HK1230587A

HK1230587A - Arylpiperazine derivative, the composition containing the same, and the use thereof in the preparation of a medicament

Info

Publication number: HK1230587A
Application number: HK17104056.4A
Authority: HK
Inventors: L．巴特; P．P．莫哈帕特拉; K．阿迪
Original assignee: 雷维瓦药品公司
Priority date: 2009-02-26
Filing date: 2017-04-20
Publication date: 2017-12-08

Description

Aryl piperazine derivatives, compositions containing them and their use in the preparation of medicaments

The patent application of the invention is divisional application of invention patents with international application numbers of PCT/US2010/025687, international application dates of 2010, 26.2.2010 and application numbers of 201080019233.6 in Chinese national phase, namely composition, synthesis and method using aryl piperazine derivatives.

Cross Reference to Related Applications

This application claims benefit and priority from U.S. provisional application No. 61/155,791, filed on 26/2/2009, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to compositions of arylpiperazine derivatives, synthesis of arylpiperazine derivatives, and methods of using arylpiperazine derivatives. The invention more particularly relates to syntheses, compositions and methods utilizing aryl piperazine-based compounds for the pharmacological treatment of schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism, and depression.

Background

Drugs used to treat psychosis are known as antipsychotics. Typical antipsychotics (sometimes referred to as traditional antipsychotics) were the first generation of antipsychotic drug class, used to treat psychosis, including schizophrenia. Typical antipsychotics include chlorpromazine, chlorpromazine,FluphenazineHaloperidolThioxanthene sulfamateTrifluoperazinePerphenazineAnd methylthiopyridazineThe second generation of antipsychotics introduced in the 90 s of the 20 th century were referred to as atypical antipsychotics. Atypical antipsychotics appear to be equally effective in reducing positive symptoms such as hallucinations and delusions, but in relieving symptoms such as mood, as compared to the first generation antipsychoticsThe negative symptoms of schizophrenia such as apathy, withdrawal, emotional depression and the like can be better than the typical antipsychotic. Currently clinically used atypical antipsychotics include aripiprazoleClozapineRisperidoneOlanzapineQuetiapineAnd ziprasidone

Atypical antipsychotics have a reduced propensity to cause extrapyramidal syndrome (EPS) and Tardive Dyskinesia (TD) compared to typical antipsychotics. Additional benefits associated with atypical antipsychotics include: better treatment of negative symptoms, better compliance, potential benefits to cognitive decline, and lower recurrence rates. However, in the atypical antipsychotic class, there are differences in both efficacy and side effects. Clozapine does not cause EPS and is clearly more effective than all other antipsychotics used to date in humans. However, it is a life-altering drug, because it causes a side effect of agranulocytosis, requiring continuous medical monitoring in some countries. This significantly limits its use. Other atypical antipsychotics with the greatest amount of efficacy data are risperidone and olanzapine. These drugs are the first line antipsychotics most commonly used today. The reason for this is that they are more clinically effective than conventional drugs and easier to use than clozapine. However, both risperidone and olanzapine are limited by side effects. Risperidone causes prolactin to increase, body weight gain, and dose-dependent EPS. Olanzapine, in addition to being associated with lipid and glucose abnormalities, is also associated with increased weight gain. Quetiapine and ziprasidone may be safer drug candidates than risperidone and olanzapine, but these drugs appear to be less clinically effective than other atypical antipsychotics. Aripiprazole is one of the next generation of atypical antipsychotics approved by the FDA for the treatment of schizophrenia at 11 months 2002 (Satyanarayana, c. et al WO 2006/030446; tsujimmori, h. et al WO 2004/063162; Salama, p. et al WO 2004/099152; wikstom, h. et al WO 2003/064393). It was approved for the treatment of acute mania and mixed episodes associated with bipolar disorder 3 months in 2005. Aripiprazole does not differ greatly from other atypical antipsychotics in therapeutic response, efficacy and tolerability.

Atypical antipsychotics are increasingly used in a variety of psychiatric conditions in children and adolescents. Conditions for which atypical antipsychotics are indicated include bipolar disorder, psychotic depression, schizophrenia, pervasive developmental delay, Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD) and conduct disorder. They are also used for symptomatic treatment of rage, insomnia and anorexia. The risk of adverse effects associated with treatment with atypical antipsychotics, especially weight gain and drug-induced diabetes, appears to be higher for younger patients.

In general, atypical antipsychotics share many side effects with typical antipsychotics, including sedation, akathisia, weight gain, extrapyramidal syndrome (EPS), neuromalignant syndrome (neurocognitive syndrome), and tardive dyskinesia; long-term use shows that new risks need to be considered, such as metabolic syndrome and QTc interval prolongation (QTc prolongation). QTc interval prolongation is known to have the potential to produce fatal torsade de pointes (TdP) arrhythmias. Drug-induced adverse metabolic effects such as weight gain, lipid abnormalities and diabetes have been identified as major risk factors for various medical conditions, which may be responsible for a part of the increased morbidity and mortality in psychiatric patients treated with atypical antipsychotics.

Off-target pharmacology and drug-drug interactions are the major causes of most of the adverse side effects associated with atypical antipsychotics. All atypical antipsychotics currently used for the treatment of schizophrenia and related psychoses have poor selectivity of therapeutic targets. For example, olanzapine, one of the most widely prescribed atypical antipsychotics, and clozapine, the most potent atypical antipsychotic, have been reported to have significant activity at more than 12 receptors, such as the dopamine (D1, D2, D3 and D4) receptors, serotonin (5-HT2A, 5-HT2C, 5-HT6 and 5-HT7) receptors, adrenergic receptors (α 1 and α 2), histamine (H1) receptors, muscarinic receptors (M1), dopamine transporter (DAT) receptors and norepinephrine transporter (NET) receptors (Miyamoto et al, Molecular Psychiatry, 2005, 10, 79). Similarly, other FDA-approved atypical antipsychotics such as risperidone and aripiprazole have also been reported to have significant activity at more than 9 of the above receptors. Current studies indicate that compounds exhibiting activity against dopamine (D2) and serotonin (5-HT1A and 5-HT2A) receptors may have the expected antipsychotic effect (Snyder, s.h., Nature 2008, 452, 38-39; Di Pietro, n.c., Seamans, j.k., pharmacosychirry 2007, 40(S1), S27-S33; Stark, a.d., etc., psychopharmacoglycology 2007, 190, 373 382), while compounds exhibiting activity against other receptors such as serotonin 5HT2C, histamine (H1) and epinephrine (α 1) may cause deleterious side effects such as arrhythmia.

While the currently clinically used atypical antipsychotics (aripiprazole, clozapine, risperidone, olanzapine, quetiapine and ziprasidone) represent a significant advance in the treatment of schizophrenic populations, there is a need for new psychotropic drugs with improved safety profiles.

Thus, the development of new antipsychotics with improved selectivity of therapeutic targets over currently available therapeutics would provide a more effective and safer drug for the treatment of schizophrenia and related psychoses.

Brief description of the invention

The present invention provides compounds, syntheses of compounds, compositions and methods of using the compounds for treating schizophrenia and related psychotic disorders, such as acute mania, bipolar disorder, autism, and depression, wherein the compounds are aryl piperazine derivatives.

The present invention provides methods for synthesizing such arylpiperazine compounds. The present invention also provides methods of using combinations of aryl piperazine-based atypical antipsychotics and aryl piperazine-based atypical antipsychotics for the treatment of schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism, and depression.

The compounds of the present invention provide a next generation of novel antipsychotics that are particularly effective and safer for the treatment of schizophrenia. They are advantageous for their highly desirable pharmacological, metabolic and pharmacokinetic characteristics. The compounds of the invention are designed as:

1) exhibits affinity for the dopamine 2(D2) receptor;

2) exhibits affinity for the serotonin 1A (5-HT1A) receptor;

3) exhibits affinity for the serotonin 2A (5-HT2A) receptor;

4) one or more metabolites are formed that are therapeutically inactive or minimally therapeutically active.

