atom or C1-12 alkyl;

R2 is a hydrogen atom;

R3 is an aromatic 5-membered heterocycle linked to the rest of the molecule through one of its carbon atoms;

R4 represents a hydrogen atom, C1-12 alkyl or aryl;

R5 denotes a hydrogen atom.

Alternatively, R4 can, together with R5 and the 2-oxo-1-pyrrolidine ring, form the following 1,3-dihydro-2H-indol-2-one ring:

where the asterisk * denotes the place of attachment of the substituents;

R6 represents a hydrogen atom or a halogen atom.

In this embodiment, R4 may not be a hydrogen atom when R3 is substituted 1H-pyrazol-5-yl. Furthermore, this embodiment of the present invention does not include 5-(2'-oxo-1'-pyrrolidinyl)methyl-1,3,4-tricarbomethoxypyrazole which is disclosed in A. Padwa et al., J. Org. Chem. 2000, 65, 5223-5232, although no biological activity is indicated for it.

In this embodiment of the present invention, when R3 is an aromatic 5-membered heterocycle bonded to the rest of the molecule through one of its carbon atoms, the specific R3 functionality may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 2-oxo-2,3-dihydro-1,3-thiazol-5- yl, each optionally substituted with 1 to 3 substituents independently selected from methyl, chlorine atom, bromine atom, amino, methylamino, dimethylamino, (2-oxo-4-propylpyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido , cyano, methoxy, phenyl, 4-methylphenylsulfonyl, benzyl or 2-(benzylamino)-2-oxoethyl.

In this embodiment of the present invention, more specific functional groups R3 are selected from 2-(methylamino)-1,3-thiazol-5-yl, 2-pyrrolidin-1-yl-1,3-thiazol-5-yl, 5-bromo -1H-imidazol-4-yl, 5-chloro-1H-imidazol-4-yl, 1H-imidazol-5-yl, 1-methyl-1H-imidazol-5-yl, 4-bromo-1-methyl-1H -imidazol-5-yl, 4-chloro-1H-imidazol-5-yl, 4-chloro-1-methyl-1H-imidazol-5-yl, 4-cyano-1-methyl-1H-imidazol-5-yl , 1H-pyrazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl.

In this embodiment of the present invention, the most specific functional groups R3 are selected from 5-bromo-1H-imidazol-4-yl, 5-chloro-1H-imidazol-4-yl, 1H-imidazol-5-yl, 4-bromo-1 -methyl-1H-imidazol-5-yl, 4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl.

In the same embodiment of the present invention, the specific R1 substituent is selected from hydrogen or ethyl.

In the same embodiment of the present invention, the particular R4 substituent is selected from hydrogen, n-propyl, 2,3,5-trifluorophenyl or phenyl.

Another embodiment of the present invention includes compounds having the specific formula (Ia),

In formula (Ia), R10 is a hydrogen atom; a halogen atom; C1-4 alkyl optionally substituted with at least one halogen atom; C1-4 alkoxy; methoxycarbonyl; nitro; amino; alkylamino, amido or alkanoylamino. Preferably R10 is a hydrogen atom.

R11 represents a hydrogen atom; a halogen atom; C1-4 alkyl optionally substituted with at least one halogen atom; C1-4 alkoxy; methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanylamino. Preferably R11 is a hydrogen atom.

R4 is C1-4 alkyl optionally substituted with at least one halogen atom; or C2-4 alkenyl optionally substituted with at least one halogen atom. Preferably R4 is n-propyl.

Furthermore, according to this aspect of the invention, a particular embodiment of the invention relates to an embodiment of the present invention, wherein R10 is selected from hydrogen, methyl, fluorine, chlorine, bromine, methoxy, methoxycarbonyl, nitro, or trifluoromethyl, wherein R11 selected from hydrogen, methyl, fluorine, chlorine, bromine, methoxy, methoxycarbonyl, nitro or trifluoromethyl, and R3 is n-propyl.

Particular compounds of this invention are compounds selected from the group consisting of:

1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one;

1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one;

1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-iodimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6,8-dibromimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one;

1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one;

5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one;

1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-Amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one ;

4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[I,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2- He;

1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin- 2-he;

4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;

1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(2-cyclopropyl-6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile;

4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one;

1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one;

4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one;

4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;

1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;

1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;

1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;

1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;

1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;

1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-bromo-1H-imidazol-4-yl)methyl-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one;

1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;

1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;

1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one;

1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide;

N-benzyl-2-(5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile;

1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;

1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

benzyl 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl]methyl]-1H-imidazol-2-ylcarbamate;

1-[(4-chloro-1-methyl-1H-imidazol-5-yl]methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;

5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one;

1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one;

1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;

1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;

3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile;

1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one;

1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;

1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;

1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile;

1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;

1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one;

1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;

1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one;

4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;

1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;

(-)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

(+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one;

1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-t-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one;

1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;

(-)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;

5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;

1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one;

1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one;

1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one;

4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;

1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;

1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;

1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one;

4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one;

4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one;

4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl]pyrrolidin-2-one;

4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;

4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one;

1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;

1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one;

1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;

1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;

1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one;

1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile;

1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;

1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one;

1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one;

4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one;

1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one;

1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one;

1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one;

1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;

1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;

2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;

2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile;

4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;

1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;

1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and

1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.

viii) US Patent No. 4696943

This invention relates to a new compound, (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

ix) US Patent No. 4,696,942

This invention relates to a new compound, (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

x) US Patent No. 5334720

In accordance with the present invention, novel compounds of formula I are provided,

,

,

where R1, R2, R3 and R4, which may be the same or different, independently represent a hydrogen atom, C1-6 alkyl, phenyl or phenyl substituted with one or more halogen, hydroxy, nitro, amino, C1-6 alkyl or C1- C6 alkoxy groups;

R5 and R6 independently represent a hydrogen atom, C1-C6 alkyl or C3-C6 cycloalkyl, or R5 and R6 together with the nitrogen atom form a C4-6 N-heterocycle;

m denotes an integer 1-2, and

n denote an integer 1-3;

provided that

two of the substituents R1, R2, R3 and R4 are independently phenyl or substituted phenyl and the other two are independently hydrogen or C1-6 alkyl;

or their pharmaceutically acceptable acid addition salts.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts of inorganic acids, for example a hydrohalic acid atom, for example hydrochloric or hydrobromic acid; or salts of organic acids, such as formic, acetic or lactic acid. Said acid may be polybasic, for example sulfuric, fumaric, maleic or citric acid.

This invention also relates to all stereoisomeric forms and optical enantiomeric forms of the compounds of formula I

In compounds of formula I, alkyl groups which may be represented by the groups R1, R2, R3, R4, R5 and R6 include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl;

cycloalkyl groups which may be represented by groups R5 and R6 include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

C1-6 alkoxy groups include methoxy, ethoxy and propoxy;

halogen groups include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The present inventors prefer compounds of formula I, or pharmaceutically acceptable acid addition salts thereof, wherein:

R1 is a hydrogen atom, phenyl or substituted phenyl, preferably phenyl;

R2 is a hydrogen atom, phenyl or substituted phenyl, preferably phenyl;

R3 is a hydrogen atom, phenyl or substituted phenyl, preferably a hydrogen atom;

R4 is a hydrogen atom, phenyl or substituted phenyl, preferably a hydrogen atom;

R5 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen or methyl;

R6 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen or methyl;

m is an integer equal to 1-2, preferably 2;

N is an integer equal to 1-2, preferably 1.

The present inventors particularly prefer compounds of formula I wherein R1 and R2 are both phenyl.

The present inventors particularly prefer compounds of formula I in which one of R5 and R6 is hydrogen and the other is hydrogen or methyl.

xi) International Patent Publication WO2005/054188

In accordance with one aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof,

,

,

Where

R1 is hydrogen, C1-20 alkyl, C3-23 cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl , aryl or heterocycle;

R2 is hydrogen, C1-20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl;

R3 is hydrogen, C1-20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl;

or R2 and R3 can together with the imidazole ring form the following 1H-benzimidazole ring

R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy, or heterocycle; R4a is hydrogen or C1-20 alkyl; or R4 and R4a together may form C3-8 cycloalkyl; R5 is a hydrogen atom; or R4, R4a and R5 may together with the 2-oxo-1-pyrrolidine ring form the following 1,3-dihydro-2H-indol-2-one ring,

R6 is a hydrogen atom or C1-20 alkyl; R7 represents a hydrogen atom; or R6 and R7 are connected to form C3-6 cycloalkyl; R8 is hydrogen, halogen, nitro, cyano, C1-20 alkyl or alkoxy; R9 is hydrogen, C1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R10 is hydrogen, C1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R11 is hydrogen, halogen, nitro, cyano, C1-20 alkyl or alkoxy; R12 is a hydrogen atom or a halogen atom;

R13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, C1-20 alkyl, unsubstituted or substituted with halogen, or alkoxy, unsubstituted or substituted with halogen; R14 represents a hydrogen atom, C1-20 alkyl or a halogen atom;

R15 is a hydrogen atom, C1-20 alkyl or a halogen atom;

provided that R4 is other than a hydrogen atom, when

,

,

N is a group of formula

.

.

An asterisk * indicates the place of attachment of the substituents.

In a preferred embodiment, this invention relates to a compound having formula I, its tautomers, geometric isomers (including cis and trans isomers, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or its pharmaceutically acceptable salt

,

,

Where

R1 is hydrogen, C1-20 alkyl, C3-8 cycloalkyl, halogen, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle;

R2 is hydrogen, C1-20 alkyl, halo, cyano, ester, carbamate or amido;

R3 is hydrogen, cyano, C1-20 alkyl, halo or ester;

or R2 and R3 together with the imidazole ring can form the following 1H-benzimidazole ring

R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl or aryl; R4a is a hydrogen atom;

R5 is a hydrogen atom; or R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form the following 1,3-dihydro-2H-indol-2-one ring

R6 is a hydrogen atom or C1-20 alkyl; R7 represents a hydrogen atom; or R6 and R7 are connected to form C3-6 cycloalkyl; R8 is a hydrogen atom; R9 is hydrogen, C1-20 alkyl, halo or alkoxy; R10 is hydrogen, C1-20 alkyl, halo or cyano; R11 represents a hydrogen atom; R12 is a hydrogen atom or a halogen atom; R13 is a hydrogen atom, a halogen atom, a heterocycle or C1-20 alkyl; R14 represents a hydrogen atom; R15 represents a hydrogen atom; provided that R4 is other than a hydrogen atom, when

is a group of formula

The term "alkyl" as used herein means saturated monovalent hydrocarbon radicals having linear (straight) or branched or cyclic structures or combinations thereof and containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-4 a carbon atom; most preferred alkyl groups have 1-3 carbon atoms. Alkyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. In this case, alkyl groups are usually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl , 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (4 -chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, azidomethyl or trifluoromethyl. The most preferred alkyl groups are methyl or n-propyl.

The term "cycloalkyl" as used herein means a monovalent group of 3 to 8 carbon atoms, typically 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or more substituents selected from the groups described above for alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

The term "alkenyl" as used herein means linear, branched or cyclic unsaturated hydrocarbon radicals, or combinations thereof, having at least one carbon-carbon double bond, which contain 2-12 carbon atoms, typically 2-4 carbon atoms. Alkenyl groups are optionally substituted with any suitable group including, but not limited to, one or more substituents selected from the group described above for alkyl groups. Typically, the alkenyl group is ethenyl (vinyl) optionally substituted with 1 to 3 halogen atoms. The preferred alkenyl group in this invention is 2,2-difluorovinyl.

The term "alkynyl" as used herein means linear, branched or cyclic unsaturated hydrocarbon radicals, or combinations thereof, having at least one carbon-carbon triple bond, which contain 2-12 carbon atoms, typically 2-6 carbon atoms, and which are optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from the group described above for alkyl groups. A preferred alkynyl group is a halogen-substituted alkynyl group (haloalkynyl group).

Groups that are defined by prefixes such as "second", "iso", "tert", etc. (eg "isopropyl", "sec-butyl") are branched derivatives.

The term "aryl" is defined herein as phenyl optionally substituted with 1 to 4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C1-3 alkyl or azido, preferably halogen or azido. In this invention, aryl groups are typically phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4 -trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferred aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. The most preferred aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5 -trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term "heterocycle" as used herein includes an aromatic or non-aromatic cycloalkyl group as defined above, having at least one O, S and/or N atom that interrupts the carbocyclic ring structure. The heterocyclic groups may optionally be substituted with alkyl groups or halogen atoms, and optionally one of the carbon atoms in the carbocyclic ring structure may be substituted with a carbonyl. Usually heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl, 1-methyl-1H-pyrrole -2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazole -4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazolyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 4-methyl -1H-imidazol-5-yl or 2-methyl-1,3-thiazol-4-yl. Preferred heterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrole -2-yl, 1H-pyrrol-2-yl.

The term "halogen atom" as used herein includes a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom. Typically, the halogen atoms are a chlorine atom, a bromine atom, and a fluorine atom. Preferred halogen atoms are fluorine atom, bromine atom and chlorine atom.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "alkoxy" as used herein means a group of the formula -ORa, where Ra is an alkyl group as defined above. The preferred alkoxy group is methoxy.

The term "aryloxy" as used herein means a group of the formula -ORb, where Rb is an aryl group as defined above. A preferred aryloxy group is phenoxy.

The term "ester" as used herein means a group of the formula -COORc, where Rc is an alkyl group or an aryl group as defined above. The preferred ester group is methoxycarbonyl.

The term "amido" as used herein refers to a group of the formula -CONH ₂ .

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "amino derivative" as used herein means an alkylamino or arylamino group in which the terms "alkyl" and "aryl" are defined above.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "guanidine" as used herein refers to a group of the formula -NHC(=NH)NH ₂ .

The term "alkylthio" as used herein means a group of the formula -SRd, where Rd is an alkyl group as defined above. One alkylthio group is methylthio.

The term "alkylsulfonyl" as used herein means a group of the formula -S(=O) ₂ Re, where Re is an alkyl group as defined above. One alkylsulfonyl group is methylsulfonyl.

The term "alkylsulfinyl" as used herein means a group of the formula -S(=O)Rf, where Rf is an alkyl group as defined above. One alkylsulfinyl group is methylsulfinyl.

The term "arylthio" as used herein means a group of the formula -SRg, where Rg is an aryl group as defined above.

The term "arylsulfonyl" as used herein means a group of formula -S(=O) ₂ Rh, where Rh is an aryl group as defined above.

The term "arylsulfinyl" as used herein means a group of the formula -S(=O)Ri, where Ri is an aryl group as defined above.

The term "carbamate" as used herein means a group of the formula -N(H)C(O)ORl, where Ri is alkyl or aryl, as defined above. Typically, the carbamate groups are (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. One carbamate group is (benzyloxycarbonyl)amino.

The term "alkanoylamino" as used herein means a group of the formula -NHC(=O)Rk, where Rk is an alkyl group as defined above.

The term "(arylcarbonyl)amino" as used herein means a group of the formula -NHC(=O)Rm, where Rm is an aryl group as defined above. One (arylcarbonyl)amino is benzoylamino.

Typically, RI is hydrogen, C1-10 alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl, or 4-chlorophenoxy; hydroxy; C3-6 cycloalkyl; a halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; a heterocycle unsubstituted or substituted with alkyl groups; or guanidine.

In some embodiments of this invention, RI is a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; a chlorine atom; bromine atom; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably Rl is a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; a chlorine atom or 1H-pyrrol-2-yl. Most preferably Rl is a hydrogen atom; methyl; methylthio; nitro; cyano; amino or chlorine atom.

Typically R2 is a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; a halogen atom; ester; cyano; alkyl carbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably R2 is a hydrogen atom; methyl; hydroxymethyl; (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl; [(benzyloxy)carbonyl]amino, chlorine atom or cyano. In some embodiments of this invention, R2 is a hydrogen atom, a chlorine atom, or cyano.

Usually R3 represents a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with hydroxy; a halogen atom; ester or cyano. In some embodiments of this invention, R3 is a hydrogen atom; hydroxymethyl; a chlorine atom; cyano.

In some embodiments of this invention, R3 is hydrogen or cyano. In some embodiments, R3 is a hydrogen atom.

Usually R4 represents a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with halogen atoms; C2-4 alkenyl substituted with halogen atoms, or a phenyl group unsubstituted or substituted with azido and/or halogen atoms. Preferably, R4 is hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 3-chloro -4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido -2,4,6-trifluorophenyl.

More preferably, R4 is hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 3- chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R4 is n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3 ,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

As a rule, R4a represents a hydrogen atom.

As a rule, R5 denotes a hydrogen atom.

Typically, R6 is hydrogen or C1-10 alkyl, unsubstituted or substituted with hydroxy or azido. Preferably R6 is hydrogen or azidomethyl. More preferably R6 is a hydrogen atom.

Usually R7 represents a hydrogen atom.

In other embodiments of this invention, R6 and R7 are connected and form cyclopropyl.

In other embodiments of the present invention, R2 and R3 may, together with the imidazole ring, form the following 1H-benzimidazole ring

Usually R8 denotes a hydrogen atom.

Typically R9 is a hydrogen atom, a halogen atom, 1-3 alkyl or alkoxy. In some embodiments of this invention, R9 is hydrogen, methyl, chlorine, or methoxy. In some embodiments of this invention R9 denotes a hydrogen atom.

Usually R10 represents a hydrogen atom; a halogen atom; cyano; C1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy. In some embodiments of this invention, R10 is methyl, a hydrogen atom, trifluoromethyl, a fluorine atom, cyano, or methoxy. In some embodiments of this invention, R10 is a hydrogen atom, trifluoromethyl, a fluorine atom, or cyano.

Usually R11 represents a hydrogen atom.

In other embodiments of this invention, R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form a 1,3-dihydro-2H-indol-2-one ring.

Usually R12 represents a hydrogen atom or a halogen atom. In some embodiments of this invention, R12 is a hydrogen atom, a chlorine atom, or a fluorine atom. In some embodiments, R12 is a hydrogen atom.

Usually R13 represents a hydrogen atom; C1-3 alkyl; a halogen atom; or a thiazolyl unsubstituted or substituted with alkyl groups, such as methylthiazolyl. In some embodiments of this invention, R13 is a hydrogen atom, a chlorine atom, a bromine atom, or methyl. In some embodiments of this invention, R13 is a chlorine atom, a bromine atom, or methyl.

Usually R14 represents a hydrogen atom.

Usually R15 represents a hydrogen atom.

