HK1146269A

HK1146269A - 1,4-diaza-bicycl0(3.2.2)n0nyl pyrimidinyl derivatives useful as nicotinic acetylcholine-receptor ligands

Info

Publication number: HK1146269A
Application number: HK11100374.3A
Authority: HK
Inventors: D‧彼得斯; D‧B‧蒂莫曼; G‧M‧奥尔森; E‧Φ‧尼尔森; J‧K‧克里斯坦森; J‧P‧雷德罗伯; T‧迪林
Original assignee: 神经研究公司
Priority date: 2007-08-17
Filing date: 2008-08-14
Publication date: 2011-05-20

Description

Novel 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives useful as nicotinic acetylcholine receptor ligands

Technical Field

The present invention relates to novel 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives and their use in the preparation of pharmaceutical compositions. The compounds of the present invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors.

Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the Central Nervous System (CNS), the Peripheral Nervous System (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Background

The endogenous cholinergic neurotransmitter acetylcholine exerts its biological effects via two cholinergic receptor types, muscarinic acetylcholine receptors (machrs) and nicotinic acetylcholine receptors (nachrs).

As it is well known that muscarinic acetylcholine receptors dominate quantitatively over nicotinic acetylcholine receptors in the brain region where memory and cognition are important, much research on the development of therapeutic agents for memory-related disorders has focused on the synthesis of modulators of muscarinic acetylcholine receptors.

However, recent attention has emerged to the development of nAChR modulators. Several diseases are associated with degeneration of the cholinergic system, namely senile dementia of the alzheimer type, vascular dementia and cognitive decline caused by organic brain damage diseases directly related to alcoholism. Indeed, several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency.

WO 2004/029053 and WO 2005/074940 describe diazabicyclic aryl derivatives useful as nicotinic acetylcholine receptor modulators. However, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention is not described.

Summary of The Invention

The present invention seeks to provide novel nicotinic modulators for the treatment of diseases or disorders associated with cholinergic receptors.

The compounds of the invention may also be used as diagnostic tools or monitoring agents in various diagnostic methods, in particular in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.

In its first aspect, the present invention provides novel 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of formula I

A stereoisomer thereof or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein

Ar represents an aryl group selected from phenyl and naphthyl, which aryl group may be optionally substituted one or more times with a substituent selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy, alkoxy, methylenedioxy, and ethylenedioxy; or a heteroaryl group selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl, which heteroaryl group may optionally be substituted one or more times with a substituent selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy, and alkoxy.

In its second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carrier or diluent.

In a further aspect, the present invention relates to the use of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of cholinergic receptors.

In a final aspect, the present invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the present invention.

Other objects of the present invention will be apparent to those skilled in the art from the following detailed description and examples.

Detailed Description

1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives

In a first aspect, novel 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives are provided. The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention can be represented by formula I

In a preferred embodiment, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein

Ar is an aryl group selected from phenyl and naphthyl, which aryl group may be optionally substituted one or more times with substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy and alkoxy: or substituted once by methylenedioxy or ethylenedioxy.

In a more preferred embodiment, Ar represents phenyl, which phenyl may be optionally substituted once or twice with substituents selected from halo, trifluoromethyl and trifluoromethoxy, or once with methylenedioxy or ethylenedioxy.

In an even more preferred embodiment, Ar represents phenyl, which phenyl may be optionally substituted once or twice with substituents selected from halo, trifluoromethyl and trifluoromethoxy.

In another more preferred embodiment, Ar represents phenyl, which phenyl may be optionally substituted with methylenedioxy or ethylenedioxy.

In a more preferred embodiment, Ar represents phenyl substituted with methylenedioxy.

In a preferred embodiment, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Ar represents a heteroaryl group selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl, which heteroaryl group may optionally be substituted one or more times with substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy and alkoxy.

In a more preferred embodiment, Ar represents an optionally substituted heteroaryl selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl.