In one aspect, the present invention provides an arylpiperazine derivative comprising a compound of formula (1) or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof:

wherein:

a is- (CH)₂)_n-、-O-(CH₂)_n-、-S-(CH₂)_n-、-S(O)(O)-(CH₂)_n-、-NH-(CH₂)_n-、-CH₂-O-(CH₂)_n-、-(CH₂)_n-O-CH₂-CH₂-、-CH₂-S-(CH₂)_n-、-(CH₂)_n-S-CH₂-CH₂-、-CH₂-S(O)(O)-(CH₂)_n-、-(CH₂)_n-S(O)(O)-CH₂-CH₂-、-O-C(O)-(CH₂)_n-、-S-C(O)-(CH₂)_n-、-NH-C(O)-(CH₂)_n-、-CH₂-C(O)-O-(CH₂)_n-、-CH₂-C(O)-NH-(CH₂)_n-、-CH₂-C(O)-S-(CH₂)_n-、-(CH₂)_n-C(O)-O-CH₂-CH₂-、-(CH₂)_n-C(O)-NH-CH₂-CH₂-、-(CH₂)_n-C(O)-S-CH₂-CH₂-、-CH₂-O-C(O)-(CH₂)_n-、-CH₂-NH-C(O)-(CH₂)_n-、-CH₂-S-C(O)-(CH₂)_n-、-(CH₂)_n-O-C(O)-CH₂-CH₂-、(CH₂)_n-NH-C(O)-CH₂-CH₂-or (CH)₂)_n-S-C(O)-CH₂-CH₂-, where n is an integer of 1 to 7;

b is O, S, S (O) (O) or NR⁵(ii) a And

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷and R⁸Each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted cycloheteroalkylHeteroarylalkyl, acylhydrocarbyloxycarbonyl, acyloxyalkyloxycarbonyl, acyloxyalkylcarbonylamino, acyloxyalkyloxycarbonylamino, alkoxyalkoxyalkoxyoxycarbonylamino, hydrocarbyloxy, hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyloxydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylamino, hydrocarbylsulfinyl, hydrocarbylsulfonyl, hydrocarbylthio, amino, hydrocarbylamino, arylalkylamino, dihydrocarbylamino, arylalkyloxy, arylalkyloxycarbonyloxydroxy, arylalkyloxycarbonylhydrocarbylamino, aryloxycarbonyl, aryloxycarbonylhydrocarbyloxy, aryloxycarbonylhydrocarbylamino, carboxyl, carbamoyl, carbamate, carbonate, cyano, halogen, heteroaryloxycarbonyl, hydroxyl, phosphate, phosphonate, sulfate, sulfonate or sulfonamide, wherein R is R, wherein R is a hydrogen atom, a halogen atom, a hydroxyl group, a phosphate, a phosphonate, a sulfate, a sulfonate or a sulfonamide group¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸And A may be optionally substituted with isotopes including, but not limited to²H (deuterium),³H (tritium),¹³C、³⁶Cl、¹⁸F、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P and³⁵S。

in one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention.

In one aspect of the invention, a method of treating one of psychosis, schizophrenia, acute mania, bipolar disorder, autism, or depression is set forth comprising administering a compound of the present invention to a patient in need thereof.

In one aspect of the invention, the compounds of the invention are useful for the treatment of psychosis, schizophrenia, acute mania, bipolar disorder, autism, or depression.

In one aspect of the invention, the compounds of the invention are useful for the preparation of medicaments for the treatment of the following diseases: psychosis, schizophrenia, acute mania, bipolar disorder, autism, or depression, psychosis, schizophrenia, acute mania, bipolar disorder, autism, or depression.

Detailed Description

The present invention relates to syntheses, compositions, and methods of using aryl piperazine derivatives that are useful for treating schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism, and depression. The present invention provides compounds, compositions and methods for the pharmacological treatment of schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism and depression.

Definition of

Unless otherwise indicated, the following terms used in the present application, including the specification and claims, have the definitions given below. Any term not directly defined herein should be understood to have a meaning commonly associated with its understanding in the art.

It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Definitions of standardized chemical terms can be found in reference works including "Advanced Organic Chemistry third edition" volumes A and B, Plenum Press, New York, of Carey and Sundberg (1992). The practice of the present invention will employ, unless otherwise indicated, conventional methods of mass spectrometry, protein chemistry, biochemistry, recombinant DNA technology and pharmacology, which are within the skill of the art. The compositions and formulations described herein can be practiced using pharmaceutically acceptable excipients and salts that are available in Remington's Pharmaceutical Sciences, 18 th edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

"Compound of the invention" refers to a compound encompassed by structural formula (1) disclosed herein. The compounds of the present invention may be identified by their chemical structure and/or chemical name. Chemical structure is a recognized chemical compound when there is a conflict between chemical structure and chemical nameDeterminant of the substance. The compounds of the present invention may contain one or more chiral centers and/or double bonds and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds of the present invention may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds set forth. The compounds of the present invention also include isotopically-labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include, but are not limited to²H、³H、¹³C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. In addition, it should be understood that when partial structures of the compounds of the invention are illustrated, the raised dashes indicate the point of attachment of the partial structure to the rest of the molecule.

"composition of the invention" means at least one compound of the invention and a pharmaceutically acceptable vehicle with which the compound is administered to a patient. When administered to a patient, the compounds of the present invention are administered in isolated form, i.e., separately from the synthetic organic reaction mixture.

"alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical hydrocarbyl groups include, but are not limited to: a methyl group; ethyl groups such as ethyl, vinyl, ethynyl; propyl groups such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-en-1-yl, prop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butyl, for example but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, cyclobut-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like; and the like.

The term "hydrocarbyl" is expressly intended to include groups having any degree or level of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having a mixture of single, double, and triple carbon-carbon bonds. When referring to a particular saturation level, the expressions "alkyl", "alkenyl" and "alkynyl" are used. Preferably, the hydrocarbyl group contains 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

"alkyl" refers to a saturated branched, straight-chain or cyclic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to: a methyl group; an ethyl group; a propyl group such as prop-1-yl, prop-2-yl (isopropyl), cycloprop-1-yl, and the like; a butyl group such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), cyclobut-1-yl, etc.; and the like.

"alkenyl" refers to an unsaturated branched, straight chain or cyclic hydrocarbon group having at least one carbon-carbon double bond, which is obtained by the removal of one hydrogen atom from a single carbon atom of a parent olefin. The group may be in either the cis or trans conformation about the double bond. Typical alkenyl groups include, but are not limited to: a vinyl group; propenyl, for example prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl, prop-2-en-1-yl; butenyl groups such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like; and the like.

"alkynyl" refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon triple bond, which is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to: an ethynyl group; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like; and so on.

"acyl" refers to the group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"acyloxyalkyloxycarbonyl" refers to the group-c (o) OCR 'R "oc (o) R'", wherein R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -C (O) OCH₂OC(O)CH₃、-C(O)OCH₂OC(O)CH₂CH₃、-C(O)OCH(CH₃)OC(O)CH₂CH₃、-C(O)OCH(CH₃)OC(O)C₆H₅And the like.

"Acylalkyloxycarbonyl" refers to the group-C (O) OCR ' R "C (O) R '", wherein R ', R "and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may optionally be defined herein as one or moreAnd (4) substituent substitution. Representative examples include, but are not limited to: -C (O) OCH₂C(O)CH₃、-C(O)OCH₂C(O)CH₂CH₃、-C(O)OCH(CH₃)C(O)CH₂CH₃、-C(O)OCH(CH₃)C(O)C₆H₅And the like.

"acyloxyalkyloxycarbonylamino" refers to the group-NRC (O) OCR 'R "OC (O) R'", wherein R, R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -NHC (O) OCH₂OC(O)CH₃、-NHC(O)OCH₂OC(O)CH₂CH₃、-NHC(O)OCH(CH₃)OC(O)CH₂CH₃、-NHC(O)OCH(CH₃)OC(O)C₆H₅And the like.

"acylalkyloxycarbonylamino" refers to the group-NRC (O) OCR 'R "C (O) R'", wherein R, R ', R "and R'" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -NHC (O) OCH₂C(O)CH₃、-NHC(O)OCH₂C(O)CH₂CH₃、-NHC(O)OCH(CH₃)C(O)CH₂CH₃、-NHC(O)OCH(CH₃)C(O)C₆H₅And the like.

"acylamino" refers to an "amido" group as defined herein.

"hydrocarbylamino" means a group-NHR, wherein R represents a hydrocarbyl or cycloalkyl group, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.

"hydrocarbyloxy" refers to a group-OR, wherein R represents a hydrocarbyl OR cycloalkyl group, as defined herein, which may be optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

"hydrocarbyloxycarbonyl" refers to the group-C (O) -hydrocarbyloxy, wherein hydrocarbyloxy is as defined herein.

"hydrocarbyloxycarbonylalkoxy" refers to the group-OCR' R "C (O) -hydrocarbyloxy, wherein hydrocarbyloxy is as defined herein. Likewise, wherein R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -OCH₂C(O)OCH₃、-OCH₂C(O)OCH₂CH₃、-OCH(CH₃)C(O)OCH₂CH₃、-OCH(C₆H₅)C(O)OCH₂CH₃、-OCH(CH₂C₆H₅)C(O)OCH₂CH₃、-OC(CH₃)(CH₃)C(O)OCH₂CH₃And the like.