In a general embodiment of the invention of the present invention, the compounds of formula I, or pharmaceutically acceptable salts thereof, are compounds in which

R1 is selected from a hydrogen atom; C1-10 alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C3-6 cycloalkyl; a halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; a heterocycle unsubstituted or substituted with an alkyl group; or guanidine; R2 is selected from a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; a halogen atom; ester; cyano; alkylcarbamate; or [(N-methoxy-N-methyl)amino]carbonyl.

R3 is selected from a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with hydroxy; a halogen atom; ester or cyano; R4 is selected from a hydrogen atom; C1-4 alkyl, unsubstituted or substituted with halogen atoms; C2-4 alkenyl substituted with halogen atoms or a phenyl group unsubstituted or substituted with azido and/or halogen atoms;

R4a is a hydrogen atom; R5 is a hydrogen atom; R6 is selected from hydrogen or C1-10 alkyl, unsubstituted or substituted with hydroxy or azido;

R7 represents a hydrogen atom; or R6 and R7 may be combined to form cyclopropyl; or R2 and R3 together with the imidazole ring can form the following 1H-benzimidazole ring

R8 is a hydrogen atom; R9 is selected from hydrogen atom, halogen atom, C1-3 alkyl; alkoxy;

R10 is selected from a hydrogen atom; a halogen atom; cyano or Cil alkyl, unsubstituted or substituted with halogen atoms; or alkoxy; R1 represents a hydrogen atom; or R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form the following 1,3-dihydro-2H-indol-2-one ring

R12 is selected from a hydrogen atom or a halogen atom;

R13 is selected from a hydrogen atom; C1-3 alkyl; a halogen atom; thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl;

R14 represents a hydrogen atom;

R15 represents a hydrogen atom; provided that R4 is other than a hydrogen atom when

is a group of formula

In one of the embodiments of this invention, the compounds of formula I, or their pharmaceutically acceptable salts, are compounds in which

R1 is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, trifluoromethyl, 2,2,2- trifluoroethyl, hydroxymethyl, chloromethyl, cyanomethyl, 2-(methylthio)ethyl, chlorine atom, bromine atom, nitro, cyano, amino, aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl, phenyl, 2-furyl, 3-furyl; 1H-pyrrol-2-yl, 1-methyl-1H-pyrrol-2-yl, 2-thienyl, 1H-pyrazol-3-yl, 1,2,3-thiadiazol-4-yl or 1H-imidazol-2- silt;

R2 is selected from hydrogen, methyl, hydroxymethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (benzyloxycarbonyl)amino, chlorine or cyano;

R3 is selected from hydrogen, hydroxymethyl, chlorine, cyano;

or R2 and R3 together with the imidazole ring can form the following 1H-benzimidazole ring

R8 is a hydrogen atom;

R9 is selected from hydrogen, methyl; a chlorine atom; methoxy;

R10 is selected from methyl, hydrogen atom, trifluoromethyl, fluorine atom, cyano or methoxy;

R is a hydrogen atom;

R4 is selected from hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 3-chloro- 4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido- 2,4,6-trifluorophenyl.

R4a is a hydrogen atom;

R5 is a hydrogen atom;

or R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form the following 1,3-dihydro-2H-indol-2-one ring

R12 is selected from a hydrogen atom; a chlorine atom; a fluorine atom;

R13 is selected from a hydrogen atom; a chlorine atom; a bromine atom; methyl;

R14 represents a hydrogen atom;

R15 represents a hydrogen atom;

R6 is selected from a hydrogen atom; azidomethyl;

R7 represents a hydrogen atom;

or R6 and R7 are connected to form cyclopropyl; provided that R4 is other than a hydrogen atom, when

is a group of formula

In one embodiment of the invention, the compounds of formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R1 is selected from a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; a chlorine atom; or 1H-pyrrol-2-yl;

R2 is selected from a hydrogen atom; a chlorine atom; cyano;

R3 is selected from hydrogen, cyano;

or R2 and R3 together with the imidazole ring can form the following 1H-benzimidazole ring

R8 is a hydrogen atom;

R9 is a hydrogen atom;

R10 is selected from hydrogen, trifluoromethyl, fluorine, cyano;

R11 represents a hydrogen atom;

R4 is selected from hydrogen, n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl; 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl;

R4a is a hydrogen atom;

R5 is a hydrogen atom;

or R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form the following 1,3-dihydro-2H-indol-2-one ring

Where

R12 represents a hydrogen atom;

R13 is selected from methyl; a chlorine atom; a bromine atom;

R14 represents a hydrogen atom;

R15 represents a hydrogen atom;

R6 represents a hydrogen atom;

R7 represents a hydrogen atom;

provided that R4 is other than a hydrogen atom, when

R11 is a group of formula

In one embodiment of the present invention, the compounds of formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R1 is selected from hydrogen, methyl, methylthio, nitro, cyano, amino, chlorine;

R2 is selected from hydrogen atom, chlorine atom, cyano;

R3 is a hydrogen atom;

R4 is selected from n-propyl, 2,2-difluorovinyl, phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5 -trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl;

R4a is a hydrogen atom;

R5 is a hydrogen atom;

or R4, R4a and R5 together with the 2-oxo-1-pyrrolidine ring can form the following 1,3-dihydro-2H-indol-2-one ring

R12 represents a hydrogen atom;

R13 is selected from chlorine atom, bromine atom, methyl;

R14 represents a hydrogen atom;

R15 represents a hydrogen atom;

R6 represents a hydrogen atom; R7 represents a hydrogen atom.

In some embodiments of this invention, the compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-t-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide; 4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; methyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-ylmethyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-ethyl-5-methyl-1H-imidazol-1-yl]methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl ]-4-propylpyrrolidin-2-one; 1-[(2-chloro-(1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[ 2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one, 1-[(4-chloro-1H-imidazol-1-yl)methyl-4-(3.4 ,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2- chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl }-1H-imidazol-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H -imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; benzyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamate; N-[( 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide; oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;N-1-(1-[2-oxo-4-(3 ,4,5-trifluorophenyl) pyrroldin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide; 1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; {1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetonitrile; 1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl]pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile; 1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-ylmethyl}-4-propylpyrrolidin-2-one; 1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile; 1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile; and 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments of this invention, the compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments of this invention, the compounds are: 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluoromethyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

Some compounds are: (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

The acid addition salt form of a compound of formula I which exists in its free base form can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acid and the like, or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic , cyclamic, salicylic, p-aminosalicylic, pamic acid, etc.

Compounds of formula I containing acidic hydrogen atoms can be converted into their therapeutically active, non-toxic base addition salt form, for example a metal or amine salt, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases include, for example, salts with N-methyl -D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine, and the like.

The reverse salt forms may be converted to the free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included in the scope of this invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. Said stereogenic center may be in the R- or S-configuration, with the R and S designations being used in accordance with the rules given in Pure Appl. Chem. 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms. It is intended that such forms, although not expressly indicated in the above formula, be included within the scope of the present invention.

Another preferred embodiment of this invention also relates to compounds of formula IA and their tautomeric form IB

With regard to reference in this invention to a compound or compounds, it should be understood that the invention covers the specified compound in each of its possible isomeric forms and mixtures thereof, unless there is a specific indication of a particular isomeric form.

The compounds of this invention may exist in various polymorphic forms. Although they are not explicitly indicated in the above formula, it is assumed that these forms are included in the scope of this invention.

The scope of this invention also includes prodrug forms of the compounds of formula I and their various subfields and subgroups.

xii) US Patent Application No. 20090018148

According to one aspect, this invention relates to compounds having formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers) or their pharmaceutically acceptable salts,

,

,

Where

R1 is a hydrogen atom or C1-6 alkyl;

R2 is a hydrogen atom or C1-4 alkyl;

R3 is a group of the formula -CHR5R6 or a benzyl group;

R4 is C1-8 alkyl optionally substituted with alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle;

R5 is C2-4 alkyl;

R6 is C2-4 alkyl, amido or -COOR7;

R7 is C1-4 alkyl.

In accordance with one aspect, this invention relates to compounds:

when R1 is hydrogen, R2 is methyl, R3 is -CHR5R6, R6 is ethoxycarbonyl and R5 is ethyl, then R4 is other than methyl, n-propyl, isopropyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl , 4-methylbenzyl or 2-phenylethyl;

when R1 is hydrogen, R2 is methyl, R3 is benzyl, then R4 is other than isopropyl, n-butyl, 3-methylbutyl, benzyl, phenylethyl or 3-phenylpropyl;

when R1 and R2 are methyl, R3 is benzyl, R4 is other than methyl, 3-methylbutyl, benzyl, 3-phenylpropyl and 4-chlorophenylmethyl.

Finally, 8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7-dihydropurine-2,6-dione is considered.

Typically, when R3 is a benzyl group, R4 is C1-8 alkyl optionally substituted with alkoxycarbonyl.

Generally, when R3 is a group of formula -CHR5R6, then R4 is C1-8 alkyl optionally substituted with C3-6 cycloalkyl, aryl, or heterocycle.

The term "alkyl" in this specification is a group that denotes saturated monovalent hydrocarbon radicals, including linear (straight) or branched fragments or combinations thereof and containing 1-8 carbon atoms, preferably 1-6 carbon atoms, more preferably alkyl groups having 1-4 carbon atoms. The alkyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl groups may optionally be substituted with cycloalkyl, the meaning of which is defined below. Preferred alkyl groups according to the invention are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, isobutyl , n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1- phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3 -nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. The most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

The term "cycloalkyl" as used herein means a monovalent group of 3 to 8, preferably 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or more substituents selected from the group described above for alkyl groups. A preferred cycloalkyl group according to the present invention is cyclohexyl.

The term "aryl" as used herein means a phenyl group optionally substituted with 1 to 4 substituents independently selected from halogen, amino, nitro, alkoxy, or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term "phenyl" as used herein refers to an aromatic hydrocarbon group of the formula -C ₆ H ₅ .

The term "benzyl group" in this description means a group of the formula -CH ₂ -aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-aminobenzyl. In some embodiments of this invention, the alkyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

The term "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In some embodiments of this invention, the halogen atom is bromine.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "ethynyl" as used herein refers to a group of the formula -C≡CH.

The term "alkoxy" as used herein means a group of the formula -ORa, where Ra is an alkyl group as defined above. In some embodiments of this invention, the alkoxy group is methoxy.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "amido" as used herein refers to a group of the formula -C(=O)NH ₂ .

The term "acyl" as used herein means a group of the formula -C(=O)Rb, where Rb is an alkyl group as defined above. In some embodiments of this invention, the acyl group is acetyl (-C(=O)Me).

The term "alkoxycarbonyl (or ester)" as used herein means a group of formula -COORc, where Rc is an alkyl group; with the proviso that Rc is not alkyl substituted at the alpha position with a hydroxy group. In some embodiments of this invention, the alkoxycarbonyl group is ethoxycarbonyl.

The term "heterocycle" as used herein means a 5-membered ring containing one or two heteroatoms selected from O or N. Said heterocycle may be substituted with one or two C1-4 alkyls or nitro. In some embodiments of this invention, the heterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). The most preferred heterocycle is (5-nitro-2-furyl).

In general, R1 is a hydrogen atom or C1-6 alkyl. Typically R1 is hydrogen or C1-6 alkyl optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. In some embodiments of this invention, R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl, or n-hexyl . In some embodiments of this invention, R1 is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, or 2-propynyl. In some embodiments of this invention R1 denotes a hydrogen atom.

In general, R2 is a hydrogen atom or C1-4 alkyl. Typically, R2 is a hydrogen atom or unsubstituted C1-4 alkyl. In some embodiments of this invention, R2 is hydrogen, methyl, or n-butyl. In some embodiments of this invention, R2 is methyl.

In general, R3 is a group of the formula -CHR5R6 or a benzyl group. In some embodiments of this invention, R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl, or 3-bromobenzyl. In some embodiments of this invention, R3 is 1-(ethoxycarbonyl)propyl.

In general, R4 is C1-8 alkyl optionally substituted with alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle. Typically R4 is C1-8 alkyl optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. In some embodiments of this invention, R4 is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl. In some embodiments of this invention, R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5- nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. In some embodiments of this invention, R4 is 3-methoxybenzyl, 3-nitrobenzyl, or (5-nitro-2-furyl)methyl.

In general, R5 is C2-4 alkyl. Typically R5 is unsubstituted C2-4 alkyl. In some embodiments of this invention, R5 is ethyl.

In general, R6 is C2-4 alkyl, amido or -COOR7. Typically R6 is unsubstituted C2-4 alkyl, amido or -COOR7. In some embodiments of this invention, R6 is ethyl, amido, or ethoxycarbonyl. In some embodiments of this invention, R6 is ethoxycarbonyl.

In general, R7 is C1-4 alkyl. Typically R7 is unsubstituted C1-4 alkyl. In some embodiments of this invention, R7 is ethyl.

Generally, this invention provides compounds having formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers) or their pharmaceutically acceptable salts,

,

,

Where

R1 is hydrogen, C1-6 alkyl optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl;

R2 is hydrogen or unsubstituted C1-4 alkyl;

R3 is a group of the formula -CHR5R6 or a benzyl group;

R4 is C1-8 alkyl optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl;

R5 is unsubstituted C2-4 alkyl;

R6 is unsubstituted C2-4 alkyl, amido or -COOR7;

R7 is unsubstituted C1-4 alkyl;

provided that when R1 is hydrogen, R2 is methyl, R3 is -CHR5R6, R6 is ethoxycarbonyl, and R5 is ethyl, then R4 is other than n-propyl, isopropyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2-phenylethyl.

In the embodiment of the invention described above, sometimes when R3 is a benzyl group, then R4 is C1-8 alkyl optionally substituted with alkoxycarbonyl.

In the embodiment described above, sometimes when R3 is a group of formula -CHR5R6, then R4 is C1-8 alkyl optionally substituted with C3-6 cycloalkyl, aryl, or heterocycle.

In one embodiment of the present invention,

R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl;

R2 is a hydrogen atom, methyl or n-butyl;

R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R4 is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl , 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl;

with the proviso that when R1 is hydrogen, R2 is methyl and R3 is 1-(ethoxycarbonyl)propyl, then R4 is other than n-pentyl, 3-bromobenzyl or 2-phenylethyl.

In the embodiment described above, sometimes when R3 is 3-bromobenzyl, R4 is C1-8 alkyl optionally substituted with alkoxycarbonyl.

In the embodiment described above, sometimes when R3 is 3-pentyl, 1-(aminocarbonyl)propyl, or 1-(ethoxycarbonyl)propyl, R4 is other than 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment of this invention, R1 is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R2 is methyl;

R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl) methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R1 is hydrogen, R2 is methyl and R3 is 1-(ethoxycarbonyl)propyl, then R4 is other than 3-bromobenzyl.

In the embodiment of the present invention described above, sometimes when R3 is 3-bromobenzyl, R4 is 1-(ethoxycarbonyl)propyl.

In the embodiment described above, sometimes when R3 is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, R4 is other than 1-(ethoxycarbonyl)propyl.

In one embodiment of the present invention, R1 is a hydrogen atom; R2 is methyl; R3 is 1-(ethoxycarbonyl)propyl; and R4 is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Another embodiment of the present invention includes compounds wherein R2 is methyl, R3 is a group of formula -CHR5R6 where R5 is C2-4 alkyl, R6 is amido, or -COOR7 where R7 is methyl or ethyl.

In some embodiments of this invention, the compounds are: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio] butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8 -yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate ; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl} thio)butanoate; ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl]butanoate; and ethyl 2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments of this invention, the compounds are: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio] butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio]butanoate ; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl} thio)butanoate; ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; and ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments of this invention, the compounds are: ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; and ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio )butanoate.

The acid addition salt form of a compound of formula I which exists in its free base form can be obtained by treating the free base with a suitable acid such as an inorganic acid, for example a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acid. and the like, or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic , cyclamic, salicylic, p-aminosalicylic, pamic acid, etc.

Compounds of formula I containing acidic hydrogen atoms can be converted into their therapeutically active, non-toxic base addition salt forms, for example metal or amine salts, by treatment with suitable organic and inorganic bases. Suitable salt forms with bases include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, salts of lithium, sodium, potassium, magnesium, calcium, and the like, salts with organic bases include, for example, salts with N-methyl- D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine, and the like.

The reverse salt forms may be converted to the free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included in the scope of this invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. Said stereogenic center may be in the R- or S-configuration, with the R and S designations being used in accordance with the rules given in Pure Appl. Chem. 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

With regard to reference in this invention to a compound or compounds, it should be understood that the invention covers the specified compound in each of its possible isomeric forms and mixtures thereof, unless there is a specific indication of a particular isomeric form.

The compounds of this invention may exist in various polymorphic forms. Although they are not explicitly indicated in the above formula, it is assumed that these forms are included in the scope of this invention.

xiii) US Patent No. 7465549

In some embodiments of this invention, the compound includes optionally substituted N-alkylated derivatives of 2-oxopyrrolidine. In some embodiments of this invention, said compounds are alkylamide derivatives substituted at positions 4 and/or 5 of the pyrrolidone ring. Examples of optionally substituted N-alkylated 2-oxopyrrolidine derivatives include, but are not limited to, compounds such as (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl] butanamide, (2S )-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide, (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide and (2S)-2-[4-( 3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide.

In some embodiments of this invention, the compounds further include optionally substituted N-alkylated derivatives of 2-oxo-piperidinyl. In some embodiments of this invention, said compounds are alkylamide derivatives substituted at positions 4 and/or 5 and/or 6 of the 2-oxo-piperidinyl ring. Examples of the optionally substituted N-alkylated derivative of 2-oxopyrrolidine include, but are not limited to, compounds that are listed in International Patent Application PCT/EP02/05503 such as (2S)-2-[5-(iodomethyl)-2-oxo- 1-piperidinyl]butanamide, (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-phenyl-1-piperidinyl]butanamide, (2S)- 2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide; and (2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidinyl]butanamide.

In some embodiments of this invention, the compounds include any acetam compound of Formula I, in racemic or isomeric form, or a pharmaceutically acceptable salt thereof.

,

,

Where

R is a hydrogen atom or hydroxy;

R1 and R2 independently represent a hydrogen atom or an alkyl group with 1-4 carbon atoms, and

R3 and R4 independently represent a hydrogen atom, a C1-C4 alkyl group or -(CH2)n-NR5R6 where n is 1, 2 or 3 and R5 and R6 independently represent a hydrogen atom or a C1-C4 alkyl group carbon.