In an even more preferred embodiment, the heteroaryl is optionally substituted one or two times with substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy and alkoxy.

In a more preferred embodiment, the heteroaryl is optionally substituted one or two times with substituents selected from halo, trifluoromethyl and trifluoromethoxy.

In another more preferred embodiment, Ar represents a heteroaryl group selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl.

In an even more preferred embodiment, Ar represents furyl, and in particular furan-2-yl or furan-3-yl.

In another even more preferred embodiment, Ar represents thienyl, and in particular thien-2-yl or thien-3-yl.

In a third even more preferred embodiment, Ar represents a pyrrolyl group.

In a fourth even more preferred embodiment, Ar represents benzofuranyl, and in particular benzofuran-2-yl.

In a fifth even more preferred embodiment, Ar represents benzothienyl, and in particular benzo [ b ] thiophen-2-yl.

In a sixth even more preferred embodiment, Ar represents indolyl, and in particular 1H-indol-5-yl.

In a most preferred embodiment, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention is

4- (5-thiophen-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-thiophen-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-benzofuran-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-benzo [ b ] thiophen-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- [5- (1H-indol-5-yl) -pyrimidin-2-yl ] -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-benzo [1, 3] dioxol-5-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-furan-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane; or

4- (5-furan-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

or a pharmaceutically acceptable salt thereof.

Any combination of two or more embodiments described herein is considered to be within the scope of the present invention.

Pharmaceutically acceptable salts

The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention may be provided in any form suitable for administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts and prodrug-or prodrug forms of the compounds of the invention.

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts, such as hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, acetate derived from acetic acid, aconate derived from aconic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, pamoate derived from pamoic acid, heptanoate derived from heptanoic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, lactate derived from lactic acid, lactate, hydrobromide derived from lactic acid, hydrobromide derived from hydrobromic acid, fumarate derived from ascorbic acid, benzoate derived from benzenesulfonic acid, cinnamate derived from cinnamic acid, cinnamate derived from citric acid, maleate derived from citric acid, pamoate derived from pamoate, heptanoate derived from heptanoic acid, fumarate derived from fumaric, Maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, phthalate derived from phthalic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, tartrate derived from tartaric acid, toluene-p-sulfonate derived from p-toluenesulfonic acid, and the like. Such salts may be formed by processes well known and described in the art.

Other acids which may be considered pharmaceutically acceptable, such as oxalic acid, may be used in the preparation of intermediates useful in obtaining the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention and their pharmaceutically acceptable salts.

Pharmaceutically acceptable cationic salts of the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention include, without limitation, the sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and ammonium salts, and the like, of the compounds of the invention containing anionic groups. Such cationic salts can be formed by well known and art-described methods.

Examples of other pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and the like. Such salts may be formed by processes well known and described in the art.

The metal salts of the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention include the alkali metal salts, e.g. sodium salts, of the compounds of the invention containing a carboxyl group.

In the context of the present invention, an "onium salt" of an N-containing compound is also considered to be a pharmaceutically acceptable salt. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

Labelled compounds

The compounds of the invention may be used in labelled or unlabelled form. In the context of the present invention, one or more atoms of the scored compound may be replaced with an atomic mass or mass number different from the atomic mass or mass number typically found in nature. The label may facilitate quantitative detection of the compound.

The labeled compounds of the invention may be used as diagnostic tools in various diagnostic methods, as radiotracers or monitoring agents, and for in vivo receptor imaging.

The labelled isomer of the present invention preferably comprises at least one radionuclide as label. Positron emitting radionuclides are all candidate compounds that can be used. In the context of the present invention, the radionuclide is preferably selected from²H (deuterium) is added to the reaction mixture,³h (tritium) is introduced into the reaction chamber,¹³C，¹⁴C，¹³¹I，¹²⁵I，¹²³i and¹⁸F。

the physical method of detecting the labeled isomer of the present invention may be selected from Positron Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and computer Axial X-ray Tomography (CAT), or a combination thereof.