"hydrocarbyloxycarbonylalkylamino" refers to the group-NRCR' R "C (O) -hydrocarbyloxy, wherein hydrocarbyloxy is as defined herein. Also, wherein R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -NHCH₂C(O)OCH₃、-N(CH₃)CH₂C(O)OCH₂CH₃、-NHCH(CH₃)C(O)OCH₂CH₃、-NHCH(C₆H₅)C(O)OCH₂CH₃、-NHCH(CH₂C₆H₅)C(O)OCH₂CH₃、-NHC(CH₃)(CH₃)C(O)OCH₂CH₃And the like.

"Alkylsulfonyl" refers to the group-S (O)₂R, wherein R is hydrocarbyl or cycloalkyl, which as defined herein may be optionally substituted by one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

"Hydrocarbylsulphinyl" refers to the group-S (O) R, wherein R is hydrocarbyl or cycloalkyl, which as defined herein may be optionally substituted by one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

"hydrocarbylthio" refers to the group-SR, where R is hydrocarbyl or cycloalkyl, which as defined herein may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

"amido" or "acylamino" refers to the group-NR 'c (o) R ", wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino, benzylcarbonylamino, and the like.

"amino" refers to the group-NH₂。

"aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, and benzol,Coronene, fluoranthene, fluorene, hexanol and hexanolExamples of the derivative include, for example, an aromatic derivative such as phenol, hexadiene, asymmetric, symmetric, indane, indene, naphthalene, octacene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, perylene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthylene. Preferably, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms.

"arylalkyl" refers to an aryl radical having carbon atoms (typically terminal or sp) bonded thereto³Carbon atom) is substituted with an aryl group. Typical arylalkyl groups include, but are not limited to: benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. When referring to a particular hydrocarbyl moiety, the terms arylalkyl, arylalkenyl, and/or arylalkynyl are used. Preferably the arylalkyl group is (C)₆-C₃₀) The alkyl, alkenyl or alkynyl part of an arylalkyl radical, e.g. an arylalkyl radical, is (C)₁-C₁₀) The aromatic base is (C)₆-C₂₀) More preferably, the arylalkyl group is (C)₆-C₂₀) The alkyl, alkenyl or alkynyl part of an arylalkyl radical, e.g. an arylalkyl radical, is (C)₁-C₈) The aromatic base is (C)₆-C₁₂)。

"Aryloxyalkyl" refers to an-O-arylalkyl group, wherein the arylalkyl group, as defined herein, may be optionally substituted with one or more substituents, as defined herein.

"Aryloxycarbonyloxyl" refers to the group-OCR' R "C (O) -arylalkoxy, wherein arylalkoxy is as defined herein. Likewise, wherein R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -OCH₂C(O)OCH₂C₆H₅、-OCH(CH₃)C(O)OCH₂C₆H₅、-OCH(C₆H₅)C(O)OCH₂C₆H₅、-OCH(CH₂C₆H₅)C(O)OCH₂C₆H₅、-OC(CH₃)(CH₃)C(O)OCH₂C₆H₅And the like.

"Aryloxycarbonylalkylamino" refers to the group-NRCR' R "C (O) -arylalkoxy, wherein arylalkoxy is as defined herein. Also, wherein R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -NHCH₂C(O)OCH₂C₆H₅、-N(CH₃)CH₂C(O)OCH₂C₆H₅、-NHCH(CH₃)C(O)OCH₂C₆H₅、-NHCH(C₆H₅)C(O)OCH₂C₆H₅、-NHCH(CH₂C₆H₅)C(O)OCH₂C₆H₅、-NHC(CH₃)(CH₃)C(O)OCH₂C₆H₅And the like.

"Aryloxycarbonyl" refers to the group-C (O) -O-aryl, wherein aryl, as defined herein, may be optionally substituted with one or more substituents as defined herein.

"Aryloxycarbonylalkoxy" refers to the group-OCR' R "C (O) -aryloxy, wherein aryloxy is as defined herein. Likewise, wherein R' and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -OCH₂C(O)OC₆H₅、-OCH(CH₃)C(O)OC₆H₅、-OCH(C₆H₅)C(O)OC₆H₅、-OCH(CH₂C₆H₅)C(O)OC₆H₅、-OC(CH₃)(CH₃)C(O)OC₆H₅And the like.

"Aryloxycarbonylhydrocarbylamino" refers to the group-NRCR' R "C (O) -aryloxy, wherein aryloxy is as defined herein. Also, wherein R, R ', R', and R "are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: -NHCH₂C(O)OC₆H₅、-N(CH₃)CH₂C(O)OC₆H₅、-NHCH(CH₃)C(O)OC₆H₅、-NHCH(C₆H₅)C(O)OC₆H₅、-NHCH(CH₂C₆H₅)C(O)OC₆H₅、-NHC(CH₃)(CH₃)C(O)OC₆H₅And the like.

"carbamoyl" refers to the group-C (O) NRR where each R group is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein.

"carbamate" refers to a group-NR 'c (o) OR "wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to: carbamic acid methyl ester (-NHC (O) OCH)₃) And a urethane group (-NHC (O) OCH)₂CH₃) And carbamic acid phenylmethyl ester (-NHC (O) OCH)₂C₆H₅) And the like.

"carbonate group" means the group-OC (O) OR, where R is hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as described hereinDefinitions may be optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to: methyl carbonate group (-C (O) OCH)₃) Cyclohexyl carbonate (-C (O) OC)₆H₁₁) Phenyl carbonate group (-C (O) OC₆H₅) And a benzyl carbonate group (-C (O) OCH)₂C₆H₅) And the like.

"carboxy" means the group-C (O) OH.

"cyano" means the group-CN.

"cycloalkyl" refers to substituted or unsubstituted cycloalkyl. When a particular saturation level is intended, the term "cycloalkyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In a preferred embodiment, the cycloalkyl group is (C3-C)₁₀) A cyclic hydrocarbon group, more preferably a (C3-C7) cyclic hydrocarbon group.

"Cycloheteroalkyl" refers to a saturated or unsaturated cyclic hydrocarbon group in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatoms. Typical heteroatoms substituted for one or more carbon atoms include, but are not limited to N, P, O, S, Si and the like. When a particular saturation level is intended, the term "cycloheteroalkyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, quinuclidines, and the like.

"Cycloheteroaralkoxycarbonyl" refers to a group-C (O) -OR, wherein R is cycloheteroalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"Dihydrocarbylamino" means a group-NRR 'where R and R' independently represent a hydrocarbyl or cycloalkyl group, which may be optionally substituted as defined herein by one or more substituents as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di- (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, and the like.

"derived from a drug" refers to a fragment structurally related to the drug. The structure of this fragment is identical to that of the drug, but in which the hydrogen atom attached to the heteroatom (N or O) is replaced by a covalent bond to another group, usually an introducing group (promoity). Note that when the drug is in the form of a salt of a carboxylic, phosphonic or phosphoric acid, the corresponding structural fragment from the drug is believed to be derived from the protonated acid form.

"drug" refers to a compound that exhibits therapeutic and/or prophylactic and/or diagnostic utility when administered to a patient or mammal in an effective amount.

"ester group" refers to the group-C (O) OR, wherein R is hydrocarbyl, substituted hydrocarbyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylhydrocarbyl, substituted heteroarylhydrocarbyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to: carbomethoxy (-C (O) OCH)₃) Cyclohexyl (-C (O) OC₆H₁₁) Phenyl ester group (-C (O) OC₆H₅) And phenylmethyl ester (-C (O) OCH)₂C₆H₅) And the like.

"ether group" refers to the group-OR, wherein R is a hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl group, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"halogen" means fluorine, chlorine, bromine or iodine.

"Heterohydrocarbyloxy" means an-O-heterohydrocarbyl group, wherein the heterohydrocarbyl group, as defined herein, may be optionally substituted with one or more substituents as defined herein.

"Heterohydrocarbyl, heteroalkyl, heteroalkenyl, heteroalkynyl" refers individually to one or more carbons thereinHydrocarbyl, alkyl, alkenyl, and alkynyl groups, each independently substituted with the same or different heteroatom groups. Typical heteroatom groups include, but are not limited to: -O-, -S-, -O-, -S-, -OS-, -NR '-, ═ N-N ═ N-, -N-NR' -, -PH-, -p- (O)₂-、-O-P(O)-、-S(O)-、-S(O)₂-、-SnH₂-and the like, wherein R' is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, which may be optionally substituted with one or more substituents as defined herein.

"heteroaryl" refers to a monovalent heteroaromatic group obtained by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from: acridine, arsoline, carbazole, carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazoleAzole, naphthyridine,Oxadiazole, oxadiazole,Oxazole, orindine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group is a 5-to 20-membered heteroaryl group, and more preferably a 5-to 10-membered heteroaryl group. Preferably the heteroaryl group is derived from: thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, and derivatives thereof,Azoles and pyrazines.