An example of such an acetam compound includes, but is not limited to, the compound of formula I where R, R1, R2, R3 and R4 are hydrogen, 2-oxopyrrolidineacetamide, known collectively as piracetam, as described in UK Patent Nos. 1039113 and 1309692.

In some embodiments of this invention, the compounds also include optionally substituted N-alkylated derivatives of 2-oxo-azepanyl. Preferably, said compounds are alkylamide derivatives substituted in positions 4 and/or 5 and/or 6 and/or 7 of the 2-oxo-azepanyl ring. Examples of the optionally substituted N-alkylated derivative of 2-oxo-azepanyl include, but are not limited to, compounds that are listed in International Patent Application PCT/EP02/05503 such as 2-[5-(iodomethyl)-2-oxo-1- azepanil]butanamide.

xiv) US Patent Application No. 2006258704

This invention relates to new compounds of formula I

,

,

Where

n is 0 or 1, where R<1> does not exist when n=0 and R<1> does not exist when n=1;

A<1> represents an oxygen atom or a sulfur atom;

X is -CONR<7>R<8>, -COOR<9>, -CO-R<10> or CN;

R<1>, when present, R<2>, R<3>, R<4>, and R<5> are the same or different, and each independently represents a hydrogen atom, a halogen atom, hydroxy, thiol, amino, nitro, nitrooxy , cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative,

with the proviso that at least one of the R substituents is selected from R<1> when R<2>, R<3>, R<4> or R<5> is not a hydrogen atom;

R<6> is hydrogen, alkyl, aryl, or -CH2-R<6a>, where R<6a> is aryl, heterocycle, halogen, hydroxy, amino, nitro, or cyano;

R<7>, R<8> and R<9> are the same or different, and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or hydroxy derivative; and R<10> denotes a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle or thio derivative;

their pharmaceutically acceptable salts, geometric isomers (including cis and trans isomers, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one of the substituents R<1> to R<5> is other than a hydrogen atom. Some unsubstituted compounds are disclosed in US Pat. In particular, these compounds block the ability of Ras to transform normal cells into cancer cells and therefore can be included in several chemotherapeutic compositions for the treatment of cancer.

US Pat. No. 5,516,759 discloses ring-unsubstituted 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivatives that are present at the N-terminus of dodecapeptides with LHRH (lutropin-releasing hormone) antagonist activity. Such LHRH antagonists are useful in the treatment of various conditions in which sex steroid suppression plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, and others.

In the definitions below, unless otherwise indicated, R<11> and R<12> are the same or different, and each is independently an amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle, or oxy derivative , thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative, each of which is optionally substituted with any suitable group, including, but not limited to, one or more substituents selected from lower alkyl or other groups, as described below, as substituents for alkyl.

The term "hydroxy derivative" as used herein includes -OR<11> groups, where R<11> is defined above, with the exception of "hydroxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, hydroxyether, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, or heterocyclooxy, such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy. , methylenedioxy, carbonate.

The term "thio derivative" as used herein includes the groups -S-R<11> where R<11> is defined above, with the exception of "thio derivative". Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

The term "amino derivative" as used herein includes the groups -NHR<11> or -NR<11>R<12>, where R<11> and R<12> are defined above. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

The term "acyl derivative" as used herein means a radical derived from a carboxylic acid and is thus defined as including groups of the formula R<11>-CO-, where R<11> is as defined above, and may also be a hydrogen atom. Preferred are acyl derivatives of the formula -COR<11>, where R<11> is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, and heterocycle. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term "sulfonyl derivative" as used herein includes the group of formula -CO-R<11>, where R<11> is defined above, with the exception of "sulfonyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term "sulfinyl derivative" as used herein includes the group of formula -CO-R<11>, where R<11> is as defined above, with the exception of "sulfinyl derivative". Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term "alkyl" as used herein includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and typically containing 1-20 carbon atoms, most commonly 1 to 12 carbon atoms, preferably 1-7 carbon atoms for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise indicated, "lower alkyl"), each of which is optionally substituted, preferably from 1 to 5 substituents independently selected from the group that includes a halogen atom, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyether, oxyamido , heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy (preferably C6-10) and aryl (preferably C6-10).

Some embodiments of this invention include alkyl groups containing from 1 to 7 carbon atoms, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen atom, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. Most preferred are C14 alkyl and C3-7 cycloalkyl, each of which is optionally substituted with one or more hydroxy, halogen, lower alkyl, and/or azido.

In some embodiments of this invention, the alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3- trifluoropropyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodine-2,2-difluoroethyl.

The term "lower alkyl" as used herein, and unless otherwise indicated, means a C1-C7 saturated, linear, branched or cyclic hydrocarbon. Non-limiting examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, iso-hexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, optionally substituted with any suitable group including, but not limited to, one or more substituents selected from the group described above for alkyl groups. Preferably, the lower alkyl is methyl.

The term "alkenyl" as used herein includes both branched and straight, unsaturated hydrocarbon radicals having at least one double bond and optionally substituted with at least one substituent selected from the group consisting of a halogen atom, hydroxy , thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl, and heterocycle.

In some embodiments of this invention, the alkenyl groups are C2-C12 alkenyls, in particular C2-6 alkenyls such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1- propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like, optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl, and acyl. Most preferred is vinyl optionally substituted with one or more halogens and/or lower alkyls, in particular 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term "alkynyl" as used herein includes a monovalent branched or straight hydrocarbon radical containing at least one carbon-carbon triple bond, e.g., ethynyl, 2-propynyl (= propargyl) and the like, and optionally substituted, at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, alkylthio, alkyl and acyl.

In some embodiments of this invention, the alkynyl groups are C2-12 alkynyl, in particular C2-6 alkynyl, optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl, such as phenyl, or alkyl, preferably cycloalkyl.

Some embodiments of this invention are ethynyl, propynyl and butynyl optionally substituted with lower alkyl and/or a halogen atom, and in particular 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl .

When present as bridging groups, the alkyl, alkenyl and alkynyl are straight chain or branched and are C1-12, preferably C1-C4 alkylene or C2-C12-, preferably C2-4 alkenylene or - alkynylene groups, respectively.

Groups in which branched derivatives are defined for convenience by prefixes such as "n", "sec", "iso", etc. (for example, "n-propyl", "sec-butyl"), unless otherwise indicated, have a straight form.

The term "aryl" as used herein includes an organic radical derived from an aromatic hydrocarbon having at least one ring, most commonly 1 to 3 rings, and typically containing 6-30 carbon atoms, by removal of one hydrogen atom, such as phenyl and naphthyl, each optionally substituted with one or more substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6alkylthio, hydroxyester, hydroxyamido, aryl, C1-6alkoxy, C6-10aryloxy, C1-6alkyl, C1-6haloalkyl. Aryl radicals are preferably monocyclic or bicyclic radicals containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each optionally substituted with one or more substituents independently selected from halo, nitro, amino, azido, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl, sulfonyl, and phenyl.

In some embodiments of this invention, aryl is phenyl optionally substituted with one or more halogen, lower alkyl, azido, or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term "halogen atom" as used herein includes Cl, Br, F, I.

The term "hydroxy" as used herein means a group of the formula -OH.

The term "thiol" as used herein means a group of the formula -SH.

The term "cyano" as used herein refers to a group of the formula -CN.

The term "nitro" as used herein refers to a group of the formula -NO ₂ .

The term "nitrooxy" as used herein refers to a group of the formula -ONO ₂ .

The term "amino" as used herein refers to a group of the formula -NH ₂ .

The term "azido" as used herein refers to a group of the formula -N ₃ .

The term "carboxy" as used herein refers to a group of the formula -COOH.

The term "sulfonic acid" as used herein means a group of the formula -SO ₃ H.

The term "sulfonamide" as used herein refers to a group of the formula -SO ₂ NH ₂ .

The term "ester" as used herein includes a group of formula -COO-R<11>, where R<11> is defined above, excluding hydroxy derivative, thio derivative or amine derivative. Esters of formula -COOR<11> are preferred, wherein R<11> is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R<11> is lower alkyl, in particular methyl.

The term "ether" includes a group selected from C1-50 linear or branched alkyl or C2-50 linear or branched alkenyl or alkynyl group, or a combination thereof, interrupted by one or more oxygen atoms.

The term "amido" includes a group of the formula -CONH ₂ or -CONHR<11> or -CONR<11>R<12>, where R<11> and R<12> are defined above.

The term "heterocycle" is defined herein as including an aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, containing at least one O, S, and/or N atom that interrupts the carbocyclic ring structure, wherein one of the carbon atoms of the carbocyclic ring structure may optionally be substituted with a carbonyl, and said moiety is optionally substituted with any suitable group including, but not limited to, one or more substituents selected from lower alkyl or other groups as described above for alkyl groups. Non-limiting examples of heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isoxazolyl, oxazolyl, thianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1- оксидопиридил, фенантридинил, акридинил, пиримидинил, фенантролинил, фенотиазинил, фуразанил, бензодиоксолил, изохроманил, индолинил, ксантенил, гипоксантинил, птеридинил, 5-азацитидинил, 5-азаурацинил, триазолoпиридинил, имидазолoпиридинил, пирролопиримидинил, пиразолопиримидинил, тетрагидрофуранил, тетрагидропиранил, пиперидинил, пиперидил, piperazinil, imidazolidinil, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-ox opyrrolidinyl, sugar residues (eg glucose, pentose, hexose, ribose, fructose, which may also be substituted) optionally substituted with alkyl or as described above for alkyl groups. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, or groups in which the monocyclic heterocyclic group has a bridged alkylene group, for example quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

The heterocycle may be selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from atom halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl. In some embodiments of this invention, the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl, and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl, and in particular from 2-thienyl and 3-thienyl optionally substituted with one or more halogen atoms, acyl such as formyl, cyano and/or lower alkyl such as methyl.

It should be understood that in the above definitions, when a substituent such as R<1>, R<2>, R<3>, R<4>, R<5>, R<7>, R<8>, R <9>, R<10>, attached to the rest of the molecule via a heteroatom or carbonyl, straight or branched alkylene bridge, C1-12-, preferably C1-4-alkylene or C2-12, preferably 2-4- the alkenylene or α-alkynylene bridging group may optionally be located between the heteroatom or carbonyl and the point of attachment to the rest of the molecule.

The acid addition salt form of a compound of formula I which exists in its free base form can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acid and the like, or an organic acid such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic , salicylic, p-aminosalicylic, pamoic acid, etc.

Compounds of formula I containing acidic hydrogen atoms can be converted into their therapeutically active, non-toxic base addition salt form, for example a metal or amine salt, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases include, for example, salts with N-methyl -D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine, and the like.

The reverse salt forms may be converted to the free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included in the scope of this invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. Said stereogenic center may be in the R- or S-configuration, with the R and S designations being used in accordance with the rules given in Pure Appl. Chem. 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

In addition, some compounds of formula I which contain alkenyl groups may exist as Z- (zusammen) or E- (entgegen) isomers. In each case, this invention includes both mixtures and individual individual isomers.

Several substituents on the piperidinyl or azepanyl ring can also be located either in cis or trans to each other relative to the plane of the piperidinyl or azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms. It is intended that such forms, although not expressly indicated in the above formula, be included within the scope of the present invention.

With regard to reference in this invention to a compound or compounds, it should be understood that the invention covers the specified compound in each of its possible isomeric forms and mixtures thereof, unless there is a specific indication of a particular isomeric form.

The scope of this invention also includes prodrug forms of the compounds of formula I and their various subfields and subgroups.

The term "prodrug" as used herein includes forms of the compound that are rapidly transformed in vivo to form the parent compound of the invention, for example, by blood hydrolysis. Prodrugs are compounds containing groups that are modified by biotransformation prior to their pharmacological action. Such groups include fragments that are easily oxidized, cyclized or cleaved, while the compound remains or becomes pharmacologically active after biotransformation. Metabolically cleavable groups, for example, form a class of groups well known to those skilled in the art. These include, but are not limited to, groups such as alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), unsubstituted and substituted carbocyclic aroyl (e.g., benzoyl, substituted benzoyl, and 1- and 2-naphthoyl), alkoxycarbonyl (eg, ethoxycarbonyl), trialkylsilyl (such as trimethyl and triethylsilyl), monoesters derived from dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinyl, and the like. Compounds containing biotransformable groups have the advantage that they may have better bioavailability as a result of the increased solubility and/or absorption rate that the presence of the biotransformable group imparts to the parent compound. T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery System", Vol. 14 of the ACS Symposium Series; Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "R substituent" independently refers to R<1>, R<2>, R<3>, R<4> or R<5>.

According to one variant of its implementation, this invention relates to a compound of formula I, the definition of which is given above, where n is 0. The specified connection is a 6-ring structure (2-thioxo - or 2-oxo-piperidinyl derivatives), in which R< 1> does not exist since n=0 and is represented by formula (IA).

According to a further embodiment, this invention relates to a compound of formula I according to the present invention, as defined above, wherein n is 1. Said compound is a 7-membered ring structure (2-thioxo or 2-oxo-azepanyl derivatives) in which R<1> exists because n=1 and is represented by formula (IB).

According to another embodiment, the invention relates to said compound as defined above, wherein n=0, R<3> and/or R<4> is other than a hydrogen atom, and R<2> and R<5> represent an atom hydrogen.

According to another embodiment, this invention relates to said compound as defined above, wherein n=1, R<2>, R<3> and/or R<4> is other than a hydrogen atom, and wherein R<1> and R<5> denotes a hydrogen atom.

According to another variant of its implementation, the specified invention relates to the specified connection, as defined above, where only one substituent R selected from R<3> or R<4> when n=0, or from R<2>, R<3 > or R<4> when n=1 is other than a hydrogen atom, and the remaining substituents R denote a hydrogen atom. In this case, the authors of the present invention have in mind monosubstituted 2-thioxo - or 2-oxo-piperidinyl or 2-thioxo - or 2-oxo-azepanyl derivatives.

According to another variant of its implementation, this invention relates to compounds of formula I according to the present invention, as defined above, where A<1> denotes an oxygen atom. In this case, the authors of the present invention have in mind 2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another variant of its implementation, this invention relates to compounds of formula I according to the present invention, as defined above, where X represents CONR<7>R<8>, in particular, CONH ₂ . In this case, the authors of the present invention have in mind the amide derivatives of 2-oxo-(or thioxo)-piperidinyl or 2-oxo-(or thioxo)azepanil.

According to another embodiment, this invention relates to compounds of formula I according to the present invention, as defined above, where R<6> denotes a hydrogen atom, C1-4 alkyl or a CH ₂ -R<6a> group, where R<6a> denotes heterocycle. Most preferably R<6> is C1-4 alkyl, especially ethyl. When R<6> is ethyl, the present inventors mean derivatives of 2-(2-oxo-(or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo-(or thioxo)-1 -azepanil) butanamide.

According to another variant of its implementation, this invention relates to compounds of formula I according to the present invention, as defined above, where the carbon atom to which R<6> is attached has the S-configuration. When R<6> is ethyl, A is an oxygen atom, and X is CONR<7>R<8>, the present inventors refer to derivatives of (2S)-2-(2-oxo-1- piperidinyl)butanamide or (2S)-2-(2-oxo-1-azepanyl)butanamide.

In one embodiment, the invention relates to a compound as defined above, wherein R<2> when n=1, R<3> and R<4> are the same or different, and each independently represents a hydrogen atom, a halogen atom, nitro, nitrooxy, cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R<1> when exists, R<2> when n=0, and R<5> denote a hydrogen atom;

R<6> denotes a hydrogen atom, alkyl, aryl or -CH ₂ -R<6a>, where R<6a> represents aryl, heterocycle, halogen atom, hydroxy, amino, nitro or cyano;

with the proviso that when R<6> is a hydrogen atom, X is -CONR<7>R<8>, and that the compound is not

nor methyl (2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoate,

nor methyl (2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this embodiment of the present invention, the compound is generally such that when R<6> is benzyl, X is —COOCH ₃ and n=1, then R<2> is other than methyl when R<3> and R<4> both represent a hydrogen atom and R<4> is other than methyl when R<2> and R<3> both represent a hydrogen atom.

In another embodiment, this invention relates to a compound as defined above, wherein R<2> when n=1, R<3> and R<4> are the same or different and each independently represents a hydrogen atom; cyano; carboxy; amido;

C1-12 alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cycloalkyl, acyl, aryl, and heterocycle;

C2-12 alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

C2-12 alkynyl, each of which is optionally substituted with one or more substituents selected from halo, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

an acyl derivative of formula -CO-R<11> wherein R<11> is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, and heterocycle;

an ester of the formula -CO-OR<11>, where R<11> is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and aryl;

a heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-hydroxypyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom , alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;

aryl, each optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azido, sulfonyl, aryl and nitro.

In another embodiment, this invention relates to a compound as defined above, wherein R<2> when n=1, R<3> and R<4> are the same or different and each independently represents a hydrogen atom;

C1-7 alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

C2-6 alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl which is optionally substituted with one or more substituents selected from C1-6 alkyl, halogenated alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl and nitro.

According to another embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<2>, R<3> and R<4> when n=1, or from the group R<3> and R<4> when n=0 is independently C1-4 alkyl or C3-7 cycloalkyl optionally substituted with one or more halogen, hydroxy, lower alkyl and/or azido.

According to another embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<2>, R<3> and R<4> when n=1, or from the group R<3> and R<4> when n=0 is independently vinyl optionally substituted with one or more halogen atoms and/or lower alkyl.

According to another embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<2>, R<3> and R<4> when n=1, or from the group R<3> and R<4> when n=0 is independently ethynyl, propynyl and butynyl optionally substituted with one or more halogen and/or lower alkyl.

According to another embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<2>, R<3> and R<4> when n=1, or from the group R<3> and R<4> when n=0 is independently phenyl optionally substituted with one or more halogen atoms, lower alkyl, azido and/or nitro.

According to another embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<2>, R<3> and R<4> when n=1, or from the group R<3> and R<4> when n=0 is independently 2-thienyl or 3-thienyl optionally substituted with one or more halogen, acyl, cyano and/or lower alkyl.

According to a particular embodiment, this invention relates to a compound as defined above, wherein at least one of the R substituents is selected from the group R<3>, R<4> and R<2> when n=1, or from the group R<3> and R<4>, when n=0, denotes hydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl-5-methyl-2-thienyl, 5-formyl-2- ethynyl, 5-cyano-2-thienyl, 3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1- butynyl, 1-butynyl, 2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to another variant of its implementation, this invention relates to compounds, as defined above, where R<1>, R<2>, R<4> and R<5> denote a hydrogen atom.