Process for producing 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives

The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of this invention can be prepared by conventional methods of chemical synthesis, such as those described in the preparation examples. The starting materials for the processes described herein are well known or can be readily prepared by conventional methods from commercially available chemicals.

One compound of the invention may also be converted to another compound of the invention using conventional methods.

The reaction end products described herein may be isolated by conventional techniques, e.g., by extraction, crystallization, distillation, chromatography, and the like.

Biological activity

The present invention seeks to provide novel ligands and modulators of nicotinic receptors, which may be useful in the treatment of diseases or disorders related to cholinergic receptors, and in particular nicotinic acetylcholine receptors (nAChR). Preferred compounds of the invention exhibit outstanding nicotinic acetylcholine α 7 receptor subtype selectivity.

Due to their pharmacological profile the compounds of the invention may be useful for the treatment of various CNS related diseases, PNS related diseases, diseases involving smooth muscle contraction, endocrine disorders, diseases involving neurodegeneration, diseases involving inflammation, pain and diseases and disorders with withdrawal symptoms caused by the termination of abuse of chemical substances.

In a preferred embodiment, the compounds of the invention are useful for the treatment, prevention or alleviation of cognitive disorders, learning deficit, memory deficits and dysfunctions, Down's syndrome, Alzheimer's disease, Attention Deficit Hyperactivity Disorder (ADHD), Tourette's syndrome, psychosis, depression, bipolar disorders, mania, manic depression, schizophrenia, cognitive or attention deficits associated with schizophrenia, Obsessive Compulsive Disorder (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS dementia, senile dementia, autism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, anxiety, non-OCD anxiety, convulsive disorders, epilepsy, and other disorders, Neurodegenerative diseases, transient hypoxia, induced neurodegeneration, neuropathy, diabetic neuropathy, periferal dyslexia, tardive dyskinesia, movement disorders, mild pain, moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, post-operative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, treatment of post-neuralgia or peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, Ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, fibromyalgia, chronic fatigue syndrome, mutism, trichotillomania, jet lag, arrhythmia, smooth muscle contraction, angina pectoris, premature labor, diarrhea, asthma, stress, Tardive dyskinesia, hyperkinesia, premature ejaculationErectile difficulty, hypertension, inflammatory diseases, inflammatory dermatoses, acne, rosacea, crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, or withdrawal symptoms caused by the cessation of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepinesClass and benzodiazepinesQuasi drugs and alcohol.

In a more preferred embodiment, the compounds of the invention are useful for the treatment, prevention or alleviation of pain, mild or moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, post-therapeutic neuralgia, or peripheral nerve injury.

In a more preferred embodiment, the compounds of the invention are useful for treating, preventing or ameliorating a disease, disorder or condition associated with smooth muscle contraction, convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, or erectile difficulty.

In a more preferred embodiment, the compounds of the invention are useful for the treatment, prevention or alleviation of neurodegenerative diseases, transient hypoxia or induced neurodegeneration.

In a more preferred embodiment, the compounds of the invention are useful for the treatment, prevention or alleviation of inflammatory diseases, inflammatory skin diseases, acne, rosacea, crohn's disease, inflammatory bowel disease, ulcerative colitis, or diarrhoea.

In a further preferred embodiment, the compounds of the invention are useful for the treatment, prevention or alleviation of diabetic neuropathy, schizophrenia, cognitive or attention deficits associated with schizophrenia or depression.

Finally, the compounds of the invention are useful in the treatment of withdrawal symptoms caused by the termination of use of addictive substances. Such addictive substances include those containing, for example, tobacco, opioids, such as heroin, cocaine and morphine, benzodiazepinesAnd benzodiazepinesNicotine of quasi drugs and alcohol products. Withdrawal from addictive substances is often a traumatic experience characterized by anxiety and frustration, anger, anxiety, concentration difficulties, restlessness, a slow heart rate and appetizing and weight gain.