"heteroaryloxycarbonyl" refers to the group-C (O) -OR, wherein R is heteroaryl as defined, which may be optionally substituted with one OR more substituents as defined herein.

"Heteroarylhydrocarbyl" refers to an acyclic hydrocarbyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with a heteroaryl group. When referring to a particular hydrocarbyl moiety, the terms heteroarylalkyl, heteroarylalkenyl, and/or heteroarylalkynyl are used. Preferably the heteroarylalkyl group is a 6-30 carbon member heteroarylalkyl group, e.g. the alkyl, alkenyl or alkynyl part of the heteroarylalkyl group is 1-10 membered, the heteroaryl part is a 5-20 membered heteroaryl group, more preferably a 6-20 membered heteroarylalkyl group, e.g. the alkyl, alkenyl or alkynyl part of the heteroarylalkyl group is 1-8 membered and the heteroaryl part is a 5-12 membered heteroaryl group.

"hydroxy" means the group-OH.

"oxy" means a divalent group ═ O.

The term "patient" as used herein encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. The term does not denote a particular age or gender.

By "pharmaceutically acceptable" is meant approved or approvable by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2, 2, 2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, Muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or a salt coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like.

"pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

"phosphate group" refers to the group-OP (O) (OR ') (OR "), wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"phosphonate" refers to the group-p (o) (OR ') (OR "), wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"preventing" refers to reducing the risk of acquiring a disease or disorder (i.e., causing at least one clinical symptom of a disease not manifested in a patient who may be exposed to or susceptible to the disease but who has not yet experienced or manifested symptoms of the disease).

"protecting group" refers to an atomic group that reduces or prevents reactivity when attached to a reactive group in a molecular mask. Examples of protecting groups can be found in the following references: green et al, "Protective Groups in organic Chemistry", (Wiley, 2 nd edition, 1991) and Harrison et al, "Complex of synthetic organic Methods", Vol.1-8 (John Wiley and Sons, 1971-. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxy-carbonyl ("FMOC"), nitroveratroxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, groups in which the hydroxy group is acylated or alkylated, such as benzyl and trihydrocarbylsilyl ethers and allyl ethers.

"racemate" refers to an equimolar mixture of enantiomers of a chiral molecule.

"substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituent(s). Typical substituents include, but are not limited to: -X, -R⁵⁴、-O^－、＝O、-OR⁵⁴、-SR⁵⁴、-S、＝S、-NR⁵⁴R⁵⁵、＝NR⁵⁴、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂O^－、-S(O)₂OH、-S(O)₂OR⁵⁴、-OS(O)₂O³¹、-OS(O)₂R⁵⁴、-P(O)(O^-)₂、-P(O)(OR¹⁴)(O³¹)、-OP(O)(OR⁵⁴)(OR⁵⁵)、-C(O)R⁵⁴、-C(S)R⁵⁴、-C(O)OR⁵⁴、-C(O)NR⁵⁴R⁵⁵、-C(O)O^－、-C(S)OR⁵⁴、-NR⁵⁶C(O)NR⁵⁴R⁵⁵、-NR⁵⁶C(S)NR⁵⁴R⁵⁵、-NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵and-C (NR)⁵⁶)NR⁵⁴R⁵⁵Wherein each X is independently halogen; r⁵⁴、R⁵⁵、R⁵⁶And R⁵⁷Each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR⁵⁸R⁵⁹、-C(O)R⁵⁸or-S (O)₂R⁵⁸Or optionally R⁵⁸And R⁵⁸Together with the atoms to which they are both attached form a cycloheteroalkyl ring or substituted cycloheteroalkyl ring; and R⁵⁸And R⁵⁸Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl.

"sulfate group" means a group-OS (O) OR, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"sulfonamido" refers to the group-s (o) NR ' R "where R ' and R" are independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein, or optionally R ' and R "together with the atoms to which both are attached form a cycloheteroalkyl ring or a substituted cycloheteroalkyl ring. Representative examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4- (NR' ") -piperazinyl, or imidazolyl, wherein said groups may be optionally substituted with one or more substituents as defined herein. R' "is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one or more substituents as defined herein.

"sulfonate group" means the group-S (O) OR, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, which may be optionally substituted with one OR more substituents as defined herein.

"mercapto" means the group-SH.

"thioether group" refers to the group-SR, wherein R is a hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl group, as defined herein, which may be optionally substituted with one or more substituents as defined herein.

In one embodiment, "treating" any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or reducing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter that may not be recognized by the patient. In yet another embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically (e.g., stabilization of a recognizable symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a patient for the treatment of a disease, is sufficient to effect treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated, and can be determined by one of ordinary skill in the art without undue experimentation.

Reference will now be made in detail to the preferred embodiments of the present invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the invention to these preferred embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Compounds of the invention

In one aspect of the invention, compounds of formula (1) or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof are set forth:

wherein:

b is O, S, S (O) (O) or NR⁵(ii) a And

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷and R⁸Each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, acylhydrocarbyloxycarbonyl, acyloxyalkyloxycarbonyl, acyloxyalkylcarbonylamino, acyloxyalkyloxycarbonylamino, hydrocarbyloxy, hydrocarbyloxycarbonyl, hydrocarbyloxycarbonylalkoxycarbyloxyoxy, hydrocarbyloxycarbonylalkoxyamino, hydrocarbyloxysarbonylhydrocarbylsulfinyl, hydrocarbylsulfonyl, hydrocarbylthio, amino, hydrocarbylamino, arylalkylamino, dihydrocarbylamino, arylalkyloxy, arylalkyloxycarbonylalkoxycarbyloxy, arylalkyloxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylhydrocarbyloxy, aryloxycarbonyl, aryloxycarbonylamino, arylalkyloxycarbonylalkyloxy, aryloxycarbonylamino, arylalkyloxycarbonylalkylcarbonylamino, arylalkyloxycarbonylalkoxycarbonylamino, arylalkyloxycarbonylalkylcarbonyl-amino, arylalkyloxycarbonyl-alkoxy-alkoxycarbonyl, arylalkyloxycarb, Carboxy, carbamoyl, carbamate, carbonate, cyano, halogen, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate, sulfate, sulfonate or sulfonamide group, wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸And A may be optionally substituted with isotopes including, but not limited to²H (deuterium),³H (tritium),¹³C、³⁶Cl、¹⁸F、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P and³⁵S。

in another aspect, compounds of formula (1a) or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof are described:

wherein:

b is O, S, S (O) (O) or NR⁵(ii) a And

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷and R⁸Each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, acylHydrocarbyloxycarbonyl, acyloxyalkyloxycarbonyl, acyloxyalkyloxycarbonylamino, hydrocarbyloxy, hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyloxydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylamino, hydrocarbylsulfinyl, hydrocarbylsulfonyl, hydrocarbylthio, amino, hydrocarbylamino, arylalkylamino, dihydrocarbylamino, arylalkyloxy, arylalkyloxycarbonylhydrocarbyloxy, arylalkyloxycarbonylhydrocarbylamino, arylalyloxycarbonyl, arylalyloxycarbonyloxyl, arylalkyloxycarbonylhydrocarbylamino, carboxy, carbamoyl, carbamate, carbonate, cyano, halogen, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate, sulfate, sulfonate or sulfonamide, wherein R is selected from the group consisting of¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸And A may be optionally substituted with isotopes including, but not limited to²H (deuterium),³H (tritium),¹³C、³⁶Cl、¹⁸F、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P and³⁵S。

in another aspect of the invention, A is- (CH)₂)_n-。

In another aspect of the invention, A is-O- (CH)₂)_n-、-S-(CH₂)_n-、-CH₂-O-(CH₂)_n-、-(CH₂)_n-O-CH₂-CH₂-、-CH₂-S-(CH₂)_n-or- (CH)₂)_n-S-CH₂-CH₂-。

In another aspect of the invention, A is-NH-C (O) - (CH)₂)_n-、-CH₂-NH-C(O)-(CH₂)_n-、-CH₂-C(O)-NH-(CH₂)_n-or- (CH)₂)_n-C(O)-NH-CH₂-CH₂-。

In another aspect of the invention, B is O.

In another aspect of the invention, R⁴Is H.

In another aspect of the invention, R¹And R²Each independently is H, halogen, halogenated hydrocarbyl or hydrocarbyloxy.