According to another variant of its implementation, this invention relates to compounds, as defined above, where R<1>, R<2>, R<3> and R<5> denote a hydrogen atom.

According to another variant of its implementation, this invention relates to compounds, as defined above, where n=1 and R<1>, R<3>, R<4> and R<5> denote a hydrogen atom.

Within all of the above limits, when the carbon atom to which R<6> is attached is asymmetric, it may have the "S" configuration.

The individual compounds of this invention, as defined above, are selected from the group consisting of: 2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-propyl-1-piperidinyl ]butanamide, 2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide, 2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[ 5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-phenyl-1-piperidinyl] butanamide, 2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide, 2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide, 2-[5-( 3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-difluorovinyl)-2 -oxo-1-piperidinyl]butanamide, 2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-dichlorovinyl)-2-oxo-1 -piperidinyl]butanamide, 2-(5-ethynyl-2-oxo-1-piperidinyl]butanamide, 2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[ 5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(5-cyano-2-thienyl) -2-oxo-1-piperidinyl]butanamide, 2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(4-methyl-2-thienyl) -2-oxo-1-piperidinyl]butanamide, 2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide, 2-[2-oxo-5-( 1-propynyl)-1-piperidinyl]butanamide, 2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-methyl-1-butynyl)-2-oxo-1 -piperidinyl]butanamide, 2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2 -[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl ]butanamide, 2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-propyl)-1-piperidinyl]butanamide, 2-[2-oxo-4-( 3,3,3-trifluoropropyl)-1-piperidinyl]butanamide, 2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(iodomethyl)-2-oxo-1-piperidinyl ]butanamide, 2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-phenyl-1-piperidinyl)butanamide, 2-[2-oxo-4-(2 -thienyl)-1-piperidinyl]butanamide, 2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide, 2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3- azidophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dibromovinyl)-2 -oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-(4-ethynyl-2-oxo-1-piperidinyl]butanamide, 2 -[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2 -[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2 -[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl ]butanamide, 2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide, 2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3 -methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-difluoropropyl) )-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-chloro-2,2-difluoroethy k)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2.2, 2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-5-propyl-1-azepanyl)butanamide , 2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[5- (iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-5-phenyl-1-azepanyl)butanamide, 2-[2-oxo-5-(2-thienyl]-1-azepanyl]butanamide, 2-[2-oxo-5-(3-thienyl]-1-azepanyl]butanamide, 2-[5-(3- chlorophenyl]-2-oxo-1-azepanyl]butanamide, 2-[5-(3-azidophenyl]-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-difluorovinyl)-2-oxo -1-azepanyl]butanamide, 2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl ]butanamide, 2-(5-ethynyl-2-oxo-1-azepanyl]butanamide, 2-[5-(5-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[5- (5-formyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[5-(5-cyano-2-thienyl)- 2-oxo-1-azepanyl]butanamide, 2-[5-(3-bromo-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[5-(4-methyl-2-thienyl]- 2-oxo-1-azepanyl]butanamide, 2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl]-1-azepanyl]butanamide, 2-[2-oxo-5-(1 -propynyl)-1-azepanyl]butanamide, 2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-methyl-1-butynyl]-2-oxo-1- azepanyl]butanamide, 2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-difluoropropyl]-2-oxo-1-azepanyl]butanamide, 2- [5-(2-chloro-2,2-difluoroethyl]-2-oxo-1-azepanyl]butanamide, 2-[5-(2-bromo-2,2-difluoroethyl]-2-oxo-1-azepanyl] butanamide, 2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2 -oxo-6-propyl-1-azepanyl]butanamide, 2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[6-(cyclopropylmethyl)-2-oxo -1-azepanyl]butanamide, 2-[6-(iodomethyl]-2-oxo-1-azepanyl]butanamide, 2-16-(azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo -6-phenyl-1-azepanyl]butanamide, 2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide, 2-[2 -oxo-6-(3-thienyl)-1-azepanyl]butanamide, 2-[6-(3-chlorophenyl]-2-oxo-1-azepanyl]butanamide, 2-[6-(3-azidophenyl)-2 -oxo-1-azepanyl]butanamide, 2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-dibromovinyl)-2-oxo-1 -azepanyl]butanamide, 2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(6-ethynyl-2-oxo-1-azepanyl]butanamide, 2-[6- (5-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[6-(5-formyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[6- (5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6- (4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide, 2 -[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide, 2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3-methyl-1 -butynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-difluoropropyl)-2- oxo-1-azepanyl]butanamide, 2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2-bromo-2,2-difluoroethyl )-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(hydroxymethyl)-2-oxo- 1-azepanyl]butanamide, 2-(2-oxo-4-propyl-1-azepanyl)butanamide, 2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2- [4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(azidomethyl]-2-oxo-1 -azepanyl]butanamide, 2-(2-oxo-4-phenyl-1-azepanyl)butanamide, 2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide, 2-[2-oxo- 4-(3-thienyl)-1-azepanyl]butanamide, 2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-azidophenyl)-2-oxo- 1-azepanyl]butanamide, 2-[4-(2,2-difluorovinyl]-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl] butanamide, 2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(4-ethynyl-2-oxo-1-azepanyl]butanamide, 2-[4-(5- methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(5- cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepani l]butanamide, 2-[4-(4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide, 2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl )-1-azepanyl]butanamide, 2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide, 2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2- [4-(3-methyl-1-butynyl]-2-oxo-1-azepanyl]butanamide, 2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-( 2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-( 2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

Results were obtained using the following compounds:

(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,

(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xv) International Patent Publication WO2008/132139

In some embodiments of this invention, the compounds have formula (I), namely:

,

,

Where

Y is O or S. In some embodiments of this invention, Y is O. R1 is hydrogen or C1-6 alkyl;

R2 is a hydrogen atom;

R3 is -CONR5R6, -COR7, imidazolyl, imidazopyridinyl, imidazopyridazinyl; R5, R6 are the same or different and are independently selected from hydrogen and C1-6 alkyl;

R7 is C1-6 alkyl;

A is a monocyclic or bicyclic heterocyclic moiety selected from the group consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol- 3(2H)-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl , hexahydro-4Н-thieno[3,2-b]pyrrol-4-yl, 2,3-dihydro-1Н-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2Н )-yl, 1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 3,4 -dihydroquinolin-1(2H)-yl, 1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl, 1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R4 is either R^a or R^b, depending on whether A is a monocyclic or bicyclic heterocycle;

where A is a monocyclic heterocyclic fragment, R^ denotes R^a selected from the group that includes a hydrogen atom; C1-6 alkyl optionally substituted with a substituent selected from halo, C1-4 alkoxy, C1-4 alkylthio, azido, nitrooxy, or aryl; C2-6 alkenyl optionally substituted with a halogen atom; C2-6 alkynyl optionally substituted with a halogen atom; azido; alkoxycarbonylamino; arylsulfonyloxy; substituted or unsubstituted aryl; or a 3-8 membered substituted or unsubstituted heterocycle;

where A is a bicyclic heterocyclic fragment, R^ denotes R^ selected from the group that includes a hydrogen atom; nitro; cyano; a halogen atom; heterocycle; amino; aryl; C1-6 alkyl optionally substituted with at least one halogen atom, or C1-6 alkoxy optionally substituted with at least one halogen atom.

In some embodiments of this invention, the compounds are the following:

For compounds where A=Y is selected from 2-oxo-piperidin-1-yl, 2-oxoazepan-1-yl, 2-oxo-1,3-benzothiazol-3(2H)-yl or 2-oxo-1, 3-benzoxazol-3(2H)-yl, R3 must be selected from imidazolyl, imidazopyridinyl or imidazopyridazinyl.

For compounds where A=Y is 5-oxoimidazolidin-1-yl, R^ and R^ are hydrogen, R3 is -CONR5R6, R5 and R6 are as defined above, then R^ cannot be alkyl, aralkyl or substituted aralkyl.

Where A=Y is either 2-oxo-piperidin-1-yl or 2-oxoazepan-1-yl, R^, R^ and R^a all represent a hydrogen atom, then R^ cannot represent 2-phenylimidazo [1,2-a]pyridin-3-yl.

In a particular embodiment, A=Y is selected from the group consisting of:

,

,

where X is O or S, in a more specific embodiment of the present invention O; in another embodiment of the present invention, X is S.

The asterisks in the figure above indicate the attachment sites for R^a substituents.

In a specific embodiment of the present invention, when R^ is -CONR5R6 and R^ is C-μg alkyl, the carbon atom to which RI and R^ are attached preferably has the "S" configuration.

In a particular embodiment of this invention, R^ is a hydrogen atom, methyl, ethyl, and R^ is a hydrogen atom. In a particular embodiment of this invention, R3 is -CONH ₂ .

In yet another specific embodiment of this invention, R^ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl, or imidazo [1,2-b]pyridazin-3-yl. In a particular embodiment of this invention, R^ is C1-6 alkyl which may be substituted with a halogen atom; or phenyl.

In another particular embodiment of this invention, R^b is a hydrogen atom, a halogen atom, nitro, cyano, or C-μg alkyl optionally substituted with a halogen atom.

In another embodiment of the present invention, the compounds that can be used in the treatment of the above disorders, in particular epilepsy, have the formula (I-E), as well as their geometric isomers, enantiomers, diastereomers and mixtures thereof, or their pharmaceutically acceptable salt,

,

,

Where

X is O or S;

R-I denotes a hydrogen atom or C1-6 alkyl, in a more specific embodiment of the present invention denotes a hydrogen atom;

R3 is imidazolyl, imidazopyridinyl, imidazopyridazinyl; R^b denotes a hydrogen atom; nitro; cyano; a halogen atom; C1-6 alkyl optionally substituted with a halogen atom; C1-6 alkoxy optionally substituted with a halogen atom.

Another aspect of the present invention includes new compounds having formula (I-A), their geometric isomers, enantiomers, diastereomers and mixtures thereof and their pharmaceutically acceptable salt,

,

,

Where

R1 is hydrogen or C1-6 alkyl, preferably hydrogen, methyl or ethyl; more specifically, R^ is ethyl.

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl, preferably R^ is -CONH ₂ .

R^a denotes a hydrogen atom or aryl; with the proviso that 2-(5-oxoimidazolidin-1-yl]acetamide is excluded. Preferably, R^a is aryl, eg phenyl, which may be substituted, preferably halogen, nitro, alkoxy, in particular nitro.

In a particular embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which R1 and R^ are attached preferably has the "S" configuration.

Another aspect of the present invention includes novel compounds having the formula (I-B1 or I-B2), their geometric isomers, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

where X in the formula (I-B2) denotes either S or O, in a more specific embodiment of the present invention denotes S;

R1 is hydrogen or C1-6 alkyl, preferably hydrogen, methyl or ethyl; more specifically, R^ is ethyl.

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl; preferably R^ is -CONH ₂ .

R^a denotes a hydrogen atom; C1-6 alkyl, optionally substituted halogen or C1-4 alkoxy; aryl or C2-6 alkenyl optionally substituted with a halogen atom. Preferably R^a is C1-6 alkyl optionally substituted with a halogen atom, or C2-6 alkenyl optionally substituted with a halogen atom or aryl. In a more specific embodiment of this invention, R^a is C1-6 alkyl, optionally substituted with a halogen atom or aryl.

In a particular embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which RI and R^ are attached preferably has the "S" configuration.

Another aspect of this invention includes novel compounds having the formula (I-B3), their geometric isomers, enantiomers, diastereomers and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R1 is hydrogen or C-μg alkyl, preferably hydrogen, methyl or ethyl; more preferably R1 is ethyl.

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl; preferably R^ is -CONH ₂ , R^a is C1-5 alkyl optionally substituted with halogen or C1-4 alkoxy; aryl or C2-6 alkenyl, optionally substituted with a halogen atom.

Preferably, R^ is C1-6 alkyl optionally substituted with a halogen atom, or C2-6 alkenyl optionally substituted with a halogen atom.

In a particular embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which RI and R^ are attached preferably has the "S" configuration.

Another aspect of this invention includes novel compounds having the formula (I-C), their geometric isomers, enantiomers, diastereomers and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R1 is a hydrogen atom or C1-6 alkyl, in particular a hydrogen atom, methyl or ethyl,

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl; in particular, R^ stands for -CONH ₂ .

R^ is methyl, ethyl, butyl optionally substituted with a halogen atom or C1-4 alkoxy, unsubstituted phenyl or phenyl substituted with a halogen atom, C1-6 alkyl optionally substituted with a halogen atom, or C1-4 alkoxy; or R^ is C2-6 alkenyl optionally substituted with a halogen atom. Preferably R^ is methyl optionally substituted with a halogen atom, unsubstituted phenyl or phenyl substituted with a halogen atom.

In a specific embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which R1 and Rβ are attached preferably has the "S" configuration.

Another aspect of this invention includes compounds having the formula (I-D1 or I-D2), their geometric isomers, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R-I denotes a hydrogen atom or C1-6 alkyl, in particular a hydrogen atom; R3 is imidazolyl, imidazopyridinyl or imidazopyridazinyl. In one embodiment of the present invention, R^ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl, or imidazo[1 ,2-b]pyridazin-3-yl. In a more specific embodiment of this invention, R^ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl, R^ a is a hydrogen atom, C1-6 alkyl optionally substituted with a halogen atom, or C1-4 alkoxy; aryl; or C2-6 alkenyl optionally substituted with a halogen atom. In a particular embodiment of this invention, R^a is C1-6 alkyl optionally substituted with a halogen atom; aryl; or C2-6 alkenyl optionally substituted with a halogen atom. In a more specific embodiment of this invention, R^a is C1-6 alkyl, optionally substituted with a halogen atom; or aryl; for example propyl or phenyl;

provided that when R^ and R^a represent a hydrogen atom, R^ is not 2-phenylimidazo[1,2-a]pyridin-3-yl.

Another aspect of this invention includes, compounds having the formula (I-F1, I-F2 or I-F3), their geometric isomers, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R-I is hydrogen or C1-6 alkyl, preferably hydrogen, methyl or ethyl; more preferably R^ is a hydrogen atom.

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl or imidazopyridazinyl; and in a more specific embodiment of this invention, R3 is -CONH ₂ , 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3- yl or imidazo[1,2-b]pyridazin-3-yl. R^b denotes a hydrogen atom; a halogen atom; nitro; cyano; C1-4 alkyl optionally substituted with a halogen atom; C1-4-alkoxy optionally substituted with a halogen atom. In a more specific embodiment of the invention, R^ is a hydrogen atom, a halogen atom or cyano, more specifically a halogen atom.

In a specific embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which R1 and Rβ are attached preferably has the "S" configuration.

Another aspect of this invention includes compounds having the formula (I-F4), their geometric isomers, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R-I is a hydrogen atom or C1-6 alkyl, preferably a hydrogen atom;

R3 is imidazolyl, imidazopyridinyl or imidazopyridazinyl; more specifically R^ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl or imidazo[1,2- b]pyridazin-3-yl. More specifically R^ is 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl.

R^b denotes a hydrogen atom; a halogen atom; nitro; cyano; C1-4 alkyl optionally substituted with a halogen atom; C1-4-alkoxy optionally substituted with a halogen atom; in particular, R^ denotes a hydrogen atom, a halogen atom or cyano.

In a particular embodiment of the present invention, when R^ is -CONH ₂ and R^ is C1-6 alkyl, the carbon atom to which RI and R^ are attached preferably has the "S" configuration.

Another aspect of this invention includes compounds having any of the formulas (I-G1, I-G2 or I-G3), their geometric isomers, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof,

,

,

Where

R-I is a hydrogen atom or C1-6 alkyl; preferably a hydrogen atom;

R3 is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl; in a more specific embodiment of the present invention, R^ is -CONH ₂ , 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3- yl or imidazo[1,2-b]pyridazin-3-yl. In a still more specific embodiment of the present invention, R3 is 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl;

R4D is a hydrogen atom; a halogen atom; C1-4 alkyl optionally substituted with a halogen atom; C1-4 alkoxy optionally substituted with a halogen atom.

Specific examples of a compound of the present invention are compounds selected from the group consisting of: (2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-[3-(2,4-dinitrophenyl]-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide; 2- [5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2 -oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide; (2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H )-yl)propanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl) propanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide; 2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide; 2- (2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2- [2-oxo-5-(2,2,2-trifluoroethyl]-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b] pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin- 2-one; 1-(imidazo[1,2-a]pi ridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepane-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one; 5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepane-2-one; 5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepane-2-one; 1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one; 1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one; 4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one; 2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one; 1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one; 2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propanamide; 5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3( 2H)-one; 2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide; 2-(6-bromo-2-oxo-3,4-dihydroquinoline-1( 2H)-yl)acetamide, 1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one, 2-(6-iodo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide, 2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide, 7-chloro-2-{[2-(trifluoromethyl)imidazo[1 ,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)- 1,2,4,5-tetrahydro-3H-2-benzazepin-3-one, 7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3- benzazepin-2-one, and 7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3 -benzazepine-2-one.

In some embodiments, the compounds of the present invention are compounds selected from the group consisting of: 1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one; 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; and 5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one.

The following paragraphs give definitions of the various chemical groups that make up the compound of the invention and are intended to apply equally throughout the specification and claims, unless a broader definition is given in another specific definition.

"C1-6 alkyl" refers to alkyl groups having 1 to 6 or 1 to 4 carbon atoms. The term is exemplarily explained by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, trifluoromethyl, and the like. "Aryl" refers to an unsaturated aromatic carbocyclic group containing 6 to 14 carbon atoms, which has one ring (eg phenyl) or multiple fused rings (eg naphthyl). Preferred aryls include phenyl, naphthyl, phenanthrenyl, and the like.

"Heterocycle" means a saturated or unsaturated ring system containing, in addition to carbon atoms, at least one heteroatom, such as a nitrogen, oxygen and/or sulfur atom. "Heterocycle" includes both "heteroaryl" and "heterocycloalkyl".

"Heteroaryl" means a monocyclic heteroaromatic or bicyclic or tricyclic fused heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazopyridinyl, benzothiazolyl, benzoxazolyl, quinolisinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridine 3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazothiazolyl or imidazothiadiazolyl.

"C2-6 alkenyl" refers to alkenyl groups preferably containing 2 to 6 carbon atoms and having at least one or two alkenyl unsaturation sites. Preferred alkenyl groups include ethenyl (vinyl, -CH=CH ₂ ), n-2-propenyl (allyl, -CH ₂ CH=CH ₂ ) and the like.