In this context, "treatment" encompasses treatment, prevention and relief of withdrawal symptoms and abstinence and treatment that results in voluntary reduction of the intake of addictive substances.

In another aspect, the compounds of the invention are useful as diagnostic agents, e.g., for identifying and localizing nicotinic receptors in different tissues.

Currently, suitable amounts of Active Pharmaceutical Ingredient (API) are contemplated to range from about 0.1 to about 1000mg API/day, more preferably from about 10 to 500mg API/day, most preferably from about 30 to about 100mg API/day, but depending on the precise mode of administration, form of administration, indication in question, the weight of the patient and in particular the patient in question and also the preferences and experience of the attending physician and veterinarian.

Preferred compounds of the invention exhibit biological activity in the submicromolar and micromolar range, i.e., less than 1 to about 100. mu.M.

Pharmaceutical composition

In another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention.

Although the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention for use in therapy may be administered as the starting compound, it is preferred that the active ingredient, optionally in the form of a physiologically acceptable salt, is incorporated in the composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers thereof, and optionally other therapeutic and/or prophylactic ingredients known and used in the art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the invention may be administered by any suitable means appropriate to the intended treatment. Preferred modes of administration include oral, especially in the form of tablets, capsules, dragees, powders or liquids, and parenteral, especially epicutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the invention can be produced by any skilled person by using standard methods and conventional techniques appropriate for the formulation in question. When desired, compositions suitable for producing sustained release of the active ingredient may be used.

The pharmaceutical compositions of the present invention may be those suitable for oral, rectal, tracheal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powder and liquid aerosol administration, or for administration by slow release systems. Examples of suitable sustained release systems include semipermeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices may be in the form of shaped articles, e.g., films, or microcapsules.

The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention can therefore be formulated, together with conventional adjuvants, carriers or diluents, into pharmaceutical compositions and unit dosage forms thereof. Such forms include solids, particularly tablets, filled capsules, powders and pills, as well as liquids, particularly aqueous and non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled with the above forms, all for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral administration. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without other active compounds or ingredients, and such unit dosage forms may contain any suitable dosage of the active ingredient commensurate with the intended daily dosage range to be employed.

The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention can be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, a compound of the present invention or a pharmaceutically acceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5 or 10 to about 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" means a formulation comprising an active ingredient and an encapsulating material as a carrier, which provides a capsule in which the active ingredient, with or without a carrier, is enclosed by a carrier, which is thus associated with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and thereby solidified.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid formulations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection formulations can be formulated as aqueous polyethylene glycol solutions.

Thus, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives according to the invention can be formulated for parenteral administration (e.g. injection, e.g. bolus injection or continuous infusion) and can be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In addition, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable coloring, flavoring, stabilizing and thickening agents as needed.

Suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous substance, for example a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical epidermal administration, the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention can be formulated as an ointment, cream or lotion or as a transdermal patch. For example, ointments and creams may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia gum, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solution or suspension can be applied directly to the nasal cavity by conventional means, such as a dropper, pipette or nebulizer. The composition may be provided in a single dose or in multiple doses.

Administration to the respiratory tract may be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack together with a suitable propellant, for example a chlorofluorocarbon (CFC), such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may suitably also comprise a surfactant such as lecithin. The dosage of the medicament may be controlled by means of a fitted metal valve.

Alternatively, the active ingredient may be in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives, for example hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Suitable powder carriers will form a gel in the nasal cavity. The powder compositions may be presented in unit dose form, for example in the form of capsules or cartridges (e.g. of gelatin) or in the form of blister packs from which the powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds will generally have a small particle size, for example on the order of 5 microns or less. Such particle sizes may be obtained by means of methods well known in the art, for example by micronization.