The compounds of the invention described herein may have one or more of the following characteristics or properties:

(a) the compounds of the invention may have affinity for the dopamine D2 receptor;

(b) the compounds of the invention may have affinity for the serotonin 5-HT1A receptor;

(c) the compounds of the invention may have affinity for the serotonin 5-HT2A receptor;

(d) regardless of the electrophysiological properties of the parent drug, the primary metabolite has negligible inhibitory activity on the HERG (human ether-a-go-go related gene) potassium channel at normal therapeutic concentrations of the parent drug in plasma (e.g., the metabolite concentration must be at least 5-fold the normal therapeutic concentration of the parent compound before activity against the HERG potassium channel is observed);

(e) the compounds of the invention and their metabolites do not cause or have reduced occurrence of metabolic drug-drug interactions (DDIs) when co-administered with other drugs;

(f) the compounds of the invention and their metabolites do not substantially elevate Liver Function Test (LFT) values when administered alone;

(g) the oral bioavailability of the compounds is consistent with oral administration with standard pharmaceutical oral formulations; however, the compounds and compositions thereof may also be administered with any delivery system that produces constant and controllable blood levels over time.

In one aspect, the present invention provides compounds having any two or more of the above-identified characteristics or properties. In another aspect, the present invention provides compounds having at least any three or more of the above-identified characteristics or properties. Preferably, the compounds of the present invention have all seven characteristics or properties.

Additional modifications to the compounds disclosed herein will be readily apparent to those skilled in the art. Thus, analogs and salts of the exemplified compounds are within the scope of the invention. With knowledge of the compounds of the invention, the skilled person can synthesize these compounds from available substrates using known methods. The term "analog" as used herein refers to a compound that is substantially identical to another compound but may have been modified, for example, by the addition of additional pendant groups. The term "analog" as used herein may also refer to a compound that is substantially identical to another compound but has atomic or molecular substitution at a particular position of the compound.

The invention further relates to enantiomerically separated compounds and compositions comprising said compounds. The isolated enantiomeric forms of the compounds of the present invention do not substantially contain each other (i.e., enantiomeric excess). In other words, the "R" form of the compound is substantially free of the "S" form of the compound, and thus the "S" form is in enantiomeric excess. In contrast, the "S" form of a compound is substantially free of the "R" form of the compound, and thus the "R" form is in enantiomeric excess. In one embodiment of the invention, the isolated enantiomeric compound is at least about 80% enantiomeric excess. Thus, for example, the compound is in at least about 90% enantiomeric excess, preferably at least about 95% enantiomeric excess, more preferably at least about 97% enantiomeric excess, or even more preferably at least 99% or greater than 99% enantiomeric excess.

Synthesis of Compounds of the invention

The compounds of the present invention can be obtained via the synthetic methods illustrated in schemes 1-2. Several methods for synthesizing aryl piperazine derivatives have been described in the art. The starting materials and building blocks for the preparation of the compounds of the invention and their intermediates are commercially available or can be prepared by well known Synthetic methods (see, for example, Green et al, "Protective Groups in Organic Chemistry," (Wiley, 4 th edition, 2006); Harrison et al "Complex of Synthetic Organic methods," Vol.1-8 (John Wiley and Sons, 1971-), "Beilstein Handbook of Organic Chemistry, Frankfurt, Germany; Feiser et al," Reagents for Organic Synthesis, "Vol.1-45, Karger, 1991; March, Advanced Organic Chemistry," Wiley Interscience, 4 th edition, 1991; Larock "Comprehensive Organic Chemistry variants," Wiley-VCH, publication, 2, edition, John of silica, 1996; Ready et al, environmental Chemistry, 1996). Other methods for synthesizing the arylpiperazine derivatives described herein are described in the art or will be apparent to the skilled artisan in view of the references provided above, and these other methods can be used to synthesize the compounds of the invention. Thus, the approaches presented in the schemes herein are illustrative and not comprehensive.

In one method, an arylpiperazine derivative comprising formula (1) is prepared as described in scheme 1. Starting structural unit 6-nitrobenzoThe oxazinone 1 was purchased from commercial sources Sigma-Aldrich. Compound 1 can also be synthesized from methods well known in the literature. Reduction of the nitro moiety of Compound 1 with a reducing agent such as potassium borohydride (KBH4) in the presence of a mild Lewis acid cuprous chloride (1) (CuCl) in a protic solvent such as methanol to give a 6-aminobenzeneAn oxazinone-2. Preparation of target benzo(s) by coupling of amine 2 with appropriate carboxylic acid 3 under standard coupling conditions using Dicyclohexylcarbodiimide (DCC) as coupling agent in the presence of mild base 4- (N, N-dimethylamino) pyridine (DMAP) in polar aprotic solvent mediumAn oxazinone 4. Carboxylic acid 3 is prepared by alkylation of the appropriate aryl piperazine with the appropriate bromo carboxylic acid ester followed by saponification. Benzo by treatment with hydrogen chloride under standard conditionsConversion of a keton derivative 4Is hydrochloride. Benzo may also be substituted by methods well known in the artThe oxazinones 4 are converted to other forms of pharmaceutically acceptable salts such as methanesulfonate and lower aliphatic carboxylate.

Scheme 1

In another method, an arylpiperazine derivative comprising formula (1) is prepared as described in scheme 2. The starting building block, 4-methoxy-2-nitrophenol 6, was purchased from commercial source Sigma-Aldrich. By reacting under mild base potassium carbonate (K)₂CO₃) In the presence of acetone heating with bromoethyl acetate 7 to alkylate nitrophenol 6 to give ester 8. Using aluminium chloride (AlCl) in anhydrous dichloromethane₃) Treatment of the ester 8 at reflux temperature gives the corresponding nitrophenol derivative 9. Compound 11 was prepared by alkylating nitrophenol 9 with 1, 4-dibromobutane 10 under the same reaction conditions as described for the preparation of compound 8 (scheme 2). Compound 11 is reacted with aryl piperazine 12 in the presence of N, N-Diisopropylethylamine (DIEA) in acetonitrile at about 60-70 ℃ for 8-16h to provide compound 13. When compound 13 is subjected to reducing conditions using iron (III) chloride at reflux temperature in the presence of metallic iron in a solvent mixture of ethanol and acetic acid, the corresponding benzo is obtainedThe oxazinone 14, which is converted to the hydrochloride salt 15 by treatment with hydrogen chloride under standard conditions. Other standard nitro reduction conditions, such as hydrogenation in the presence of a palladium on activated carbon (Pd/C) catalyst, also give the corresponding cyclized product 14. Benzo may also be substituted by methods well known in the artConversion of the oxazinones 14 to other forms of pharmaceutically acceptable salts, e.g. mesylate anda lower aliphatic carboxylic acid salt.

Scheme 2

Therapeutic use of compounds of formula (1)

The present invention relates to syntheses, compositions and methods based on the use of aryl piperazine based compounds that are useful in the treatment of schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism and depression. The present invention provides methods for the synthesis of such aryl piperazine-based antipsychotics. The present invention also provides methods of using combinations of aryl piperazine-based antipsychotics and aryl piperazine-based antipsychotics for treating schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism, and depression.

According to the present invention, a compound of formula (1) and/or a composition comprising a compound of formula (1) is administered to a patient, preferably a human, suffering from schizophrenia. In addition, in certain embodiments, the compounds and/or compositions of the present invention are administered to a patient, preferably a human, as a therapeutic or prophylactic measure against acute mania, bipolar disorder, autism, and depression.

Thus, one skilled in the art can readily determine and use a compound of structural formula (1) and/or a composition containing one or more compounds of structural formula (1) to treat a medical condition in need of an antipsychotic agent.

Therapeutic/prophylactic administration

The compounds of formula (1) and/or compositions containing one or more compounds of formula (1) may be advantageously used in human medicine. As previously detailed above, the compounds of structural formula (1) and/or compositions containing one or more compounds of structural formula (1) are useful in the treatment of schizophrenia and related psychoses, such as acute mania, bipolar disorder, autism, and depression.

When used to treat or prevent the above diseases or disorders, the compounds and/or compositions of the present invention may be administered or administered alone or in combination with other drugs. The compounds and/or compositions of the present invention may also be administered or administered alone or in combination with other pharmaceutically active agents, including other compounds and/or compositions of the present invention.

The present invention provides methods of treatment and prevention by administering to a patient a therapeutically effective amount of a composition and/or compound of the present invention. The patient may be an animal, more preferably a mammal, most preferably a human.

Preferably, the compounds and/or compositions of the present invention comprising one or more compounds and/or compositions of the present invention are administered orally. The compounds and/or compositions of the present invention may also be administered by any other convenient route, for example by infusion or bolus injection, absorption through epithelial or mucosal layers (e.g., oral, rectal, intestinal, etc.). Can be administered systemically or locally. Various delivery systems (e.g., liposome encapsulation, microparticles, microcapsules, capsules, etc.) are known for administration of the compounds and/or compositions of the present invention. Methods of administration include, but are not limited to: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal (intragastric), transdermal, rectal, by inhalation or topically (especially to the ear, nose, eye or skin).

In a particularly preferred embodiment, the compounds and/or compositions of the present invention may be delivered via a sustained release system, preferably an oral sustained release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRCCrit. Ref biomed. Eng.14: 201; Saudek et al, 1989, N.Engl. J.Med.321: 574).