"C2-6 alkynyl" refers to alkynyl groups preferably having 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation; preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH) and the like.

"C3-8 cycloalkyl" means a saturated carbocyclic group of 3 to 8 carbon atoms having one ring (eg cyclohexyl) or multiple fused rings (eg norbornyl). Preferred cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.

The term "heterocycloalkyl" refers to a C3-8 cycloalkyl group as defined above, wherein 1 to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, where R is a hydrogen atom or C1-6 alkyl .

"Alkoxy" refers to the group -OR, where R includes "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3-8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl ".

"Amino" refers to the group -NRR', where each R, R' independently represents a hydrogen atom, "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3-8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", and where R and R' together with the nitrogen atom to which they are attached, may optionally form a (3-8)-membered heterocycloalkyl cycle.

"Amido" refers to the group -C(=O)NRR', where each R, R' independently represents a hydrogen atom, "C1-5 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3- 8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", and where R and R' together with the nitrogen atom to which they are attached may optionally form a (3-8)-membered heterocycloalkyl ring.

"Acylamino" refers to the group -NRC(O)R', where the values of R and R' are given above in this description for the amino group.

"Ureido" refers to the group -NR"C(O)NRR, where R and R' are given above in this description for the amino group, and the value of R" is defined above in this description. "Sulfanyl" refers to a -SR group, where R is "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3-8 cycloalkyl", "heterocycloalkyl", "aryl", or "heteroaryl" .

"Sulfinyl" refers to the group -S(=O)R, where R is "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3-8 cycloalkyl", "heterocycloalkyl", " aryl" or "heteroaryl".

"Sulfonyl" refers to the group -S(=O) ₂ R, where R is "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C3-8 cycloalkyl", "heterocycloalkyl", "aryl" or "heteroaryl".

"Halogen atom" means a fluorine, chlorine, bromine and iodine atom.

The term "substituted or unsubstituted": Unless otherwise limited by the definition of an individual substituent, the groups included in the above set, such as the groups "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl", etc. may optionally be substituted with 1 to 5 substituents selected from the group consisting of "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "cycloalkyl", "heterocycloalkyl", " amino, amido, acylamino, ureido, aryl, heteroaryl, alkoxy, halogen, cyano, hydroxy, mercapto, nitro, amido, sulfanyl, sulfinyl ", "sulfonyl" and the like.

The acid addition salt form of a compound of formula I which exists in its free base form can be obtained by treating the free base with a suitable acid such as an inorganic acid, for example a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acid. and the like, or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic , cyclamic, salicylic, p-aminosalicylic, pamic acid, etc.

Compounds of formula I containing acidic hydrogen atoms can be converted into their therapeutically active, non-toxic base addition salt form, for example a metal or amine salt, by treatment with appropriate organic and inorganic bases. Suitable salt forms with a base include, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases include, for example, salts with N-methyl -D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine, and the like.

The reverse salt forms may be converted to the free forms by treatment with an appropriate base or acid.

The compounds of formula (I) and their salts may be in the form of a solvate, which is included in the scope of this invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. Said stereogenic center may be in the R- or S-configuration, with the R and S designations being used in accordance with the rules given in Pure Appl. Chem. 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compounds of formula (I), or mixtures thereof (including all possible mixtures of stereoisomers). With regard to reference in this invention to a compound or compounds, it should be understood that this invention covers the specified connection in each of its possible isomeric forms and mixtures thereof, unless there is a specific indication of a particular isomeric form.

The compounds of this invention may exist in various polymorphic forms. Although they are not explicitly indicated in the above formula, it is assumed that these forms are included in the scope of this invention.

Some of the compounds of formula (I) may also exist in tautomeric forms. It is intended that such forms, although not expressly indicated in the above formula, be included within the scope of the present invention.

The scope of this invention also includes prodrug forms of the compounds of formula (I) and their various subfields and subgroups.

In a specific embodiment, this invention relates to a compound selected from the group consisting of: (2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide; 2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide; 2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide; 2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide; 2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide; (+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide; (2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide; 2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide; 2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl]butanamide; 2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide; (2S)- 2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2- b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5- propylpiperidin-2-one, 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one, 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2- 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin 2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one, 1-{[6-chloro-2- (trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one; 5-propyl-1 -{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylme tyl)-5-phenylazepan-2-one; 5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepane-2-one; 1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one; 1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one; 4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl]acetamide; 2-(2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2- (6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide, 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H) -one; 6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one; 2-(6-nitro-2-oxo-1,3-benzothiazole-3(2H)- yl)acetamide; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H )-yl)propanamide; 2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2-(6-methyl-2-oxo-1,3-benzothiazol-3 (2H)-yl)acetamide, 6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one, 1-(1H-imidazol-4-ylmethyl)pyrazolo[ 1,5-a]pyridin-2(1H)-one, 2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide, 5-chloro-2-(1H- imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one; 2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide; 2-(6 -bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide; 1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one; 2-( 6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-cyano-2-ox co-3,4-dihydroquinolin-1(2H)-yl)acetamide; 7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one; 7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one; 7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one; and 7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one .

xvi) UK Patent No. 1039113

The novel compounds of this invention are N-substituted lactams of the general formula:

,

,

where N is an integer from 3 to 5 and R is

a radical in which m is 0, 1 or 2 and R' is a hydrogen atom or an alkyl, cycloalkyl, alkenyl or alkynyl radical which may contain from 3 to 6 carbon atoms, or an aryl radical, and R" is a hydrogen atom or the alkyl radical, or both R' and R" together with the nitrogen atom to which they are attached, form a heterocyclic ring such as the pyrrolidine ring.

xvii) UK Patent No. 1309692

In accordance with the present invention, novel N-substituted lactams of the general formula are provided:

,

,

where X denotes a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, p denotes an integer taking values from 1 to 6, Y denotes a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, or cycloalkyl, and R' and R", which may be the same or different, denote hydrogen atoms or alkyl, alkenyl, alkynyl, cycloalkyl or aryl radicals, or R' and R" together with the nitrogen atom to which they attached, form a heterocyclic radical which may contain additional heteroatoms, provided that at least one of the symbols X and Y is other than a hydrogen atom.

Valproate

In some embodiments of the present invention, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof.

Analogues and derivatives of valproate suitable for use in the methods and compositions of the present invention include compounds of the formula:

,

,

where independently for each case:

X is -OH, C _1-10 alkoxy, -O-alkaline metal, -N(R ¹ ) ₂ , -SH or -SC _1-10 alkyl;

R is linear or branched C _1-30 alkyl; And

R1 is H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, or aralkyl;

with the proviso that R may be unsubstituted or substituted with one or more -OH, C _1-10 alkoxy, -N(R ¹ ) ₂ , -SH, -S-C _1-10 alkyl or aryl.

In other embodiments of the present invention, valproate analogs and derivatives suitable for use in the methods and compositions of the present invention include compounds of the formula:

,

,

where independently for each case:

X is -OH, C _1-10 alkoxy, -O-alkaline metal, -N(R ¹ ) ₂ , -SH or -SC _1-10 alkyl;

R is CH[(CH ₂ ) ₂ CH ₃ ] ₂ ; And

R1 is H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, or aralkyl;

with the proviso that R may be unsubstituted or substituted with one or more -OH, C _1-10 alkoxy, -N(R ¹ ) ₂ , -SH, -S-C _1-10 alkyl or aryl.

In other embodiments of the present invention, valproate analogs and derivatives suitable for use in the methods and compositions of the present invention include compounds of the formula:

,

,

where independently for each case:

X is -OH, -O-alkali metal, -SH or -NH ₂ ; And

R is CH[(CH ₂ ) ₂ CH ₃ ] ₂ .

Methods for obtaining compounds of the above formula can be found, for example, in US patent No. 4558070; 4595695; 4654370; 4895873; 4913906; 5017613; 5019398; 5049586; 5162573; 5440023; 5856569; 6131106 and 6610326.

Other names and descriptions of valproate are contemplated in this specification, such as Depakote, Valrelease, 2-propylpentanoate, valproic acid, VPA, and sodium valproate.

Methods for the treatment of CNS disorders accompanied by cognitive impairment, which use the administration of an SV2A inhibitor

In accordance with one aspect of the present invention, methods and compositions are provided for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or methods for reducing the rate of cognitive decline in a subject suffering from a central nervous system (CNS) disorder that is accompanied by cognitive impairment ( in particular age-related cognitive impairment, MCI causing memory loss, mild cognitive impairment (aMCI), dementia, AD, prodromal phase of Alzheimer's disease, PTSD, schizophrenia, ALS, and anticancer therapy-associated cognitive impairment), or a subject at risk, who is in need of such treatment by administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In some embodiments of the present invention, the SV2A inhibitor is administered in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments of the present invention, the SV2A inhibitor is selected from the group that includes levetiracetam, seletracetam, and brivaracetam, or derivatives or analogs thereof, or pharmaceutically acceptable salts, or solvates, or hydrates, or polymorphs, or prodrugs. In other embodiments, the SV2A inhibitor is levetiracetam, or a derivative thereof, or an analog thereof, or a pharmaceutically acceptable salt or solvate or hydrate or polymorph thereof, or a prodrug thereof. In other embodiments, the SV2A inhibitor is brivaracetam, or a derivative thereof, or an analog thereof, or a pharmaceutically acceptable salt or solvate or hydrate or polymorph thereof, or a prodrug thereof. In other embodiments, the SV2A inhibitor is seletracetam, or a derivative thereof, or an analog thereof, or a pharmaceutically acceptable salt or solvate or hydrate or polymorph thereof, or a prodrug thereof. In some embodiments of the present invention, the CNS disorder that is accompanied by cognitive impairment is age-related cognitive impairment, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). In one embodiment of the present invention, MCI is a memory loss-inducing mild cognitive impairment. In some embodiments of the present invention, the CNS disorder that is accompanied by cognitive impairment is dementia, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient. The subject may be a human or other mammal, such as a non-human primate, or a rodent (eg, a rat). In some embodiments of the present invention, the subject is a human patient.

The use of SV2A inhibitors and their pharmaceutically acceptable salt, hydrate, solvate or polymorphic modification in combination with valproate or its analogue, derivative or pharmaceutically acceptable salt reduces the amount of valproate required for the treatment of CNS disorders accompanied by cognitive impairment and other affective disorders, including MCI causing memory loss MCI, AAMI, ARCE, dementia, AD, PTSD, schizophrenia, ALS, or anticancer therapy-associated cognitive impairment. In one embodiment of the present invention, the subject suffering from such a cognitive impairment is a human patient and thus the side effects caused by valproate are reduced without reducing efficacy. In addition, the combination of an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and valproate, or an analogue, derivative, or pharmaceutically acceptable salt thereof, is superior to either of these drugs when administered alone at their optimum dose and, therefore, represents an improved treatment option for CNS disorders accompanied by cognitive impairment.

It should be understood that the compounds and substances used in the compositions and methods of the present invention should preferably readily cross the blood-brain barrier when administered peripherally. However, compounds that cannot cross the blood-brain barrier can still be effectively administered directly to the central nervous system, for example, intraventricularly or via another neuro-compatible route.

As used herein, administration of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and valproate or an analog, derivative or pharmaceutically acceptable salt thereof "in combination" includes simultaneous administration and/or administration at different times, such as sequential administration. The simultaneous administration of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and valproate or an analog, derivative or pharmaceutically acceptable salt thereof may optionally be combined with additional doses of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and /or valproate or its analogue, derivative or its pharmaceutically acceptable salt. Simultaneous administration of drugs includes administration as a co-formulation or, alternatively, as separate compositions.

In accordance with the present invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof, may be administered to a subject by any suitable method or by any suitable routes. In some embodiments of the present invention, the drugs are administered orally; however, intravenous subcutaneous, intra-arterial, intramuscular, intraspinal, rectal, intrasternal, intraperitoneal, intraventricular or transdermal administration, topical application or administration by inhalation is also contemplated. The agents may be administered orally, for example, in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets, and the like, which are prepared by methods known in the art. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, and polymorphs thereof, alone or in combination with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, may be administered to a subject by various routes. For example, an SV2A inhibitor, or a salt, solvate, hydrate, or polymorph thereof, is administered intravenously, and valproate, or an analog, derivative, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered orally.

In some embodiments, implementation of the present invention, the introduction is a slow or prolonged release. The term "sustained release" is widely used in the pharmaceutical field, and is used herein to refer to the controlled release of an active compound or agent from a dosage form into the environment over (during or in the process) an extended period of time, for example, for more or equals one hour. The sustained release formulation will release the drug at a substantially constant rate over an extended period of time, or a substantially constant amount of drug will be released gradually over an extended period of time. The term "sustained release" as used herein includes the terms "controlled release", "sustained release", "delayed release", "sustained release" or "slow release" as these terms are used in the pharmaceutical sciences. In some embodiments of the present invention, sustained release dosages are administered as a patch or via a dispenser.

Dosing regimens for agents and compositions in accordance with the methods of the present invention will vary depending on the particular compound or composition selected, the route of administration, the type of condition being treated, the age and condition of the patient, the course of the disease, or stage of treatment, and ultimately account, will be administered at the discretion of the attending physician. It should be understood that the amount of SV2A inhibitor or pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof administered, alone or in combination with valproate or an analogue, derivative or pharmaceutically acceptable salt, is an amount effective to produce the desired biological effect, such as positive results, including clinical results, for example, an amount that normalizes neural activity in areas of the brain that exhibit abnormal activity (including, but not limited to, DG, CA3 and/or entorhinal cortex), and /or leading to an improvement in cognitive functions. It should be understood that an effective amount may be administered in more than one dose and during a course of treatment.

When administered via an implant, device, or composition for slow or sustained release, an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, alone or in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, as appropriate, you can enter once or periodically one or more times during the life of the patient. For clinical use, other administration intervals, intermediate or shorter, may be used, as may be determined by the skilled person, in accordance with the methods of the present invention.

The required duration of administration of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analogue, derivative or pharmaceutically acceptable salt thereof, can be determined by the skilled artisan through routine experimentation. For example, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analogue, derivative or pharmaceutically acceptable salt thereof, can be administered over 1-4 weeks, 1-3 months, 3- 6 months, 6-12 months, 1-2 years or more, up to the full lifespan of the patient.

It is known in the art that normalization to body surface area is a suitable method for extrapolating doses between species. The human equivalent dose (HED) for a given dosage can be estimated using the following formula, which accounts for differences in body surface area (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologics Evaluation and Research ):

HED = dose for animal X (Km animal/Km human)

where the Km coefficient is body weight divided by body surface area (the Km value for the rat was determined to be 6 and the human Km is 37; see Reagan-Saw, Nihal, Ahmad, 2007). Thus, a dose of 10 mg/kg in rats is equivalent to 1.6 mg/kg in humans (10 mg/kg × (6/37) = 1.6 mg/kg). To calculate the human dose in milligrams from the mg/kg dose, the mg/kg dose is multiplied by the typical adult weight of 70 kg.

In some embodiments of the present invention, the dose of the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is between 0.1 and 5 mg/kg/day (which, given a typical 70 kg human patient, is between 7 up to 350 mg/day).

In some embodiments of the present invention, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, may be administered at doses in accordance with, for example, US Patent Application 12/580464, International Patent Publication PCT/US2009/005647, Patent Application US 61/105847, US Patent Application 61/152631, US Patent Application 61/175536 and US Patent Application 61/441251. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered every 12 hours or 24 hours at a daily dose of about 0.001 to 5 mg/kg, about 0.001 to 0.5 mg/kg , about 0.01 to 0.5 mg/kg, about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 2 to 4 mg/kg, or about 2 to 3 mg/kg, or about 3 to 4 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3 mg/kg, or about 0.3 to 0 .4 mg/kg, or about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.5 to 2 mg/kg, or about 0.8 to 1.6 mg/kg kg, or about 0.8 to 3.6 mg/kg, or about 0.5 to 4 mg/kg, or about 0.04 up to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.05 to 3 mg/kg, or about 0.08 to about 1.6 mg/kg, or about 0.08 to 3.6 mg/kg, or about 0.05 to 2 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 up to 5 mg/kg, or about 0.05 to 0.5 mg/kg, or about 0.8 mg/kg, or about 1.6 mg/kg, or about 3.6 mg/kg, or about 0 .08 mg/kg, or approximately 0.16 mg/kg, or approximately 0.36 mg/kg. Other dosages that are greater than, intermediate to, or less than the indicated dosages may also be used and may be determined by the skilled person in accordance with the methods of the present invention. For multiple administrations over several days or weeks or longer, depending on the condition, treatment is continued until a sufficient level of cognitive function is achieved.

In some embodiments of the present invention, the dose of the SV2A inhibitor is 0.001-5 mg/kg/day (which, given a typical 70 kg human patient, is approximately 0.07-350 mg/day). Doses that may be used include, but are not limited to, 0.001 mg/kg/day, 0.0015 mg/kg/day, 0.002 mg/kg/day, 0.005 mg/kg/day, 0.0075 mg/kg /day, 0.01 mg/kg/day, 0.015 mg/kg/day, 0.02 mg/kg/day, 0.03 mg/kg/day, 0.04 mg/kg/day, 0.05 mg /kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.75 mg/kg/day, 1.0 mg/kg/day, 1.5 mg/kg/day, 2.0 mg/kg/day, 2.5 mg/kg/day, 3.0 mg/day kg/day, 4.0 mg/kg/day, or 5.0 mg/kg/day. In some embodiments of the present invention, the dose of the SV2A inhibitor is 0001-0.5 mg/kg/day (which, given a typical 70 kg human patient, is approximately 0.07-35 mg/day) or 0.01- 0.5 mg/kg/day (which is approximately 0.7-35 mg/day). Other dosages that are greater than, intermediate to, or less than the indicated dosages may also be used and may be determined by the skilled person in accordance with the methods of the present invention.

In some embodiments of the present invention, the dose of the SV2A inhibitor is from 0.1 to 5 mg/kg/day (which, considering a typical 70 kg human patient, is about 7 to 350 mg/day). Doses that may be used include, but are not limited to, 0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg /kg/day, 2.5 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day or 5 mg/kg/day. In some embodiments, the implementation of the present invention, the dose is 1-2 mg/kg/day (which, given a typical human patient weighing 70 kg is 70-140 mg/day). In other embodiments, implementation of the present invention, the dose of the SV2A inhibitor is from 0.1 to 0.2 mg/kg/day. Other dosages that are greater than, intermediate to, or less than the indicated dosages may also be used and may be determined by the skilled person in accordance with the methods of the present invention.