When desired, compositions suitable for providing sustained release of the active ingredient may be used.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

For further details regarding formulation and administration, reference may be made to the latest edition of Remington's pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

A therapeutically effective amount refers to an amount of active ingredient that ameliorates the symptoms or conditions. Therapeutic efficacy and toxicity, e.g. ED₅₀And LD₅₀And can be determined by standard pharmacological methods in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and can be determined by LD₅₀/ED₅₀Is expressed by the ratio of (A) to (B). Pharmaceutical compositions that exhibit a higher therapeutic index are preferred.

The dosage administered must of course be carefully adjusted to the age, weight and condition of the subject patient, and to the route, dosage form and regimen of administration and desired result, and the precise dosage will of course be determined by a physician.

The actual dosage depends on the nature and severity of the disease being treated and may, within the judgment of the physician, be varied according to the particular circumstances of the invention by titration of the doses to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500mg, preferably from 1 to about 100mg, and most preferably from 1 to about 10mg of active ingredient per single dose are suitable for therapeutic treatment.

The active ingredient may be administered in single or multiple daily doses. In some cases satisfactory results can be obtained as low as 0.1. mu.g/kg (intravenous) and 1. mu.g/kg (oral). The upper limit of the dosage range is currently considered to be about 10mg/kg (intravenous) and 100mg/kg (oral). Preferred ranges are from about 0.1 μ g/kg to about 10 mg/kg/day (intravenous) and from about 1 μ g/kg to about 100 mg/kg/day (oral).

Method of treatment

The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention are valuable nicotinic and therefore useful in the treatment of a variety of diseases involving cholinergic dysfunction and a variety of disorders responsive to the action of nAChR modulators.

In another aspect, the present invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of cholinergic receptors, which method comprises administering to a living animal body, including a human, in need thereof an effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of the invention.

In a preferred embodiment, the disease, disorder or condition is related to the central nervous system.

Preferred medical indications contemplated according to the present invention are those described above.

It is presently contemplated that a suitable dosage range will be from 0.1 to 1000mg daily, preferably from 10 to 500mg daily, more preferably from 30 to 100mg daily, depending generally on the precise mode of administration, form of administration, indication for which administration is intended, patient involved, weight of patient involved and further the preferences and experience of the attending physician or veterinarian.

Examples

The invention is further illustrated with reference to the following examples, which are not intended to limit the scope of the invention as claimed in any way.

Example 1

Preparation examples

All reactions involving air sensitive reagents or intermediates were carried out under nitrogen and in anhydrous solvents. Magnesium sulfate was used as a drying agent in the work-up step, and the solvent was evaporated under reduced pressure.

1, 4-diazabicyclo [3.2.2] nonane (intermediate compound)

The title compound was prepared according to j.med.chem.1993362311-2320 (and according to a slightly modified procedure described below).

1, 4-diazabicyclo [3.2.2] nonan-3-one (intermediate compound)

To a solution of 3-quinuclidinone hydrochloride (45 g; 278mmol) in 90ml of water was added hydroxylamine hydrochloride (21 g; 302mmol) and sodium acetate (CH)₃COONa×3H₂O; 83 g; 610mmol), the mixture was stirred at 70 ℃ for 1 hour and then cooled to 0 ℃. The separated crystalline material was filtered off (without washing) and dried in vacuo to give 40.0g of oxime.

3-quinuclidinone oxime (40.0g) was added in small portions to polyphosphoric acid (190g) preheated to 120 ℃ over the course of 2 hours. The temperature of the solution was maintained at 130 ℃ during the reaction. After all the oximes were added, the solution was stirred at the same temperature for 20 minutes, then transferred to an enameled vessel and allowed to reach room temperature. The acidic mixture was neutralized with potassium carbonate solution (500g in 300ml water), transferred to a 2000ml flask, diluted with 300ml water and extracted with chloroform (3X 600 ml). The combined organic extracts were dried over sodium sulfate, the solvent was evaporated and the solid residue was dried in vacuo to give 30.0g (77%) of a mixture of lactams.

The resulting mixture was crystallized from 1, 4-dioxane (220ml) to give 15.8g (40.5%) of 1, 4-diazabicyclo [3.2.2] nonan-3-one as large, colorless crystals with mp.211-212 ℃.