In another embodiment, polymeric materials may be used (see "Medical Applications of controlled Release," Langer and Wise (ed., Wiley, New York (1984); Ranger and Peppas, 1983, J.Macromol. Sci.Rev. Macromol chem.23: 61; see also Levy et al, 1985, Sci.228: 190; During et al, 1989, Ann.Neurol.25: 351; Howard et al, 1989, J.Neurosurg.71: 105). In a preferred embodiment, the polymeric material is used for oral sustained release delivery. Preferred polymers include sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose (most preferably hydroxypropyl methylcellulose). Other preferred cellulose ethers have been described in the art (Bamba et al, int.j.pharm., 1979, 2, 307).

In another embodiment, the enteric coated formulations may be used for oral sustained release administration. Preferred coating materials include polymers with pH-dependent solubility (i.e., pH-controlled release), polymers with slow or pH-dependent swelling, dissolution or erosion rates (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzymatic controlled release), and polymers that form a solid layer that is broken by increased pressure (i.e., pressure-controlled release).

In yet another embodiment, the osmotic delivery system is used for oral sustained release administration (Verma et al, drug Dev. Ind. pharm., 2000, 26: 695-. In a preferred embodiment, the method comprisesOsmotic delivery systems are used in oral sustained release delivery devices (see, e.g., Theeuwes et al, U.S. Pat. No. 3,845,770; and Theeuwes et al, U.S. Pat. No. 3,916,899).

In yet another embodiment, a controlled Release system may be placed in proximity to the target of the compounds and/or compositions of the invention, thereby requiring only a fraction of the systemic dose (see, e.g., Goodson, in "Medical Applications of controlled Release," supra, Vol.2, p.115-138 (1984)). Also useful are those described in Langer, 1990, Science 249: 1527 and 1533.

The compounds of formula (1) and/or compositions containing one or more compounds of formula (1) of the present invention may be chemically and/or enzymatically cleaved. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal can enzymatically cleave the compounds and/or compositions of the present invention.

Compositions of the invention

The compositions of the present invention comprise a therapeutically effective amount of one or more compounds of the present invention, preferably in purified form, in association with a suitable amount of a pharmaceutically acceptable vehicle, which is in a form intended to provide suitable administration to the patient. When administered to a patient, the compounds of the invention and pharmaceutically acceptable vehicles are preferably sterile. When the compounds of the present invention are administered intravenously, water is the preferred vehicle. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. present agent or pH buffer. Adjuvants, stabilizers, thickeners, lubricants and colorants may additionally be used.

Pharmaceutical compositions containing a compound of the present invention may be prepared by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The pharmaceutical compositions may be formulated in conventional manner with one or more physiologically acceptable carriers, diluents, excipients or adjuvants which facilitate processing of the compounds of the invention into pharmaceutically acceptable preparations. Suitable formulations depend on the route of administration chosen.

The compositions of the invention may take the form of: solutions, suspensions, emulsions, tablets, pills, pellets and capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form suitable for use. In one embodiment, the pharmaceutically acceptable vehicle is a capsule (see, e.g., Grosswald et al, U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutically acceptable vehicles are set forth in the art (see Remington's pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 17 th edition, 1985). Preferred compositions of the invention are formulated for oral delivery, especially for oral sustained release administration.

Compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional substances to provide pharmaceutically palatable preparations, such as sweetening agents, for example fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; colorants and preservatives. In addition, when in the form of tablets or pills, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a prolonged period. Selectively permeable membranes surrounding osmotically actively driven compounds are also suitable for orally administered compounds of the present invention. In these latter platforms, fluid from the environment surrounding the capsule is absorbed by the driver compound, which swells to move the agent or agent composition through the pores. These delivery platforms provide a substantially zero order delivery profile as opposed to the peaked profile of the immediate release formulation. Time delay materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.

For oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include: water, saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, buffers that are more acidic between pH 4 and pH 6 (e.g., acetate between about mM and about 50mM, citrate, ascorbate), and the like. In addition, a corrigent, a preservative, a coloring agent, a bile salt, acylcarnitine (acylcamitine), and the like may be added.

Compositions administered by other routes are also contemplated. For buccal administration, the compositions may be in the form of tablets, lozenges, and the like, formulated in conventional manner. Liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will generally comprise a compound of the invention and a pharmaceutically acceptable vehicle. Preferably the pharmaceutically acceptable vehicle is a liquid, such as an alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material may be added to modify the aerosol properties of a solution or suspension of the compounds of the present invention. Preferably the material is a liquid, such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611). The compounds of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa powder, butter or other glycerides. In addition to the formulations described previously, the compounds of the present invention may also be formulated as depot formulations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g. as a sparingly soluble salt.

When the compound of the present invention is acidic, it may be included in any of the above formulations as a free acid, a pharmaceutically acceptable salt, solvate or hydrate. Pharmaceutically acceptable salts substantially retain the activity of the free acid, can be prepared by reaction with a base, and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form.

Methods of use and dosages

The compounds of the present invention or compositions thereof are generally employed in an amount effective to achieve the intended purpose. For use in the treatment of schizophrenia and related psychoses such as acute mania, bipolar disorder, autism, and depression, the compounds of formula (1) and compositions containing the compounds of formula (1) are administered or administered in therapeutically effective amounts.

The amount of a compound of the invention effective to treat a particular disorder or condition disclosed herein depends on the identity of the disorder or condition and can be determined by standard clinical techniques previously described and known in the art. In addition, in vitro or in vivo assays may optionally be employed to help determine optimal dosage ranges. The amount of the compound of the invention administered will, of course, depend, inter alia, on the subject to be treated, the weight of the subject, the severity of the disease, the mode of administration and the judgment of the prescribing physician. For example, the dose may be delivered in a pharmaceutical composition by a single administration, by multiple administrations, or by controlled release. In a preferred embodiment, the compounds of the present invention are delivered by oral sustained release administration. In this embodiment, the compounds of the present invention are preferably administered 2 times per day, more preferably 1 time per day. Intermittent administration may be repeated, and administration may be provided alone or in combination with other agents, and continued as needed to effectively treat the disease state or condition.

The compounds of structural formula (1) and/or compositions containing one or more compounds of structural formula (1) within the following ranges may be administered for the pharmacological treatment of schizophrenia and related psychoses such as acute mania, bipolar disorder, autism and depression: 0.1mg to 500mg, preferably 1mg to 100mg, more preferably 5mg, 10mg, 15mg, 20mg, 25mg, 35mg or 50mg, most preferably 10mg are administered in one or more doses per day.

The desirable therapeutic or prophylactic activity of the compounds of the invention is preferably determined in vitro as well as in vivo prior to use in humans. The efficacy and safety of the compounds of the invention can also be demonstrated using animal model systems.

Preferably, a therapeutically effective dose of a compound of the invention as described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard pharmaceutical methods and can be readily determined by the skilled artisan. The dose ratio between toxic and therapeutic effects is the therapeutic index. The compounds of the present invention preferably will exhibit particularly high therapeutic indices in the treatment of diseases and conditions. The dosages of the compounds of the invention described herein will preferably be within the circulating concentration range, including effective dosages with little or no toxicity.

In one aspect of the invention, methods of treating one of psychosis, schizophrenia, acute mania, bipolar disorder, autism, or depression are set forth comprising administering a compound of the present invention to a patient in need thereof.

In another aspect of the invention, the method treats schizophrenia.

In another aspect of the invention, the method treats bipolar disorder.

In another aspect of the invention, the use comprises the treatment of schizophrenia.

In another aspect of the invention, the use comprises treating bipolar disorder.

In one aspect of the invention, the compounds of the invention are useful in the manufacture of medicaments for the treatment of psychosis, schizophrenia, acute mania, bipolar disorder, autism or depression, psychosis, schizophrenia, acute mania, bipolar disorder, autism or depression.

In another aspect of the invention, the use is for the treatment of schizophrenia.

In another aspect of the invention, the use is for the treatment of bipolar disorder.

Combination therapy

In certain embodiments of the invention, the compounds of the invention may be used in combination therapy with at least one other therapeutic agent. The compounds of the invention and the therapeutic agent may act additively, or more preferably synergistically. In a preferred embodiment, a composition comprising a compound of the invention is administered concurrently with the administration of another therapeutic agent, which may be part of the same composition. In another embodiment, a composition comprising a compound of the invention is administered before or after the administration of another therapeutic agent.

Examples

The invention is further defined by reference to the following examples which illustrate in detail the preparation of, and assays using, the compounds and compositions of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

In the following examples, the following abbreviations have the following meanings. Abbreviations, if not defined, have generally accepted meanings.