In some embodiments of the present invention, the dose of the SV2A inhibitor is from 0.01 to 2.5 mg/kg/day (which, considering a typical 70 kg human patient, is approximately 0.7-180 mg/day). Doses that may be used include, but are not limited to, 0.01 mg/kg/day, 0.02 mg/kg/day, 0.03 mg/kg/day, 0.04 mg/kg/day, 0.06 mg/kg/day, 0.08 mg/kg/day, 0.12 mg/kg/day, 0.14 mg/kg/day, 0.16 mg/kg/day, 0.18 mg/day kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day, 1.0 mg/kg/day, 1 .2 mg/kg/day, 1.4 mg/kg/day, 1.6 mg/kg/day, 1.8 mg/kg/day, 2.0 mg/kg/day, 2.2 mg/kg /day, 2.4 mg/kg/day or 2.5 mg/kg/day. In some embodiments of the present invention, the dose of the SV2A inhibitor is 0.1-2.5 mg/kg/day (which, given a typical 70 kg human patient, is approximately 7-180 mg/day), 0.1- 0.2 mg/kg/day (which is approximately 7-15 mg/day), 0.2-0.4 mg/kg/day (approximately 14-30 mg/day), 0.4-2.5 mg /kg/day (approximately 25-180 mg/day), 0.6-1.8 mg/kg/day (approximately 40-130 mg/day), 0.04-2.5 mg/kg/day (approximately 2.5-180 mg/day) or 0.06-1.8 mg/kg/day (approximately 4-130 mg/day). In some embodiments of the present invention, the dose of the SV2A inhibitor is 40 to 130 mg, 140 to 300 mg, 200 to 300 mg, or 140 to 200 mg. Other dosages that are greater than, intermediate to, or less than the indicated dosages may also be used and may be determined by the skilled person in accordance with the methods of the present invention.

In some embodiments, implementation of the present invention, the interval of introduction is 12 or 24 hours. You can also use the introduction at less frequent intervals, for example once every 6 hours. In some embodiments of the present invention, the SV2A inhibitor is administered once every 12 or 24 hours with a total daily dose of 0.1 to 5 mg/kg (for example, in the case of administration every 12 hours with a daily dose of 2 mg/kg, each administration is 1 mg /kg). In some embodiments of the present invention, the SV2A inhibitor is administered every 24 hours at a daily dose of 1 to 2 mg/kg. In another embodiment of the present invention, the SV2A inhibitor is administered every 24 hours at a daily dose of 0.1-0.2 mg/kg. In some embodiments of the present invention, the SV2A inhibitor is administered once every 12 or 24 hours with a daily dose of 0.01 to 2.5 mg/kg (for example, if administered every 12 hours with a daily dose of 0.8 mg/kg, each administration is 0.4 mg/kg). In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.1 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.4 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.6 to 1.8 mg/kg. In some embodiments, the SV2A selective inhibitor is administered every 12 or 24 hours at a daily dose of 0.04-2.5 mg/kg. In some embodiments, the SV2A selective inhibitor is administered every 12 or 24 hours at a daily dose of 0.06-1.8 mg/kg. In some embodiments, the SV2A selective inhibitor is administered every 12 or 24 hours at a daily dose of 0.001-5 mg/kg. In some embodiments, the SV2A selective inhibitor is administered every 12 or 24 hours at a daily dose of 0.001-0.5 mg/kg. In some embodiments, the SV2A selective inhibitor is administered every 12 or 24 hours at a daily dose of 0.01-0.5 mg/kg.

In some embodiments, the SV2A inhibitor is levetiracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered every 12 or 24 hours at a daily dose of about 1 to 2 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0 .4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 2.0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg kg, or about 2.0 to 4.0 mg/kg, or about 0.1 to 5 mg/kg, or about 70 to 140 mg, or about 7 to 180 mg, or about 25 to 180 mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200 to 300 mg, or about 140 to 200 mg, or about 7 to 350 mg.

In other embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered every 12 or 24 hours in accordance with one of the daily dosage ranges, which are indicated as "+" among those shown in table 1 or table 2.

Table 1
Daily doses of levetiracetam Lower
range
Upper
range 0.1 mg/kg 0.4 mg/kg 0.6 mg/kg 1 mg/kg 2 mg/kg 3 mg/kg 1.8 mg/kg + + + + 2 mg/kg + + + + 2.5 mg/kg + + + + + 3 mg/kg + + + + + 4 mg/kg + + + + + + 5 mg/kg + + + + + +

table 2
Daily doses of levetiracetam for a person weighing 70 kg Lower
range
Upper
range 7 mg 25 mg 40 mg 70 mg 140 mg 200 mg 130 mg + + + + 140 mg + + + + 180 mg + + + + + 200 mg + + + + + 300 mg + + + + + + 350 mg + + + + + +

In some embodiments, the SV2A inhibitor is brivaracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.2 to 0.4 mg/kg, or about 7 to 15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg.

In other embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered every 12 or 24 hours with a daily dose of at least 0.1 mg; 0.5 mg; 0.75 mg; 1.0 mg; 1.5 mg or 2.0 mg, but not more than with a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg. In other embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0. 01 mg/kg, 0.015 mg/kg, 0.02 mg/kg or 0.03 mg/kg, but not more than with a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg /kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg or 0.04 mg/kg.

In other embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours in accordance with one of the daily dosage ranges, which are indicated as "+" among those shown in table 3 or Table 4. For example, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof can be administered once every 12 or 24 hours with a daily dose of 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg; 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0 .1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015- 0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg , 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05 mg/kg or 0.0015-0 .04 mg/kg.

Table 3
Daily doses of brivaracetam Lower
range
Upper
range 0.0015 mg/kg 0.0075 mg/kg 0.01 mg/kg 0.015 mg/kg 0.02 mg/kg 0.03 mg/kg 0.04 mg/kg + + + + + + 0.05 mg/kg + + + + + + 0.1 mg/kg + + + + + + 0.15 mg/kg + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4 mg/kg + + + + + + 0.5 mg/kg + + + + + +

Table 4
Daily doses of brivaracetam for a person weighing 70 kg Lower
range
Upper
range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5 mg + + + + + + 5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20 mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In some embodiments, the SV2A inhibitor is seletracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments of the present invention, seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered every 12 or 24 hours with a daily dose of at least 0.1 mg; 0.5 mg; 0.75 mg; 1.0 mg; 1.5 mg or 2.0 mg, but not more than with a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 35 mg. In other embodiments of the present invention, seletracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered once every 12 or 24 hours with a daily dose of at least 0.0015 mg/kg; 0.0075 mg/kg; 0.01 mg/kg; 0.015 mg/kg; 0.02 mg/kg or 0.03 mg/kg, but not more than with a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg or 0.04 mg/kg.

In some embodiments of the present invention, seletracetam, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered according to one of the daily dosage ranges indicated as "+" among those shown in Table 5 and Table 6. For example, seletracetam or its pharmaceutically acceptable salt, hydrate, solvate or polymorph can be administered once every 12 or 24 hours with a daily dose of 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg; 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0 .1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015- 0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg , 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05 mg/kg or 0.0015-0 .04 mg/kg.

Table 5
Seletracetam daily doses Lower
range
Upper
range 0.0015 mg/kg 0.0075 mg/kg 0.01 mg/kg 0.015 mg/kg 0.02 mg/kg 0.03 mg/kg 0.04 mg/kg + + + + + + 0.05 mg/kg + + + + + + 0.1 mg/kg + + + + + + 0.15 mg/kg + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4 mg/kg + + + + + + 0.5 mg/kg + + + + + +

Table 6
Daily doses of seletracetam for a person weighing 70 kg Lower
range
Upper
range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5 mg + + + + + + 5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20 mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

The SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, may be administered at subtherapeutic doses when such administration is contemplated in combination with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, due to the valproate-dependent increase in the therapeutic index of the SV2A inhibitor. In some embodiments, the increase in the therapeutic index of the SV2A inhibitor due to the combination with valproate is greater than the therapeutic index of the SV2A inhibitor when administered in the absence of valproate by at least about 1.5-fold, or 2.0-fold, or 2.5 times, or 3.0 times, or 3.5 times, or 4.0 times, or 4.5 times, or 5.0 times, or 5.5 times, or 6.0 times, or 6, 5 times, or 7.0 times, or 7.5 times, or 8.0 times, or 8.5 times, or 9.0 times, or 9.5 times, or 10 times, or more than about 10 times once. In some embodiments of the present invention, combinations of an SV2A inhibitor with valproate reduce the dose of the SV2A inhibitor required to provide them with a therapeutic effect. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, when administered in combination with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, is administered every 12 or 24 hours at a daily dose of about 0.001 mg/kg to 5 mg/kg, or about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg, or about 0 01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/ kg, or from about 0.5 mg/kg to 5 mg/kg, or from about 0.05 mg/kg to 0.5 mg/kg. In some embodiments of the present invention, the amount of the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, administered in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, is a subtherapeutic amount. Such a sub-therapeutic amount may be, for example, a daily dose administered every 12 or 24 hours with a daily dose of less than 5 mg/kg, less than 2.5 mg/kg, less than 2 mg/kg, less than 1 .75 mg/kg, less than 1.6 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.8 mg/kg, less than 0.6 mg/kg, less less than 0.5 mg/kg, less than 0.4 mg/kg, less than 0.3 mg/kg, less than 0.2 mg/kg, less than 0.1 mg/kg, less than 0.05 mg /kg, less than 0.04 mg/kg, less than 0.03 mg/kg, less than 0.02 mg/kg, less than 0.01 mg/kg, less than 0.005 mg/kg, or less than 0.001 mg /kg.

Valproate or an analog, derivative or pharmaceutically acceptable salt thereof may be administered at dose levels up to and including the usual dosage. Valproate is prescribed for the treatment of epilepsy, bipolar disorder, migraine and post-traumatic stress disorder. Valproate has also been reported to be effective in the treatment of cognitive impairment (Koh et al., 36th annual meeting of the Society for Neuroscience, October 15, 2006, No. 273.14, D.3). Long-term subcutaneous administration of sodium valproate at 100 mg/kg/day to elderly memory-impaired rats cured their cognitive impairment, and their performance on memory tests was significantly improved. This dose gives a total plasma valproate level of 10 µg/ml (10 µg/ml total valproate). However, treatment with long-term subcutaneous administration of 50 mg/kg/day of valproate was not effective.

Valproate or an analog, derivative or pharmaceutically acceptable salt thereof may be administered at doses other than conventional levels when such administration is contemplated in combination with an SV2A inhibitor due to the SV2A inhibitor-dependent increase in the therapeutic index of valproate. In some embodiments of the present invention, the therapeutic index of valproate due to combination with an SV2A inhibitor exceeds the therapeutic index of valproate, compared with when it is administered in the absence of an SV2A inhibitor, at least about 1.5 times, or 2.0 times, or 2.5 times, or 3.0 times, or 3.5 times, or 4.0 times, or 4.5 times, or 5.0 times, or 5.5 times, or 6.0 times, or 6, 5 times, or 7.0 times, or 7.5 times, or 8.0 times, or 8.5 times, or 9.0 times, or 9.5 times, or 10 times, or more than about 10 times once. In some embodiments, the implementation of the present invention, the combination of valproate with an SV2A inhibitor reduces the dose of valproate necessary to provide them with a therapeutic effect. In some embodiments of the present invention, the amount of valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, when administered in combination with an SV2A inhibitor, is a sub-therapeutic amount. In some embodiments of the present invention, the dose of valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, when administered in combination with an SV2A inhibitor, is a dose that results in a total plasma valproate level of 0.5 to 5 µg/mL. Those skilled in the art will readily be able to determine dosages suitable for valproate or an analog, derivative or pharmaceutically acceptable salt thereof using the methods of the present invention.

In some embodiments of the present invention, when an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, is administered in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, dosages as the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, the solvate and the polymorph, and valproate, or an analog, derivative or pharmaceutically acceptable salt thereof, are sub-therapeutic in the treatment of a CNS disorder accompanied by cognitive impairment, as compared to when they are administered alone.

In some embodiments of the present invention, a suitable amount of the SV2A inhibitor is administered so as to reduce the dose of valproate (e.g., the dose required to achieve some degree of cognitive improvement or to cure age-related cognitive impairment) by at least at least about 20%, at least about 30%, at least about 40%, or at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, relative to the dose of valproate typically administered alone (i.e., alone and not in combination with other therapeutic agents or compounds). Said reduction can be expressed in terms of the amount administered at a given administration and/or the amount administered over a given period of time (reduction in administration frequency).

In some embodiments of the present invention, the combined administration of an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, and valproate, or a derivative analog thereof, or a pharmaceutically acceptable salt thereof, results in a longer or improved therapeutic effect for the subject, which is approximately 1. 5 times or 2.0 times or 2.5 times or 3.0 times or 3.5 times or 4.0 times or 4.5 times or 5.0 times or 5.5 times , or 6.0 times, or 6.5 times, or 7.0 times, or 7.5 times, or 8.0 times, or 8.5 times, or 9.0 times, or 9.5 times, or 10 times, or more than about 10 times, the effect achieved with the introduction of only valproate or only an SV2A inhibitor.

Compositions of the invention

In one aspect, the present invention provides compositions comprising an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, alone or in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof. In some embodiments of the present invention, the SV2A inhibitor and valproate may be present in the same dosage unit (eg, combined together in one capsule, tablet, powder or liquid, etc.). The composition discussed herein may contain more than one SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and/or more than one valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In some embodiments of the present invention, the SV2A inhibitor and valproate are in separate formulations that are packaged together.

The compositions described herein may additionally contain pharmaceutically acceptable excipient(s) and may contain other agents that serve to enhance and/or supplement the effectiveness of the SV2A inhibitor and/or valproate. The compositions may also contain additional agents known to be useful in the treatment of cognitive impairment.

The compositions of the present invention may be in solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. If necessary, they may be formulated with coatings, such as enteric coatings, or they may be formulated to provide controlled release of one or more active ingredients, such as sustained or sustained release, according to methods well known in the art. the field of technology. In some embodiments, the implementation of the composition is prepared in a form suitable for slow, controlled or prolonged release. The term "sustained release" is widely used in the pharmaceutical field, and is used herein to refer to the controlled release of an active compound or agent from a dosage form into the environment over (during or in the course of) an extended period of time, for example, for more than or equals one hour. The sustained release formulation will release the drug at a substantially constant rate over an extended period of time, or a substantially constant amount of drug will be released gradually over an extended period of time. The term "sustained release" in this specification includes the terms "controlled release", "sustained release", "delayed release", "sustained release" or "slow release", as these terms are used in pharmaceutical chemistry. In some embodiments of the present invention, sustained release dosages are administered as a patch or via a dispenser. The compositions may also be liquid dosage forms, including solutions, emulsions, suspensions, syrups, and elixirs.

Said compositions may be specially formulated for administration by any suitable route as described above and known in the art. Compositions for parenteral administration include sterile injectable aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders which are reconstituted in sterile injectable solutions or dispersions before use. Compositions for intraoral and oral delivery (including sublingual and buccal administration, see, for example, Danckwerts et al., and oral administration) include, but are not limited to, bioadhesive polymers, tablets, patches, liquids, and semi-solids (see ., for example, Smart et al.). Compositions for delivery through the respiratory tract (for intrapulmonary and nasal delivery) include, but are not limited to, a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers, inhalers generating small liquid droplets, drops, solutions, suspensions, sprays, powders, gels , ointments and specialized systems such as liposomes and microspheres (see, for example, Owens et al., "Alternative Routes of Insulin Delivery" and Martini et al). Compositions for transdermal administration include, but are not limited to, colloids, patches, and microemulsions. Other suitable dosage forms for the above and other routes of administration include depot injections, suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. The action of microorganisms can be prevented by the inclusion of various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the pharmaceutical injectable form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

Therapeutic compositions can be prepared according to methods well known in the art of pharmacy, see, for example, Goodman et al., 2001; Ansel, et al., 2004; Stoklosa et al., 2001; and Bustamante, et al., 1993.

In some embodiments of the present invention, a composition containing an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, comprises an SV2A inhibitor in an amount of 0.07-60 mg, 0.07-350 mg, 25-60 mg; 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg or 3-60 mg. In some embodiments of the present invention, a composition containing an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, comprises an SV2A inhibitor in an amount of 0.05-35 mg.

In some embodiments of the present invention, a composition comprising an SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in combination with valproate, or an analog, derivative, or pharmaceutically acceptable salt thereof, comprises an amount of the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or polymorphic modification, which is 0.05-35 mg, 0.07-60 mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-15 mg, 5- 30 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg or 0.07-50 mg or 3-60 mg. In some embodiments of the present invention, the amount of the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.

In addition to the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof, the compositions and methods of this invention may also include other therapeutically useful agents. These and other therapeutically useful agents may be administered as a single composition, simultaneously or sequentially, in accordance with the methods of the present invention.

Those skilled in the art will appreciate that the compositions and methods described herein may be supplemented and modified to suit the desired application, that the compositions and methods described herein may find use in other suitable applications. applications, and that these additions and modifications do not fall outside the scope of the present invention.

The present invention will become more clear from the following experimental section. However, those skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the present invention as more fully described in the embodiments of the present invention which are set forth below.

EXAMPLES

Introduction and models of cognitive impairment

Many different conditions characterized by cognitive impairment, in particular age-related memory impairment (AAMI), mild cognitive impairment (MCI), and age-related cognitive decline (ARCD), are believed to be associated with aging. Other conditions are associated with diseases, such as AD. Animal models provide an important resource for developing and evaluating treatments for these age-related cognitive impairments. The features that characterize age-related cognitive impairment in animal models generally extend to age-related cognitive impairment in humans. Thus, efficacy in similar animal models predicts efficacy in humans.

