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WO2004111038A1 - 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide - Google Patents

5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide Download PDF

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WO2004111038A1
WO2004111038A1 PCT/SE2004/000967 SE2004000967W WO2004111038A1 WO 2004111038 A1 WO2004111038 A1 WO 2004111038A1 SE 2004000967 W SE2004000967 W SE 2004000967W WO 2004111038 A1 WO2004111038 A1 WO 2004111038A1
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disorders
piperidin
pharmaceutically acceptable
chlorophenyl
bis
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Leifeng Cheng
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a pyrazine compound, to processes for preparing this compound, to its use in the treatment of obesity, psychiatric and neurological disorders, to methods for its therapeutic use and to pharmaceutical compositions containing it.
  • CB 1 modulators are useful in the treatment of obesity, psychiatric and neurological disorders (WOO 1/70700 and EP 656354).
  • CB 1 modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.
  • Pyrazinecarboxamides are reported to possess antithrombotic properties (WO 92/ 02513).
  • the compounds disclosed in this document are disclaimed from the compound claims of the present invention.
  • 5,6-Diphenyl-2-pyrazinecarboxylic acid is disclosed in CH 458 361.
  • R 1 and R 2 independently represent:
  • C 1-3 alkyl groups an optionally substituted non-aromatic Cs- ⁇ carbocyclic group; a (C 3-12 cycloalkyl)C 1-3 alkyl- group; a group -(CH 2 ) r (phenyl ) s in which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z; naphthyl; anthracenyl; a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C 1-3 alkyl groups, hydroxy or benzyl ;
  • adamantylmethyl a group - (CH 2 ) t Het in which t is 0,1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C 1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C h alky! group, a
  • R 1 represents H and R 2 is as defined above; or R 1 and R 2 together with the nitrogen atom to which they are attached represent a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C 1-3 alkyl groups, hydroxy or benzyl ;
  • X is CO or SO 2 ;
  • Y is absent or represents NH optionally substitututed by a C 1-3 alkyl group
  • R 3 and R 4 independently represent phenyl, thienyl or pyridyl each of which is optionally substituted by one, two or three groups represented by Z;
  • Z represents a Q ⁇ alkyl group, a C 1-3 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C 1-3 alkylamino, mono or di C 1-3 alkylamido, Q.aalkylsulphonyl, C 1-3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di Ci ⁇ alkyl carbamoyl, sulphamoyl and acetyl; and
  • R 5 is H, a C 1-3 alkyl group, a C 1-3 alkoxymethyl group, trifluoromethyl, a hydroxyC 1-3 alkyl group, C 1-3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C 1-3 alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula -CONHNR a R b wherein R a and R b are as previously defined for R 1 and R 2 respectively;
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent 4-methylpiperazin-l-yl or R 1 represents H and R 2 represents methyl or l-benzylpiperidin-4-yl; X is CO; Y is absent and R 5 is H; then R 3 and R 4 do not both represent 4-methoxyphenyl; and their use in the treatment of obesity, psychiatric and neurological disorders.
  • the invention relates to 5,6-bis(4-chlorophenyl)-JV-piperidin-l-yl-3-(piperidin-l-yl- carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof.
  • “Pharmaceutically acceptable salts”, where such salts are possible, include pharmaceutically acceptable acid and base addition salts.
  • AU tautomers, where possible, are included within the scope of the invention.
  • the compounds may be prepared as described in the Examples and by analogous methods.
  • the compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.
  • a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carbox- amide or pharmaceutically acceptable salts thereof are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease.
  • psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related
  • the compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea).
  • the compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
  • the compounds may also eliminate the increase in weight, which normally accompanies the cessation of smoking.
  • the present invention provides 5,6-bis(4-chlorophenyl)-iV-piperidm-l-yl- 3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxarnide or pharmaceutically acceptable salts thereof, as previously defined for use as a medicament.
  • the present invention provides the use of 5,6-bis(4-chlorophenyl)-iV- piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g.
  • Parkinson's Disease Huntington's Chorea and Alzheimer's Disease
  • immune cardiovascular, reproductive and endocrine disorders
  • septic shock diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea)
  • extended abuse, addiction and/or relapse indications e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
  • the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g.
  • psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions
  • neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis
  • treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • the compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.
  • the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and atherosclerosis.
  • a compound of the present invention may be used in combination with a compound that affects thermogenesis, lipolysis, fat absorption, satiety, or gut motility.
  • the compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol.
  • the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
  • the compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).
  • 5,6-bis(4-chlorophenyl)-iV-piperidin-l-yl-3-(piperidin-l- yl-carbonyl)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent.
  • PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
  • the combination of the invention may be used in conjunction with a sulfonylurea.
  • the present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent.
  • the cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase).
  • HMG-CoA reductase inhibitor is a statin.
  • cholesterol-lowering agent also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • the present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor).
  • IBAT inhibitor an inhibitor of the ileal bile acid transport system
  • the present invention also includes a compound of the present invention in combination with a bile acid binding resin.
  • the present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
  • a bile acid sequestering agent for example colestipol or cholestyramine or cholestagel.
  • a combination treatment comprising the administration of an effective amount of 5,6-bis(4- chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrene
  • ACE angiotensin converting enzyme
  • a method for for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of 5,6-bis(4-chlorophenyl)-iV-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of 5,6-bis(4- chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a pharmaceutical composition which comprises 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl- carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • kits comprising 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • kits comprising: a) 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • kits comprising: a) 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • a combination treatment comprising the administration of an effective amount of 5,6-bis(4-chlorophenyl)- N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.
  • obesity such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers
  • psychiatric and neurological conditions such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers.
  • Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass
  • LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS).
  • 1 H NMR measurements were performed on either a Varian Mercury 300 or a Varian Inova 500, operating at 1 H frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDCl 3 as internal standard. CDCl 3 is used as the solvent for NMR unless otherwise stated.
  • Purification was performed on a semipreparative HPLC with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M NH 4 Ac :acetonitrile 95:5).
  • the crude product was convertd to dimethyl ester by refluxing with hydrogen chloride/methanol (100 ml) and purified by HPLC, giving 12.85 g of the methyl ester.
  • the resulting methyl ester was treated with lithium hydroxide (2.95 g, 0.123 mmol) in acetonitrile (140 ml) and water (90 ml) at ambient temperature for 1.5 h.
  • the acetonitrile was removed under reduced pressure and the aqueous solution was washed once with diethyl ether. Acidification with hydrochloric acid (2M) and filtration gave the title compound (11.8 g, 66% mmol) as a pale yellow solid.
  • Compounds of the present invention are active against the receptor product of the CB 1 gene.
  • the affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al, Molecular Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354.
  • the assay may be performed as follows.
  • lO ⁇ g of membranes prepared from cells stably transfected with the CBl gene were suspended in 200 ⁇ l of 10OmM NaCl, 5mM MgCl 2 , ImM EDTA, 5OmM HEPES (pH 7.4), ImM DTT, 0.1% BSA and lOO ⁇ M GDP.
  • an EC80 concentration of agonist CP55940
  • the required concentration of test compound and O.l ⁇ Ci [ 35 S]-GTP ⁇ S. The reaction was allowed to proceed at 30°C for 45 min.
  • the compounds of the present invention are active at the CBl receptor (IC50 ⁇ 1 micromolar). Most preferred compounds have IC50 ⁇ 200 nanomolar. 5,6-bis(4- chlorophenyl)-iV-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide and pharmaceutically acceptable salts thereof are selected because of their superior potency in vitro and/or higher affinity, leading to better in vivo efficacy. The compounds also have a better selectivity profile, which is expected to improve in vivo safety.
  • the compounds of the present invention may have improved DMPK (Drag Metabolism and Pharmacokinetic) properties, for example improved metabolic stability in vitro or .bioavailability.
  • DMPK Downlink Metabolism and Pharmacokinetic
  • the compounds also have an improved solubility and/or a promising toxicological profile.