Example 1

6-amino-2H-benzo [ b ]][1，4]Oxazin-3 (4H) -one (2) (scheme 1). Stirring at 25 deg.C to obtain 6-nitro-2H-1, 4-benzoTo a suspension of oxazin-3 (4H) -one 1(0.5g, 0.0026 mol) and CuCl (0.77g, 0.0078 mol) in dry methanol (25mL) was added potassium borohydride (0.98g, 0.018 mol) in portions (exothermic with evolution of hydrogen). The reaction mixture was stirred at 25 ℃ for 30 minutes. The black precipitate formed was filtered and washed with methanol. Evaporating the combined filtrate and washings to obtain 6-amino-2H-benzo [ b ]][1，4]Oxazin-3 (4H) -one, which was purified by silica gel column chromatography with ethyl acetate. Brown solid (0.29g, 67%).¹H NMR(400MHz，CDCl₃)：4.34(s，2H)；4.81(s，2H)；6.09(dd，J＝2.8，8.4Hz，1H)；6.14(d，J＝2.8Hz，1H)；6.59(d，J＝8.4Hz，1H)；10.44(s，1H)。

Example 2

4- (4- (2-methoxyphenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b)][1，4]Oxazin-6-yl) butanamide (4a) (scheme 1). Stirring of 6-amino-2H-benzo [ b ] at room temperature][1，4]A mixture of oxazin-3 (4H) -one 2(0.08g, 0.0005 mole), 4- (4- (substituted-phenyl) piperazin-1-yl) butyric acid 3a (0.0005 mole), dicyclohexylcarbodiimide (0.1g, 0.0005 mole), 4- (dimethylamino) pyridine (0.006g, 0.00005 mole) in 10mL dichloromethane was left overnight. The reaction progress was monitored by Thin Layer Chromatography (TLC). Cooling the reaction mixture; filtration to remove precipitated urea, washing with saturated sodium bicarbonate solution, drying over sodium sulfate, and evaporation under reduced pressure to give 4- (4- (substituted-phenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b [ -b ]][1，4]Oxazin-6-yl) butanamide 4a, which is purified by silica gel column chromatography with a 0-10% gradient of ethyl acetate and methanol. The pure product 4a provides satisfactory results¹H NMR and/or mass spectroscopy data. White solid (0.06g, 29%).¹H NMR(400MHz，CDCl₃)：1.94-2.00(m，2H)；2.53-2.59(m，4H)；2.70(br s，4H)；3.14(br s，4H)；3.87(s，3H)；4.55(s，2H)；6.63(dd，J＝2.4，8.8Hz，1H)；6.84-6.88(m，2H)；6.93-6.95(m，2H)；6.99-7.04(m，1H)；7.82(d，J＝2.4Hz，1H)；9.04(br s，1H)；9.12(brs，1H).MS(ESI)：m/z＝425.2(M+H<+>)。

Example 3

4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b)][1，4]Oxazin-6-yl) butanamide (4b) (scheme 1). Compound 4b was synthesized using the protocol described for the synthesis of compound 4a in example 2 (scheme 1). White solid (0.08g, 34%).¹H NMR(400MHz，CDCl₃)：1.93-2.00(m，2H)；2.50-2.57(m，4H)；2.68(br s，4H)；3.09(br s，4H)；4.50(s，2H)；6.63(dd，J＝2.4，8.8Hz，1H)；6.88(d，J＝8.8Hz；1H)；6.99-6.92(m，1H)；7.13-7.20(m，2H)；7.71-7.72(m，1H)；8.46(br s，1H)；8.58(br s，1H).MS(ESI)：m/z＝463.2(M⁺)。

Example 4

Hydrochloric acid 4- (4- (2-methoxyphenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b)][1，4]Oxazin-6-yl) butanamide (5a) (scheme 1). To 4- (4- (substituted-phenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b)][1，4]To a solution of oxazin-6-yl) butanamide 4a in 5mL of dichloromethane was added 2mL of a 2M HCl in diethyl ether, and the solution was evaporated at 25 ℃ to give 4- (4- (substituted-phenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b ] hydrochloride][1，4]Oxazin-6-yl) butanamide 5 a. The pure product 5a was satisfactory¹H NMR and/or mass spectroscopy data. White solid (60 mg). Ms (esi): m/z 425.2 (M-HCl).

Example 5

Hydrochloric acid 4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) -N- (3-oxo-3, 4-dihydro-2H-benzo [ b][1，4]Oxazin-6-yl) butanamide (5b) (scheme 1). Compound 5b was synthesized using the protocol described for the synthesis of compound 5a in example 4 (scheme 1). White solid (40 mg). Ms (esi): m/z 463.2 (M-HCl).

Example 6

Ethyl 2- (4-methoxy-2-nitrophenoxy) acetate (8) (scheme 2). A mixture of 4-methoxy-2-nitrophenol 6(1.69g, 0.01 mole), potassium carbonate (2.76g, 0.02 mole) and ethyl bromoacetate 7(1.1mL, 0.01 mole) in 20mL of anhydrous acetone was refluxed overnight (12 h). The reaction progress was monitored by thin layer chromatography. The reaction mixture was evaporated, the residue diluted with water and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give ethyl 2- (4-methoxy-2-nitrophenoxy) acetate 8 which was purified by silica gel column chromatography with a gradient of 0-50% hexane and ethyl acetate. Yellow solid (2.18g, 85%).¹H NMR(400MHz，CDCl₃)：1.28(t，J＝7.2Hz，3H)；3.82(s，3H)；4.25(q，J＝7.2Hz，2H)；4.70(s，2H)；7.01(d，J＝9.2Hz，1H)；7.08(dd，J＝3.2，9.2Hz，1H)；7.40(d，J＝2.8Hz，1H)。

Example 7

Ethyl 2- (4-hydroxy-2-nitrophenoxy) acetate (9) (scheme 2). To a solution of ethyl 2- (4-methoxy-2-nitrophenoxy) acetate 8(1.0g, 0.004 mol) in 10mL of dichloromethane cooled in an ice bath was added chlorine in portionsAluminium oxide (1.6g, 0.0133 mol). The resulting mixture was gradually warmed to room temperature and then refluxed for 4 h. The reaction progress was monitored by Thin Layer Chromatography (TLC). The reaction mixture was washed with saturated sodium bicarbonate solution and dried over sodium sulfate to give ethyl 2- (4-hydroxy-2-nitrophenoxy) acetate 9, which was purified by silica gel column chromatography with a gradient of hexane and ethyl acetate. White solid (0.28g, 37%).¹H NMR(400MHz，CDCl₃)：1.26(t，J＝6.8Hz，3H)；4.27(q，J＝6.8Hz，2H)；4.71(S，2H)；6.32(S，1H)；6.90(d，J＝8.8Hz，1H)；6.99(dd，J＝3.2Hz；8.8Hz，1H)；7.30(d，J＝2.8Hz，1H)。

Example 8

Ethyl 2- (4- (4-bromobutoxy) -2-nitrophenoxy) acetate (11) (scheme 2). To a solution of ethyl 2- (4-hydroxy-2-nitrophenoxy) acetate 9(0.17g, 0.0007 mol) in 10mL of acetone was added potassium carbonate (0.39g, 0.0028 mol). The reaction mixture was stirred at room temperature for 10 minutes. 1, 4-dibromobutane 10(0.33mL, 0.0028 mol) was then added. The resulting mixture was heated to reflux for 12 h. The reaction progress was monitored by Thin Layer Chromatography (TLC). Acetone was evaporated, the residue was diluted with water, extracted with ethyl acetate and dried over sodium sulfate to give ethyl 2- (4- (4-bromobutoxy) -2-nitrophenoxy) acetate 11, which was purified by silica gel column chromatography with a 0-20% gradient of hexane and ethyl acetate. Yellow oil (0.52g, 92%).¹H NMR(400MHz，CDCl₃)：1.26(t，J＝6.8Hz，3H)；1.91-1.98(m，2H)；2.02-2.09(m，2H)；3.48(t，J＝6.8Hz，2H)；3.99(t，J＝6.0Hz，2H)；4.26(q，J＝6.8Hz，2H)；4.70(s，2H)；6.99-7.02(m，2H)；7.38(d，J＝3.2Hz，1H)。