Of the available models, the Long Evans rat model of cognitive impairment is particularly well suited to distinguish between disease-associated and aging-associated cognitive impairment. Indeed, extensive behavioral studies have identified natural forms of cognitive impairment in outbred aged rats of the Long Evans genetic line (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). During behavioral evaluation using the Morris Water Maze (MWM), rats recognize and remember the location of the escape platform based on the pattern of spatial cues surrounding the maze. The cognitive basis of the test is trial attempts, in which measurements are made of the movement of the animal in space in search of the location of the rescue platform. Elderly rats in the study population have no difficulty swimming to the visible platform, however, age-related impairments are observed when the platform is camouflaged, requiring the use of spatial information. The performance of the test for individual outbred elderly rats of the Long Evans genetic line varies considerably. For example, a certain proportion of rats complete the task on par with young adults. However, approximately 40-50% of older rats fall outside the range of task performance demonstrated by juveniles. Such variability among older rats reliably reflects individual differences. Thus, among the age population, some animals have cognitive impairments and are designated as age-affected (AI), while other animals do not have cognitive impairments and are designated as not affected by age-related impairments (AU). See, for example, Colombo et al., Proc. Natl. Acad. sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 691-708, (1989); Rapp and Gallagher, Proc. Natl. Acad. sci. 93: 9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); and Nicolle et al, J. Neurosci. 19:9604-9610, (1999).

The present inventors used the above described rat model to identify individual AI rats and AU rats. Then, the inventors of the present invention evaluated the behavior of the AI rats by administering various pharmacological treatments to them.

Example 1 Increased SV2A Gene Expression in Age-Related Elderly Rats

A study of the behavioral characteristics of young, age-related and non-age-impaired rats in the Morris water maze (MWM)

Behavioral tests are carried out on young (4 months) and elderly (24 months) normal male rats of the Long Evans genetic line.

The MWM device consists of a large circular pool (diameter 1.83 m, height 0.58 m) filled with water (27°C) which is rendered opaque by the addition of a non-toxic pigment or other substances. In a typical "hidden platform" test, rats learn to find a camouflaged white escape platform (34.5 cm high) that is located in the center of one of the sectors of the maze approximately 1.0 cm below the surface of the water. When conducting behavioral tests, the specified platform, operating it from outside the maze, can be lowered into the lower part of the pool or raised to its normal position. The site location remains constant from attempt to attempt. Since there are no local cues that mark the position of the platform, the ability of rats to efficiently locate it from any starting position on the pool perimeter depends on the use of information surrounding the maze. The maze is surrounded by black curtains to which white patterns are attached as configuration information for spatial clues. The second platform (37.5 cm high), whose surface is painted black, rises 2 cm above the surface of the water during cue learning to control non-recognition factors. The behavior of the rats in the pool is recorded using a camera, which is suspended at a height of 2.5 m above the center of the pool. The camera is connected to a video surveillance system (HVS Image Advanced Tracker VP200) and a computer that runs HVS software developed by Richard Baker of HVS Image, Hampton, UK.

The MWM technique has been optimized to be sensitive to the effects that aging has on cognition and optimized to reliably detect individual differences in a population of older outbred rats of the Long Evans genetic line (Gallagher et al., Behav. Neurosci ., 107:618-626, (1993)). Rats are given three attempts per day for 8 consecutive days using 60 second intervals between attempts. At each training attempt, the rats are released into the maze through one of four equally spaced starting positions along the perimeter of the pool. The starting position is changed from attempt to attempt, thus preventing the use of a reaction strategy (for example, always turn left from the starting position to find the location of the rescue platform). If, during any of the attempts, the rat does not find the escape platform within 90 seconds, then the experimenter directs the rat to the platform, where it remains for 30 seconds. Every sixth attempt includes a trial test, which evaluates the change in displacement in the space of the maze. During these tests, the rat swims for 30 seconds with the platform lowered to the bottom of the pool, after which the platform is raised to its normal position to complete the rescue attempt. After completion of the technique using the hidden platform, the rats are evaluated for the ability to learn prompts using the visible platform. The location of this platform changes from trial to trial in one of the sessions, consisting of 6 training attempts.

The proximity of the animal's position to the target is used to analyze the behavior during the training attempt and trial trial. A measure of proximity is obtained by determining the position of the animal in the maze (10 times per second) in order to record the distance from the rescue platform in an average of 1 second. For both trial trials and training trials, a correction procedure is applied so that test performance is relatively unbiased to differences in target distance from different starting positions around the pool perimeter. When this correction is made, the average swimming speed for each trial (path length/delay) is calculated. Then the amount of time required to swim to the target at a given speed from the starting position used for the attempt is subtracted from the record before the effectiveness of the attempt is evaluated, i.e. cumulative distance during training attempts and the average distance from the target during trial tests. Thus, the scores obtained in determining the proximity measure reflect the search error, which characterizes the deviation from the optimal search, i.e. a direct path to the target and search in the immediate vicinity of this place during trial tests.

Computer video surveillance records are accumulated to obtain data on the performance of the maze test for each rat. Measurements in training attempts and pilot tests are analyzed using analysis of variance (ANOVA).

In one of a series of trials, test performance during hidden, masked platform training differed between groups of young and older rats [F(1.23)=12.69, p<0.002]. In this series of trials, no difference between groups was observed for prompting trials using the visible platform. In this series of tests, latency during cue learning averaged 9.36 seconds for young rats and 10.60 seconds for older rats.

The average closeness measure of the interpolated trials is used to calculate the spatial learning index for each individual subject, as detailed in Gallagher et al., Behav. neurosci. 107:618-26, (1993). When a rat quickly learns to look for a platform close to its position, the rat's spatial learning index is low. Overall, in one series of trials, older rats differed from younger rats [F(1.23)=15.18, p<0.001]. Older rats are classified as non-disabled or impaired by the learning index profile for the young population. Older rats that fall within the normative range of young rats (score <241) are designated age-free (AU). The rest of the elderly subjects, the score of which is outside the range of effectiveness of testing for young rats, referred to as prone to age-related disorders (AI).

Preparation of RNA from behaviorally characterized rats

Twenty-four outbred rats of the Long Evans genetic line, whose behavior is characterized as described above, are sacrificed by decapitation in order to obtain fresh brain tissue. The brain is removed and microsections of the hippocampal dentate gyrus region are made from 500 micron sections taken along the transverse axis of the entire hippocampus (both left and right hippocampus) from 24 characterized rats. Each group includes 8 animals (AI, AU, and Y).

Total RNA was isolated with Trizol reagent (Invitrogen, Carlsbad, CA) according to standard protocol (homogenization in Trizol reagent followed by extraction with chloroform and precipitation with isopropanol). Total RNA is then purified using the RNeasy mini kit (Qiagen, Valencia, CA). The RNA samples are then prepared into cRNA probes at Johns Hopkins University's specialized microarray facility, largely according to Affymetrix specifications.

Briefly, 5 μg total RNA was used to synthesize the first strand cDNA using oligo-dTplus 24 promoter primer oligonucleotide probes (Proligo LLC, Boulder, CA) and the SuperScript Choice System (Invitrogen). After double-stranded cDNA synthesis, the product was purified by phenol-chloroform extraction and biotinylated antisense cRNA was generated by in vitro transcription using the BioArray RNA High Yield Transcript Labeling kit (ENZO Life Sciences Inc., Farmingdale, NY). 15 μg of biotinylated cRNA is fragmented at 94° C. for 35 min (100 mM Trix-acetate, pH 8.2, 500 mM KOAc, 150 mM MgOAc). 10 μg of the total fragmented cRNA is hybridized into the RAT 230-2 genome of the Affymetrix GeneChip array for 16 hours at 45°C with constant rotation (60 rpm).

The Affymetrix Fluidics Station 450 is then used to wash and stain the chips, removing the unhybridized target product and incubating with streptavidin-phycoerythrin conjugate to stain the biotinylated cRNA. Staining is then enhanced using goat immunoglobulin-G (IgG) as blocking reagent and a biotinylated anti-streptavidin antibody (goat) followed by a second staining step with streptavidin-phycoerythrin conjugate.

For quality control of total RNA isolated from samples, an Agilent Bioanalyzer, Lab on a Chip technology is used to confirm that all samples have optimal rRNA ratios (1:2, for 18S and 28S, respectively) and free structures from interference.

For quality control of hybridization, chip imaging, and inter-chip comparison, the following parameters are considered: conversion factor: related to overall chip intensity, to confirm the same signal intensity and staining across all samples; background: assessment of non-specific or cross-hybridization; percentage of signals present: the percentage of transcripts that are considered to be highly hybridized to the chip (available), according to a certain algorithm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH)(3'/5'): representation of RNA integrity by determining the ratio of regions in the 3'-5' direction for the constitutive GAPDH gene, its presence on the chip and a ratio close to 1 confirms good target integrity (sample); peak (BioB/BioC) to confirm the level of detection and sensitivity after hybridization.

Microchip Data Analysis

Fluorescence was measured with Affymetrix's G3000 GeneArray Scanner and image analysis of each gene chip was performed using Affymetrix's GeneChip Operating System 1.1.1 (GCQS) software using default standard parameters. All gene chips from the GeneChip array use short oligonucleotides for the genes in the RNA sample.

For cross-chip comparisons, a common simulation is used to scale all probe sets to a target intensity (TGT) of 150. The total number of available signals and conversion factors are the same for all chips. Further analyzes of presence/absence and statistical differences are carried out step by step as follows. Probe sets are defined as present in an area if they have a signal in four out of eight animals in one group.

Probe sets are annotated with Affymetrix's June 20, 2005 annotation and all probe sets presenting a specific gene are identified.

Conduct an ANOVA for the signal values of the probe sets for all available sets of probes by combining two groups of animals and comparing them with the third group. An "AI ANOVA" was carried out where the AU group was combined with the Young group and compared with the AI group.

Pearson correlations are calculated comparing the probe set signal values with the learning indices of older animals (excluding young animals) across all available probe sets. As shown in FIG. 1, the expression of genes encoding SV2A is significantly increased in individuals with age-related disorders (AI), compared with young individuals (Y) and individuals without age-related disorders (AU) in a series of experiments that are carried out as above. The obtained results show that the increased expression of SV2A correlates with the development of age-related cognitive impairments.

Example 2 Effect of Levetiracetam on Elderly Rats with Relapsing Disorders

Results in the Morris water maze

Six Long Evans genetically impaired age-related (AI) rats (which are characterized as above) are tested for their memory retention of new spatial information in MWM under different drug/control treatments (vehicle as control and two different dosages of levetiracetam). The procedure for using MWM is practically the same as that described in Example 1. Specifically in this study, after training trials, a memory retention test was performed as described below.

Rats AI provide six training attempts in one training day with 60-second intervals between each training attempt for two days in a row. At each training attempt, rats are released into the maze from one of four equally spaced starting positions along the perimeter of the pool. If during any attempt the rat fails to locate the escape platform within 90 seconds, then the experimenter directs the rat to the platform where it remains for 30 seconds. 30 min and up to 1 hour prior to all training trials on each training day, AI rats are pre-treated with one of three drug use conditions: 1) vehicle control (0.9% saline), 2) levetiracetam (5 mg/kg/day) and 3) levetiracetam (10 mg/kg/day); in the form of intraperitoneal (i.p.) injections. The same six AI rats are used in all studies so that each treatment condition is tested on all six rats. In addition, to balance any potential displacement, both the location of the escape platform and the spatial cues surrounding the water maze are different for the three processing conditions. Thus, using one set of locations and spatial cues, two rats are treated with saline control, two rats are treated with levetiracetam (5 mg/kg/day) and two rats are treated with levetiracetam (10 mg/kg/day). Using a second set of locations and spatial cues, two rats treated with saline control in the first trial are treated with either levetiracetam (5 mg/kg/day) or levetiracetam (10 mg/kg/day); two rats pretreated with levetiracetam (5 mg/kg/day) are treated with either saline control or levetiracetam (10 mg/kg/day); and two rats previously treated with levetiracetam (10 mg/kg/day) are treated with either saline control or levetiracetam (5 mg/kg/day). Using the last set of locations and spatial cues, the groups of rats are again swapped so that each group is treated under conditions different from those in which it was previously treated.

After the second day of training and the completion of twelve training attempts (over two days), the rat is returned to its cage and placed in the vivarium. After a delay of 24 hours from the last training attempt, the rats are given one trial attempt ("retention test"), which is the same MWM task as the training attempts, but the rescue platform is removed.

In the memory retention test, the MWM round pool is divided into 4 sectors. The specific sector where the rescue platform is placed in training attempts is referred to as the "target sector". The specific area in which the rescue platform is placed in training attempts is referred to as the "target annular zone". In the memory retention test, the time the AI rat spends swimming in the target sector is measured and then plotted as a percentage of the total swimming time. In FIG. 2 presents the results of one such set of memory retention tests. The time the AI rat spends in the target ring zone is also measured. In FIG. 2 presents the results of one such set of memory retention tests. Data on the amount of time collected for all three conditions of drug treatment.

In the memory retention test, the results of which are shown in FIG. 2, the time that the AI rats spent in the target sector is approximately 25%, which is equivalent to the efficiency of the test when they do not retain the memory of the location of the platform. This efficacy does not improve significantly in the group treated with levetiracetam at a dose of 5 mg/kg/day. However, the group treated with levetiracetam at 10 mg/kg/day showed a significant improvement in memory compared to rats treated with vehicle control, as evidenced by a marked increase in time spent in the target sector, up to approximately 35% of total time. swimming in the pool (see Fig. 2). This level of test performance is equivalent to that of young rats and age-free rats, indicating that treatment with a dose of 10 mg/kg/day of levetiracetam resulted in a significant recovery in the ability of AI rats to perform this test in MWM. The efficacy of treatment with a dose of 10 mg/kg/day of levetiracetam is also noticeable for the time spent in the target ring zone (see Fig. 2).

Results in the radial maze

The effect of levetiracetam on spatial memory retention in age-impaired (AI) rats was evaluated in a radial maze (RAM) behavior study using vehicle control and five different doses of levetiracetam (1.25 mg/kg/day, 2.5 mg /kg/day, 5 mg/kg/day, 10 mg/kg/day and 20 mg/kg/day). Behavioral tasks in RAM are performed on ten AI rats. All six treatment conditions are tested on all ten rats as described above for the MWM test.

The RAM device used consists of eight equally spaced arms. An elevated arm of the labyrinth (7 cm wide and 75 cm long) protrudes from each face of the octagonal central platform (30 cm in diameter, 51.5 cm high). The transparent sidewalls on the sleeves are 10cm high and angled at 65° to form a trough. A food well (4 cm in diameter, 2 cm deep) is located at the distal end of each sleeve. Froot Loops™ (Kellogg Company) is used as a reward. Blocks constructed from Plexiglas™ (30cm high x 12cm wide) can be positioned to prevent entry into any of the sleeves. Numerous additional clues are installed around the labyrinth.

Rats AI are first subjected to preliminary preparatory tests (Chappell et al., Neuropharmacology 37: 481-487, 1998). Preliminary pre-testing includes a habituation phase (4 days), a learning phase on standard take-and-go tasks (18 days), another learning phase (14 days) during which between the presentation of a subset of sleeves designated by the experimenter (e.g., 5 sleeves available and 3 sleeves are blocked) introduce a slight delay, and the completion of the task is to take - carry away in an eight-arm maze (i.e. when all eight arms are available).

In the habituation phase, rats are introduced to the maze in an 8-minute session for four consecutive days. In each of these sessions, food rewards are scattered throughout the RAM, first in the center of the platform and in the arms, and then gradually the rewards are concentrated in the arms. After this habituation phase, a standard training technique is used in which a food ball is placed at the end of each sleeve. Rats are given one try each day for 18 days. Each daily trial ends when all eight food pellets have been received, or when either 16 choices have been made or 15 minutes have elapsed. After this training phase is completed, a second training phase is performed in which the memory requirements are increased by using a small test delay. At the beginning of each test, three arms of the eight-arm labyrinth are blocked. The rats are allowed to get food from the five sleeves that were allowed access during this initial 'information phase' of testing. The rats are then removed from the maze for 60 seconds, during which time the barriers from the maze are removed, thereby allowing access to all eight arms. The rats are placed back on the central platform and allowed to receive the rest of the food rewards during this 'retention phase' of the trial. The identity and configuration of the blocked sleeves varies between trials.

The number of "mistakes" that AI rats make during the memory retention test phase is recorded. An error during the trial occurs when rats enter an arm from which food has already been taken in the pre-hold component of the test, or when they revisit an arm in a post-hold session they have already visited.

After completion of the pre-training test, the rats are subjected to longer delay intervals, in particular a one-hour delay between the information phase (presentation with some sleeves blocked) and the memory retention test (presentation of all sleeves). During the delay interval, the rats are removed from the maze to the testing room on carts in individual cages. AI rats are pre-treated 30-40 minutes prior to daily trials with one of the following six conditions: 1) vehicle control (0.9% saline), 2) levetiracetam (1.25 mg/kg/ day), 3) levetiracetam (2.5 mg/kg/day), 4) levetiracetam (5 mg/kg/day), 5) levetiracetam (10 mg/kg/day), 6) levetiracetam (20 mg/kg/day). day); as an intraperitoneal (i.p.) injection. Injections are administered every other day with intermediate days of washing out the drug from the body. Each rat AI is subjected to treatment in all six conditions within 23 days of testing. In order to balance any potential biases, the effect of the drug is evaluated using a series of increasing - decreasing doses in a series, in particular, the first series of doses is administered in ascending order, and then repeated in descending order. Thus, each dose is determined twice.

Parametric statistics (paired t-tests) were used to compare the performance of AI rats on the RAM memory retention test in the one-hour delay option and in the context of different doses of levetiracetam and vehicle control (see FIG. 3). The mean number of trial errors is significantly lower for treatment with 5 mg/kg/day levetiracetam (mean error ± standard error of the mean (SEM) = 0.75 ± 0.32) and 10 mg/kg/day ( mean error ± SEM = 0.80 ± 0.27) than with vehicle control (mean error ± SEM = 2.00 ± 0.42). Compared with vehicle control, treatment with levetiracetam significantly improved memory performance at 5 mg/kg/day (t(9)=2.18, p=0.057) and 10 mg/kg/day (t(9)=2 .37, p=0.042).

The radial sleeve maze is also used to assess the effect of combination therapy with levetiracetam (intraperitoneal administration) and valproate (subcutaneous administration). Levetiracetam itself was effective in reducing errors in AI rats in the radial maze with doses of 5-10 mg/kg dose, but not with doses of 1.25 mg/kg or 2.5 mg/kg. Valproate alone is effective at 100 mg/kg but not at 25 mg/kg or 50 mg/kg. See fig. 4. However, the combination of these two drugs gives a synergistic effect. Co-administration of valproate 50 mg/kg and levetiracetam 2.5 mg/kg, which is not an effective dose for either drug when administered alone, results in a reduction in errors in the radial maze task. The same result was obtained with an even lower dose of 1.25 mg/kg levetiracetam in combination with 50 mg/kg valproate. See fig. 5. The isobologram of levetiracetam and valproate dosages confirms that the effect of the combined administration of valproate 50 mg/kg and levetiracetam 1.25 mg/kg (VPA 50 + LEV 1.25; open circle) is a synergistic (superadditive) effect. Coadministration of valproate 50 mg/kg and levetiracetam 2.5 mg/kg (VPA 50 + LEV 2.5; dark circle), on the other hand, gives a simple additive effect, as indicated by its location on the line. See fig. 6.