1, 4-diazabicyclo [3.2.2] nonane (intermediate compound)

To 1, 4-diazabicyclo [3.2.2] in an argon atmosphere]To a solution of nonan-3-one (15.8 g; 113mmol) in anhydrous dioxane (130ml) was added LiAlH₄(4.9 g; 130 mmol). The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture was added water (5ml in 10ml dioxane) dropwise, the mixture was stirred for 0.5 hours and then filtered out through a glass filter. The solvent was evaporated and the residue was distilled at 90 deg.C (0.1mbar) using a Kugelrohr apparatus to give 1, 4-diazabicyclo [3.2.2]Nonane (11.1 g; 78%) as a colorless hygroscopic substance.

Method A

4- (5-Thien-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane hydrochloride (compound A1)

A mixture of 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane (1.0g, 3.5mmol), 2-thiopheneboronic acid (0.67g, 5.25mmol), potassium carbonate (1.45, 10.5mmol), bis (triphenylphosphine) palladium (II) chloride (148mg, 0.210mmol), 1, 3-propanediol (1.09g, 14.0mmol), 1, 2-dimethoxyethane (110ml) and water (50ml) was stirred for 7 hours. Aqueous sodium hydroxide (80ml, 1M) was added, followed by extraction with dichloromethane (3X 50 ml). The mixture was evaporated. The crude mixture was purified by silica gel column chromatography by using a mixture of dichloromethane, methanol and aqueous ammonia (9: 1+ 1%). The corresponding salt was obtained by dissolving the free base in ethanol, followed by addition of HCl in ethanol (3ml, 3M). Yield 0.23g (23%). LC-ESI-HRMS, [ M + H ] + showed 287.1331 daltons. Calculated 287.133042 daltons with a deviation of 0.2 ppm.

4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane (intermediate compound)

A mixture of 5-bromo-2-chloropyrimidine (2.5g, 12.92mmol), 1, 4-diazabicyclo [3.2.2] nonane (1.4g, 18.09mmol), triethylamine (1.3g, 12.92mmol) and dioxane (100ml) was stirred at room temperature for 3 hours. Water (100ml) was added. The mixture was extracted with ethyl acetate (3X 100 ml). The organic phase was washed with sodium carbonate (100ml, 1%) and saturated sodium chloride (75 ml). The product was isolated as an oil.

4- (5-Thien-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane fumarate (Compound A2)

Prepared according to method a from 3-thiopheneboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS [ M + H ] + showed 287, 1326 daltons. Calculated 287, 133042 daltons with a deviation of-1, 5 ppm.

4- (5-benzofuran-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane fumarate (compound A3)

Prepared according to method a from 2-benzofuranboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS [ M + H ] + shows 321, 171 daltons. Calculated 321, 171536 daltons, bias-1, 7 ppm.

4- (5-benzo [ b ] thiophen-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane fumarate (Compound A4)

Prepared according to method a from 2-benzothiopheneboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS [ M + H ] + showed 337, 1476 daltons. Calculated 337, 148692 daltons with a deviation of-3, 2 ppm.

4- [5- (1H-indol-5-yl) -pyrimidin-2-yl ] -1, 4-diaza-bicyclo [3.2.2] nonane fumarate (compound A5)

Prepared according to method a from 5-indolylboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS [ M + H ] + showed 320, 1873 daltons. Calculated 320, 18752 daltons, bias-0, 7 ppm.

4- (5-benzo [1, 3] dioxol-5-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane free base (compound A6)

Prepared according to method a from 5-benzo [1, 3] dioxolyl boronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS, [ M + H ] + showed 325.166 daltons. Calculated 325.166451 daltons, with a deviation of-1.4 ppm.

4- (5-Furan-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane free base (compound A7)

Prepared according to method a from 3-furanboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS, [ M + H ] + showed 271.1572 daltons. Calculated 271.155886 daltons with a deviation of 4.8 ppm.