Example 9

Ethyl 2- (4- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butoxy) -2-nitrophenoxy) acetate 13a (scheme 2). Ethyl 2- (4- (4-bromobutoxy) -2-nitrophenoxy) acetate 11 (0.0) was added at 60 ℃007 moles), 1- (2-substituted-phenyl) piperazine hydrochloride 12(0.16g, 0.0007 moles), N-diisopropylethylamine (0.36mL, 0.0021 moles) in 10mL acetonitrile was heated for 12 h. The reaction progress was monitored by Thin Layer Chromatography (TLC). The reaction mixture was evaporated to remove volatiles, the residue was diluted with water, extracted with ethyl acetate, the organic extract was washed with sodium bicarbonate solution and dried over sodium sulfate to give ethyl 2- (4- (4- (4- (substituted-phenyl) piperazin-1-yl) butoxy) -2-nitrophenoxy) acetate 13a, which was purified by silica gel column chromatography with a gradient of hexane and ethyl acetate. Pure product 13a gave satisfactory 1H NMR and/or mass spectral data. Colorless oil (0.3.g, 88%).¹H NMR(400MHz，CDCl₃)：1.26(t，J＝6.8Hz，3H)；1.70-1.72(m，2H)；1.82-1.85(m，2H)；2.47(t，J＝6.4Hz，2H)；2.67(br s，4H)；3.10(br s，4H)；3.86(s，3H)；3.98(t，J＝6.4Hz，2H)；4.24(q，J＝6.8Hz，2H)；4.70(s，2H)；6.84-6.96-7.08(m，6H)；7.38(d，J＝2.8Hz，1H)。

Example 10

Ethyl 2- (4- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butoxy) -2-nitrophenoxy) acetate 13b (scheme 2). Compound 13b was prepared using the protocol described for the synthesis of compound 13a in example 9 (scheme 2). Yellow oil (0.3g, 81%).¹H NMR(400MHz，CDCl₃)：1.26(t，J＝6.8Hz，3H)；1.70-1.73(m，2H)；1.80-1.85(m，2H)；2.48(t，J＝6.4Hz，2H)；2.65(br s，4H)；3.07(br s，4H)；3.99(t，J＝6.4Hz，2H)；4.26(q，J＝6.8Hz，2H)；4.70(s，2H)；6.94-7.08(m，3H)；7.13-7.16(m，2H)；7.39(d，J＝3.2Hz，1H)。

Example 11

6- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butoxy) -2H-benzo [ b][1，4]Oxazin-3 (4H) -one (14a) (scheme 2). Ethyl 2- (4- (4- (4- (substituted-phenyl) piperazin-1-yl) butoxy) -2-nitrophenoxy) acetate 13a (0.1g, 0.0002 mol) was dissolved in a mixture of 10mL ethanol and 1.2mL acetic acid in a 100mL flask equipped with an effective condenser and the stirred mixture was gently refluxed. Iron powder (0.084g, 0.0015 moles) was added followed immediately by iron (III) chloride hexahydrate (0.01g, 0.000034 moles). The mixture was refluxed for another 3h, then cooled, filtered through a Buchner funnel, and washed with ethanol. The combined filtrate and washings were evaporated. To the residue were added ethyl acetate and water, and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried and concentrated to give 6- (4- (4- (substituted-phenyl) piperazin-1-yl) butoxy) -2H-benzo [ b][1，4]Oxazin-3 (4H) -one 14a, which was purified by silica gel column chromatography with a gradient of hexane and ethyl acetate. Pure product 14a gave satisfactory 1H NMR and/or mass spectral data. A colorless oil (0.08g, 97%).¹H NMR(400MHz，CDCl₃)：1.70(br s，2H)；1.78(br s，2H)；2.47(br s，2H)；2.67(br s，4H)；3.10(br s，4H)；3.86(s，3H)；3.91(br s，2H)；4.55(s，2H)；6.38(br s，1H)；6-48-6.50(m，1H)；6.85-6.99(m，5H)；9.12(br s，1H)。MS(ESI)：m/z＝412.3(M⁺+H)。

Example 12

6- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butoxy) -2H-benzo [ b][1，4]Oxazin-3 (4H) -one (14b) (scheme 2). Compound 14b was prepared using the protocol described for the synthesis of compound 14a (scheme 2) as in example 11. Colorless oil (0.1g, 42%).¹H NMR(400MHz，CDCl₃)：1.79(br s，4H)；2.74(br s，2H)；2.96(brs，4H)；3.17(brs，4H)；3.91(s，2H)；4.05(s，2H)；6.44(s，1H)；6.48(dd，J＝2.4Hz；8.8Hz，1H)；6.85(d，J＝8.8Hz，1H)；6.96(dd，J＝2.0Hz；7.2Hz，1H)；7.12-7.19(m，2H)；9.49(s，1H)；9.87(br s，1H)。MS(ESI)：m/z＝450.2(M⁺)。

Example 13

6- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butoxy) -2H-benzo [ b ] hydrochloride][1，4]Oxazin-3 (4H) -one (15a) (scheme 2). To 6- (4- (4- (substituted-phenyl) piperazin-1-yl) butoxy) -2H-benzo [ b][1，4]To a solution of oxazin-3 (4H) -one 14a in 5mL of dichloromethane was added 2mL of a 2M HCl in diethyl ether, and the solution was evaporated at 25 ℃ to give 6- (4- (4- (substituted-phenyl) piperazin-1-yl) butoxy) -2H-benzo [ b ] hydrochloride][1，4]Oxazin-3 (4H) -one 15 a. The pure product 15a gave satisfactory results¹H NMR and/or mass spectroscopy data. White solid (0.08 g). Ms (esi): m/z 412.3 (M-HCl).

Example 14

6- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butoxy) -2H-benzo [ b ] hydrochloride][1，4]Oxazin-3 (4H) -one (15b) (scheme 2). Compound 15b was prepared using the protocol described for the synthesis of compound 15a in example 13 (scheme 2). White solid (0.28 g). Ms (esi): m/z 450.2 (M-HCl).

Pharmacological results in vitro

The arylpiperazine derivatives comprising formula (1) described in the present invention were tested in vitro pharmacological assays to evaluate their activity on dopamine D2S, serotonin-5-HT 1A and serotonin-5-HT 2A receptors. In vitro assay protocols and references are described herein.

Dopamine D2S (human recombinant) binding assay

Materials and methods:

the receptor source is as follows: human recombinants expressed in CHO cells

A radioligand: [³H]Spirocyclic piperidones (20-60Ci/mmol)

Control compound: haloperidol

Incubation conditions were as follows: at 25 ℃ in a medium containing 120mM NaCl, 5mM KCl, 5mM MgCl₂1mM EDTA in 50mM Tris-HCl (pH 7.4) for 60 minutes. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped on the filters was measured and compared to control values to determine any interaction of the test compound with the cloned dopamine-D2 short binding site (ref: Jarvis, K.R. et al, Journal of Receptor research 1993, 13(1-4), 573-.

Serotonin 5HT_1A(human recombination) binding assay

Materials and methods:

the receptor source is as follows: human recombinants expressed in HEK-293 cells

A radioligand: [³H]-8-OH-DPAT(221Ci/mmol)

Control compound: 8-OH-DPAT

Incubation conditions were as follows: the reaction was carried out at room temperature in 50mM TRIS-HCl (pH 7.4) containing 10mM MgSO4, 0.5mM EDTA, and 0.1% ascorbic acid for 1 hour. The reaction was terminated by rapid vacuum filtration onto a glass vacuum filter. Radioactivity trapped on the filters was measured and compared to control values to determine any interaction of the test compound with the cloned serotonin-5 HT1A binding site (ref: Hoyer, D. et al, Eur. journal Pharmacol.1985, 118, 13-23; Schoefter, P. and Hoyer, D. Nauyn-Schmiedberg's Arch. Pharmac.1989, 340, 135-138).

Serotonin 5HT_2A(human) binding assay

Materials and methods:

the receptor source is as follows: human cortex

A radioligand: [³H]Ketanserin (60-90Ci/mmol)

Control compound: ketanserin

Incubation conditions were as follows: the reaction was carried out in 50mM TRIS-HCl (pH 7.6) at room temperature for 90 minutes. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped on the filter was measured and compared to control values to determine any interaction of the test compound with the cloned serotonin-5 HT2A binding site (ref: Leysen, J.E. et al, mol. Pharmacol.1982, 21, 301-.

dopamine-D2S, serotonin-5 HT at 6 different concentrations_1AAnd serotonin-5 HT_2AThe measured concentrations were 0.5nM, 1nM, 10nM, 100nM, 300nM and 1000 nM.

The in vitro pharmacological activity of selected compounds obtained with radioligand binding assays is reported in the table below.

While the invention has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention. All printed patents and publications mentioned in this application are hereby incorporated by reference in their entirety.

Claims

1. A compound having the structure of formula 14b, or a pharmaceutically acceptable salt thereof:

2. the compound of claim 1, wherein the compound is in the form of its hydrochloride salt.

3. The compound of claim 1, wherein one or more hydrogens in the compound are optionally substituted with deuterium.

4. A pharmaceutical composition comprising a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition selected from psychosis, schizophrenia, acute mania, bipolar disorder or depression.

6. The use according to claim 5, wherein the disease is schizophrenia.

7. Use according to claim 5, wherein the disease is bipolar disorder.