To calculate the human equivalent dose (HED) for levetiracetam dosage for the treatment of age-related cognitive impairment in humans, the present inventors used the formula HED (mg/kg) = rat dose (mg/kg) x 0.16 (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologics Evaluation and Research), so a dose of 5 mg/kg/day in rats is equivalent to a dose of 0.8 mg/kg/day in humans, and the dose 10 mg/kg/day in rats is equivalent to 1.6 mg/kg/day in humans.

Example 3: Effect of levetiracetam on people with aMCI

An 8-week intersubject trial was conducted with 17 subjects suffering from moderate cognitive impairment (aMCI) causing memory loss and 17 age-matched controls using low-dose treatment with levetiracetam. During the course of the study, each aMCI subject is treated with both drug and placebo separately for two periods of two weeks each, with the order of treatment for the different aMCI subjects being balanced (see FIG. 7). Age-matched subjects from the control group receiving placebo served as an additional control. Cognitive testing and functional magnetic resonance imaging data are obtained for subjects after each two-week treatment or placebo period.

Participants and definition of clinical characteristics

17 right-handed patients suffering from aMCI are recruited from the Johns Hopkins Alzheimer's Research Center (ADRC) and from other referrals. An additional 17 right-handed healthy volunteers are recruited from the ADRC pool of control participants and from other referral patients. All participants are interviewed by phone regarding their cognitive status to determine if they can meet inclusion criteria for the study (including criteria for MRI scanning). All participants then undergo a neurological, psychiatric and neuropsychological examination using standard instruments and methods. The psychiatric evaluation includes a Structured Clinical Interview for DSM-IV Axis I Disorder and a Clinical Dementia Rating Scale (CDR) questionnaire. All patients suffering from aMCI have a CDR of 0.5. The diagnosis of aMCI is based on the criteria proposed by Petersen et al. (See, in particular, "Mild cognitive impairment: Aging to Alzheimer's Disease," Oxford University Press, N.Y. (2003)), which include complaints of memory (acknowledged by informant), impaired memory function on testing (1.5 standard deviations below norms) while maintaining cognitive functions (within 1 standard deviation from the norm), the absence of a decrease in functional abilities and the absence of dementia. The final diagnosis of aMCI is made by clinical consensus. Exclusion criteria include major neurological or psychiatric disorders, head trauma with loss of consciousness, history of drug use or drug dependence, and general contraindications for MRI examination (eg, presence of a pacemaker, aneurysm loops, claustrophobia). Every patient suffering from aMCI is required to have a research partner (i.e. informant) who can provide information about the patient's daily functions and confirm that medications are being taken properly. See fig. 18A and 18B.

Doctor visit for examination : The examination includes 4 visits to the doctor within 8 weeks (see Fig. 7). The baseline visit is for medical, neurological, psychiatric and neurocognitive assessments. Visits 1 and 2 are identical to the base visit but include fMRI sessions. The post-elimination visit, which coincides with the end of the 4-week elimination period, is conducted to provide a brief clinical assessment and initiate the second phase of administration of the drug or placebo.

Base visit : During the screening visit, informed consent is obtained from the patient (or informant in the case of an MCI patient). The patient and informant participate in a standardized clinical interview that is used to determine the degree of the patient's functional impairment in daily life based on the Clinical Dementia Rating Scale (CDR). Obtain a medical, neurological, and psychiatric history of the patient (including a review of current medications used), as well as a family history of dementia. Conduct a brief medical, neurological and psychiatric examination (including vital signs). Blood is drawn to perform standard laboratory tests to determine if the patient meets the inclusion criteria for the study. The patient is reassessed for MRI contraindications using a standard form developed by the Kirby Imaging Center. Conduct a brief cognitive ability test (described below in the section on neuropsychological assessment). These studies are used to determine whether the patient meets the criteria for inclusion in the study. It all ends with the completion of standardized forms. If the patient meets the study inclusion criteria, then the patient receives the investigational drug (drug or placebo, random selection) and instructions on how the drug should be taken. The patient is advised of possible suicidal thoughts and is advised to stop taking the drug and contact the study physician immediately if this occurs.

Visit 1 : At the end of the first 2-week drug/placebo period following the Baseline Visit, the medical, neurological and psychiatric examination and cognitive testing are repeated. Conduct a clinical examination for suicidal ideation. They take blood again to repeat the standard tests and determine if there are any changes associated with drug treatment; also determine the level of levetiracetam in the patient's blood. All medicines that were provided at the Base Visit (drug or placebo) are collected and the patient's compliance with the medication regimens is assessed. On the same day, either immediately before or immediately after the clinical assessment, the first fMRI session (with cognitive tests) is performed. During this visit, patients complete their first treatment period.

Post Elimination Visit : At the end of the elimination period (4 weeks) following Visit 1, the patient undergoes a brief medical evaluation, including a medical and psychiatric assessment. Take blood to determine the level of levetiracetam in the blood (to confirm the removal of the drug from the body). The patient is given a new drug (drug or placebo, alternating with that given in the previous treatment period) for the final phase of the study and instructed on how the drug is to be taken.

Visit 2 : Approximately 2 weeks after the Post-Clear Visit (i.e. 2 weeks after the start of the second treatment period), the medical, neurological and psychiatric examination and cognitive testing are repeated. The patient is examined in the clinic for suicidal ideation. They take blood again to repeat the standard tests and determine if there are any changes associated with drug treatment; also determine the level of levetiracetam in the patient's blood. All medications provided at the Visit after the drug has been cleared from the body are collected and the patient's compliance with medication regimens is assessed. On the same day, either immediately before or immediately after the clinical assessment, a second fMRI session (with cognitive tests) is performed.

Neuropsychological assessment

All participants undergo a neuropsychological examination during the evaluation of the effectiveness of treatment (Visits 1 and 2), as well as at the Base Visit. The assessment is performed outside the scanner and includes the Buschke selective memory test (Buschke and Fuld, 1974) and the verbal pair association subtest, the semantic memory subtest, the Wechsler Corrected Memory Scale (WMS-R) visual recall subtest (Wechsler, 1997), and the visual retention test Benton, since such tasks are most sensitive to the function of the medial surface of the temporal lobe and to early memory problems (Marquis et al., 2002 and Masur et al., 1994). In addition, patients are asked to perform tests to assess several general cognitive functions, such as tests to assess general mental status, executive function, attention, and general naming ability. All neuropsychological tests are performed by trained research assistants during a 60-minute session. Because the three neuropsychological examinations in this study take place over a period of 8 weeks, different versions of the neuropsychological tests are used to minimize test-specific practical effects. If necessary, the patient provides breaks during the test.

Prescribing a drug

As described above, the drug treatment period is two weeks prior to Visit 1 or 2 (with a two-week period prior to another Visit, which is the placebo phase). For patients receiving medical treatment, use half a scored tablet containing 250 mg of levetiracetam to give a dose of 125 mg/kg twice daily, corresponding to approximately 3.6 mg/kg/day (assuming the weight of an average adult is 70 kg).

All drug and placebo formulations are prepared in a 1:1 distribution. At the pharmacy, patients are randomized as they request medication and a prescribing list is kept.

Levetiracetam is rapidly and almost completely absorbed after oral administration, and its bioavailability is independent of diet. The plasma half-life of levetiracetam is approximately 7 ± 1 hour (expected to be 9-10 hours in the elderly due to decreased renal function). Absorption is rapid, with peak plasma concentration occurring approximately 1 hour after oral administration. Steady state can be achieved after 2 days with dosing in multiple doses twice a day.

A typical starting dose of levetiracetam in the treatment of epilepsy in humans is 500 mg twice daily, which is approximately 4.3 mg/kg/day. The dose is then increased to the optimal effective dose, which is up to 50 mg/kg/day. Thus, the dose used in this experiment is a quarter of the minimum human dose that is used to treat epilepsy.

Even lower doses are contemplated, such as 25-60 mg twice daily, based on previous animal studies indicating low dose efficacy. The highest effective doses of levetiracetam that have been used in an animal model are 5-10 mg/kg (in an emergency). The human equivalent dose (HED) is calculated as described above and the indicated dose for the treatment of age-related cognitive impairment in humans is equivalent to 0.8-1.6 mg/kg/day (or 28-56 mg twice daily).

MRI Data Collection

Images are acquired using high resolution techniques developed at Stark laboratory. Data is collected on a Phillips 3 Tesla scanner (Eindhoven, The Netherlands) equipped with an 8-channel SENSE (Sensitivity Encoding) head coil, which is housed at F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute (Baltimore, MD). High-resolution echo-planar images are acquired with a 64×64 acquisition matrix, repetition time is 1500 milliseconds, echo time is 30 milliseconds, vector deflection angle is 70 degrees, SENSE factor is 2, and isotropic resolution without gap is 1.5 mm × 1.5 mm × 1.5 mm. Nineteen oblique sections are obtained, parallel to the main longitudinal axis of the hippocampus, and cover the entire area of the medial surface of the temporal lobe on both sides. In addition to functional scans, structural MPRAGE scans of the brain as a whole are obtained (parameters: 150 oblique sections, isotropic resolution 1 mm).

Image analysis

Data analysis was performed using the Analysis for Functional Neuroimages software (AFNI, version 2008_07_18_1710). Images are first recorded together to correct for head movement in transverse and longitudinal scans. Exposures in which a significant number of elementary acts of movement are noted (a rotation of more than 3 degrees or a shift of 2 mm in any direction relative to the preliminary exposure), plus or minus one repetition in 1.5 seconds, are excluded from the analysis. Structural anatomical data are recorded in a standard stereotaxic span (Talairach & Tournoux, 1988) and the same parameters are then applied to functional data. Get behavioral vectors to model different types of studies.

The ROI-LDDMM (Plastic Diffeomorphic Quantitative Regions of Interest Mapping) method, which is an inter-subject alignment method, enhances the capability of multi-subject regional fMRI studies by focusing the alignment energy specifically on ROIs (areas of interest) rather than any other areas of the brain. First of all, anatomical and functional scans of all subjects are normalized to the Talairach atlas using AFNI. Sub-regions of the medial surface of the temporal lobes and hippocampus (bilateral entorhinal cortex, paranasal cortex, parahippocampal cortex, CA3/dentate region, CA1 region, and underlying tissue) are segmented in three dimensions on MPRAGE scans. The labels for the CA3 region and the dentate gyrus (DG) are combined. The anatomically determined ROIs are then used to calculate the ROI-LDDMM transform of the 3D vector field for each patient using its customized template based on the mean of the entire sample tested as the target. The ROI-LDDMM transformations for each individual patient's ROIs are then used to construct fitted coefficient maps.

The data group is analyzed by two-way analysis of variance (ANOVA), using the types of trials and the group as fixed factors, and the patient as a random factor introduced into the group. A maximum threshold p<0.05 was used along with a spatial threshold of 10 volume pixels to determine functional ROIs for the overall F-statistics. This approach, in contrast to direct pair-wise comparison of contrast, reduces the selection bias of the voxel, since any differences among different conditions are allowed for the voxel to be selected. This threshold is then combined with anatomical segmentation to include only volumetric image elements within regions of interest. This allows you to exclude voxels that do not change with any of the model factors, and effectively limit the analysis of voxels that show any change in job or group conditions. Volumetric pixels within each functional ROI are convolved for further analysis.

Cognitive tests during fMRI scans at Visits 1 and 2

The activity of the medial surface of the patient's temporal lobe is measured by functional MRI during the patient's performance of a 3-alternative sampling task against a predetermined criterion, in which the viewing participants see new, repeated and similar ("bait") stimuli. The Psychophysics Toolbox extension in Matlab 7.0 (The Math Works, Natick, MA) is used to present stimuli and collect behavioral data. Irritants are color photographs of ordinary objects. Each participant is given a series of attempts during functional imaging sessions, with each series including a mixture of three types of image pairs: similar pairs, identical pairs, and undistracted films. These pairs of images are completely randomized throughout the trial and are presented individually as a series of images (see FIG. 10A). Participants are instructed to conclude whether each object they see is new, old, or similar. Of particular interest are the participants' responses when they are presented with a second pair of similar objects ("bait"; Fig. 10B). The correct identification of the decoy stimulus by the patient as "similar" is a behavioral confirmation of image separation, i.e. separation of such practical knowledge into separate non-overlapping presentations. However, the misidentification of the bait stimulus as "old" or "new" indicates a poor image separation.

Identifying a bait stimulus as "old" means that the patient is focused on the similarity between the bait stimulus and the previously shown member of the image pair. The identification of the bait stimulus as "new" indicates that the patient also failed to recall the previously shown member of the image pair. Each series also includes a set of baseline tests that use perceptual separation tests that are known to provide a lower and more stable estimate of baseline medial temporal lobe activity (Stark & Squire, 2001 FNAS; Law et al., 2005 ).

A review of the level of activity of various subregions of the medial temporal lobe during a cognitive test, as measured by fMRI, shows that aAMCI patients have hyperactive DG/CA3 during memory tasks and have decreased activity in the entorhinal cortex compared to people in an age-matched control group.

The authors of the present invention evaluate the level of activity in DG/CA3 with successful decisions in the evaluation of memory in the control group and among aAMCI patients. Mean activity is calculated from the average activity value measured by fMRI at the time of presentation of the bait stimulus, correctly identified as "similar" by the patient, and calibrated to determine baseline activity. Fig. 8A shows that aMCI patients exhibit DG/CA3 hyperactivity in making these decisions (p=0.013). However, FIG. 8B shows that treatment with levetiracetam reduces DG/CA3 hyperactivity in aMCI patients (p=0.037). The level of activity in the aMCI of the patient treated with the drug actually normalizes to the extent that it becomes statistically indistinguishable from the activity of subjects in the control group treated with placebo. See fig. 8C for the activity averages shown in FIG. 8A and 8B.

The level of activity in the EU during successful decisions in the memory assessment is significantly lower for aMCI patients treated with placebo compared with the control group (p=0.003). See fig. 9A. However, treatment with levetiracetam normalizes activity in aMCI patients as well in the EC region. See fig. 9B. Treatment with levetiracetam increases EC activity in the memory evaluation process in aMCI patients so that it becomes statistically indistinguishable from placebo-treated control patients. See fig. 9B. See fig. 9C for the activity averages shown in FIG. 9A and 9B.

The normalization of DG/CA3 activity and EC activity during memory assessment due to treatment with levetiracetam is reflected in the changes that are observed in the effectiveness of patients performing aMCI cognitive tasks. When treated with aMCI placebo, patients performed worse than controls, much less likely to correctly identify bait stimuli as "similar" and much more likely to incorrectly identify them as "old" (p=0.009). See fig. 11. However, the performance of aMCI tasks by patients improves significantly when treated with levetiracetam. See fig. 12. The interaction of more correct identifications of "similar" with less incorrect identifications of "old" in drug treatment leads to a significant improvement in the performance of the specified memory task (p=0.039). See fig. 13 for the data table shown in FIG. 11 and 12.

Task performance in placebo-treated control subjects and drug- or placebo-treated aMCI patients are also compared in other conventional cognitive tests such as the Buschke Selective Memory Test - Delayed Recall (FIGS. 14A and 14B), the Visual Benton retention (FIGS. 15A and 15B), verbal pair association test - Recognition (FIGS. 16A and 16B), and verbal pair association test - Delayed recall (FIGS. 17A and 17B). All of these aMCI tests placebo-treated patients perform worse than placebo-treated subjects in the control group, and treatment with levetiracetam does not improve patient performance on aMCI tests.

There are a number of possible reasons why levetiracetam treatment does not improve patients' aMCI performance on these other cognitive tests. The 3-alternative pre-set criteria sampling task, which is performed during the fMRI study, is a task that is particularly sensitive to DG/CA3 function. Thus, patient performance on this task may be most attuned to changes in DG/CA3 activity as a result of levetiracetam treatment. In addition, aMCI patients receive levetiracetam for only two weeks prior to cognitive tests. It is expected that drug treatment for more than two weeks, for example, for 16 weeks or 8 months, will lead to an increase in efficiency. Finally, comparative animal studies (see example 1) show that even a lower dose could be more effective. The human dose of 125 mg twice daily is equivalent to the rat dose of 22.3 mg/kg/day. As shown in Example 2 and FIG. 3, 20mg/kg levetiracetam is too high a dose for rats and fails to improve the performance of rats in the AI task in the radial maze. Effective doses of levetiracetam used in an animal model are 5-10 mg/kg. The human equivalent dose (HED) calculated from the optimal rat dose is 0.8-1.6 mg/kg/day. This dose resulted in a dose of 28-56 mg twice daily (which is substantially lower than the 125 mg twice daily used in this study). Thus, it is expected that aMCI patients will show further normalization of DG/CA3 activity and EC activity, as well as a further increase in performance on cognitive tests, when treated at low doses that correspond to the effective dose in the rat, e.g., doses of 25- 60 mg levetiracetam twice a day.

Claims (8)

1. A method of treating a cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof or at risk of its occurrence, where the CNS disorder is a moderate cognitive impairment causing memory loss, dementia, Alzheimer's disease (AD), prodromal phase AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or cognitive impairment associated with anticancer therapy, the method comprising the step of administering to said subject brivaracetam or a pharmaceutically acceptable salt thereof in an amount of 0.7-180 mg per day. 2. The method of claim 1 wherein brivaracetam or a pharmaceutically acceptable salt thereof is in a form suitable for sustained release. 3. Pharmaceutical composition for oral administration once a day, containing 0.7-180 mg of brivaracetam or a pharmaceutically acceptable salt thereof, for the treatment of cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need of it or being in a group risk of its occurrence wherein the CNS disorder is memory loss-inducing mild cognitive impairment, dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or anticancer therapy-associated cognitive impairment. 4. The method of claim 1, wherein the method delays or retards the progression of a CNS disorder-related cognitive impairment in a subject in need or at risk of developing it. 5. The method of claim 1, wherein the method reduces the rate of cognitive decline associated with a CNS disorder in a subject in need or at risk of having it. 6. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition delays or retards the progression of a CNS disorder-related cognitive impairment in a subject in need or at risk of developing it. 7. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition reduces the rate of cognitive decline associated with a CNS disorder in a subject in need or at risk of having it.

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