4- (5-Furan-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane free base (compound A8)

Prepared according to method a from 2-furanboronic acid and 4- (5-bromo-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane. LC-ESI-HRMS, [ M + H ] + showed 271.1546 daltons. Calculated 271.155886 daltons, deviation-4.7 ppm.

Example 2

In the brain of rats³In vitro inhibition of H-alpha-bungarotoxin binding

In this example, the affinity of the 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of the invention for binding to the nicotinic receptor alpha 7-subtype was determined in a standard experiment carried out essentially as described in, for example, WO 2006/087306.

The experimental value is expressed as IC₅₀(will be³Test substance concentration at which specific binding of H- α -chrysotoxin is inhibited by 50%).

The results of the experiment are shown in table 1 below.

TABLE 1

³Inhibition of H-alpha-bungarotoxin binding

Number of Compounds	IC₅₀(μM)
Number of Compounds	IC₅₀(μM)	A1	＜0.1

Claims

1.1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivatives of formula I

Ar represents

Aryl selected from phenyl and naphthyl, which aryl may be optionally substituted one or more times with substituents selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy, alkoxy, methylenedioxy, and ethylenedioxy; or

Heteroaryl selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl, which heteroaryl may optionally be substituted one or more times with substituents selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy, and alkoxy.

2. The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar represents an aryl group selected from phenyl and naphthyl, which aryl group may be optionally substituted one or more times with a substituent selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy and alkoxy, or once with methylenedioxy or ethylenedioxy.

3. The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar represents a heteroaryl group selected from furanyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl and indolyl, which heteroaryl group may be optionally substituted one or more times by a substituent selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkyl, hydroxy, and alkoxy.

4. The 1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of claim 1, which is

4- (5-thiophen-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-thiophen-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-benzofuran-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

4- [5- (1H-indol-5-yl) -pyrimidin-2-yl ] -1, 4-diaza-bicyclo [3.2.2] nonane;

4- (5-furan-3-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane; or

4- (5-furan-2-yl-pyrimidin-2-yl) -1, 4-diaza-bicyclo [3.2.2] nonane;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of any one of claims 1-4, or a pharmaceutically-acceptable addition salt or prodrug thereof, and at least one pharmaceutically-acceptable carrier or diluent.

6. Use of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of any one of claims 1-4, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of cholinergic receptors.

7. The use of claim 6, wherein the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficit and dysfunction, Down syndrome, Alzheimer's disease, Attention Deficit Hyperactivity Disorder (ADHD), Tourette's syndrome, psychosis, depression, bipolar disorders, mania, manic depression, schizophrenia, cognitive or attention deficit associated with schizophrenia, Obsessive Compulsive Disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, autism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, anxiety, non-OCD anxiety disordersDisorders, convulsive disorders, epilepsy, neurodegenerative disorders, transient hypoxia, induced neurodegeneration, neuropathy, diabetic neuropathy, periferalic dyslexia, tardive dyskinesia, hyperkinesia, mild pain, moderate or severe pain, pain of acute, chronic or recurrent character, pain resulting from migraine, post-operative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, treatment of post-neuralgia or peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, fibromyalgia, chronic fatigue syndrome, mutism, trichotillomania, jet lag, arrhythmia, smooth muscle contraction, angina, premature labor, chronic fatigue syndrome, trichotillomania, jet lag, cardiac arrhythmia, smooth muscle contraction, and the like, Diarrhea, asthma, tardive dyskinesia, hyperkinesia, premature ejaculation, erectile difficulty, hypertension, inflammatory diseases, inflammatory dermatoses, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, or withdrawal symptoms caused by the cessation of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepinesClass and benzodiazepinesQuasi drugs and alcohol.

8. A method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors, which method comprises administering to such a living animal body in need thereof a therapeutically effective amount of a1, 4-diaza-bicyclo [3.2.2] nonyl pyrimidinyl derivative of any one of claims 1-4.