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Abstract

The present invention relates to 5,6-bis(4-chlorophenyl)-N-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide, to processes for preparing this compound, to its use in the treatment of obesity, psychiatric and neurological disorders, to methods for its therapeutic use and to pharmaceutical compositions containing it. The compound is a cannabinoid receptor 1 (CB1) modulator.

Description

5, 6-bis (4-chlorophenyl) -N-piperidinl-yl-3- (piperidin-1-yl- carbonyl) pyrazine-2-carboxamide .
Field of invention
The present invention relates to a pyrazine compound, to processes for preparing this compound, to its use in the treatment of obesity, psychiatric and neurological disorders, to methods for its therapeutic use and to pharmaceutical compositions containing it.
Background of the invention
It is known that certain CB1 modulators (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders (WOO 1/70700 and EP 656354). However, there is a need for CB1 modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.
Pyrazinecarboxamides are reported to possess antithrombotic properties (WO 92/ 02513). The compounds disclosed in this document are disclaimed from the compound claims of the present invention. 5,6-Diphenyl-2-pyrazinecarboxylic acid is disclosed in CH 458 361.
Co-pending application PCT/GB02/05742 discloses compounds of the general formula (I)
Figure imgf000002_0001
I and pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, in which R1 and R2 independently represent:
a C1-6alkyl group; an (amino)C1-4alkyl- group in which the amino is optionally substituted by one or more
C1-3alkyl groups; an optionally substituted non-aromatic Cs-^carbocyclic group; a (C3-12cycloalkyl)C1-3alkyl- group; a group -(CH2)r(phenyl )s in which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z; naphthyl; anthracenyl; a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C1-3alkyl groups, hydroxy or benzyl ;
1 -adamantylmethyl ; a group - (CH2)t Het in which t is 0,1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C1-3alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a Chalky! group, a
Cusalkoxy group or halo; or R1 represents H and R2 is as defined above; or R1 and R2 together with the nitrogen atom to which they are attached represent a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C1-3alkyl groups, hydroxy or benzyl ;
X is CO or SO2;
Y is absent or represents NH optionally substitututed by a C1-3alkyl group; R3 and R4 independently represent phenyl, thienyl or pyridyl each of which is optionally substituted by one, two or three groups represented by Z;
Z represents a Q^alkyl group, a C1-3alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C1-3alkylamino, mono or di C1-3alkylamido, Q.aalkylsulphonyl, C1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di Ci^alkyl carbamoyl, sulphamoyl and acetyl; and
R5 is H, a C1-3alkyl group, a C1-3alkoxymethyl group, trifluoromethyl, a hydroxyC1-3alkyl group, C1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C1-3alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula -CONHNRaRb wherein Ra and Rb are as previously defined for R1 and R2 respectively;
with the proviso that when R1 and R2 together with the nitrogen atom to which they are attached represent 4-methylpiperazin-l-yl or R1 represents H and R2 represents methyl or l-benzylpiperidin-4-yl; X is CO; Y is absent and R5 is H; then R3 and R4 do not both represent 4-methoxyphenyl; and their use in the treatment of obesity, psychiatric and neurological disorders.
Surprisingly a particular compound has advantageous properties and provides a selection invention from the above application.
Description of the invention
The invention relates to 5,6-bis(4-chlorophenyl)-JV-piperidin-l-yl-3-(piperidin-l-yl- carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof.
"Pharmaceutically acceptable salts", where such salts are possible, include pharmaceutically acceptable acid and base addition salts. AU tautomers, where possible, are included within the scope of the invention.
The compounds may be prepared as described in the Examples and by analogous methods.
Pharmaceutical preparations
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.
Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.
According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
Pharmacological properties
5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carbox- amide or pharmaceutically acceptable salts thereof, are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea). The compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms. The compounds may also eliminate the increase in weight, which normally accompanies the cessation of smoking. In another aspect the present invention provides 5,6-bis(4-chlorophenyl)-iV-piperidm-l-yl- 3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxarnide or pharmaceutically acceptable salts thereof, as previously defined for use as a medicament.
In a further aspect the present invention provides the use of 5,6-bis(4-chlorophenyl)-iV- piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
In a still further aspect the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof. The compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.
Combination Therapy
The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and atherosclerosis. For example, a compound of the present invention may be used in combination with a compound that affects thermogenesis, lipolysis, fat absorption, satiety, or gut motility. The compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).
In another aspect of the invention, 5,6-bis(4-chlorophenyl)-iV-piperidin-l-yl-3-(piperidin-l- yl-carbonyl)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin.
In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.
The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of 5,6-bis(4- chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, a mixed alpha/beta andrenergic blocker, an andrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) antagonist; a PDK inhibitor; or modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha; an SSRI; a serotonin antagonist; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment.
Therefore in an additional feature of the invention, there is provided a method for for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of 5,6-bis(4-chlorophenyl)-iV-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of 5,6-bis(4- chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl- carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is provided a kit comprising 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the present invention there is provided a kit comprising: a) 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit comprising: a) 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to another feature of the invention there is provided the use of 5,6-bis(4- chlorophenyl)-iV-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of 5,6-bis(4- chlorophenyl)-N-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of 5,6-bis(4-chlorophenyl)- N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxamide or pharmaceutically acceptable salts thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions. Examples
Abbreviations
DCM - dichloromethane DMF - dimethylformamide
DMAP - 4-dimethylaminopyridine
EDC - l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
TEA - triethylamine
TFA - trifluoroacetic acid DMSO-dimethyl sulfoxide
DEA - Diethylamine
PCC - Pyridinium chlorochromate
DCM - Dichloromethane
PyBOP - benzotriazol-1-yl-oxytri-pyrrolidinophosphonium hexafluorophosphate HBTU - O-Benzotriazol-l-yl-ΛζN,N',N'-tetramethyluronium Hexafluorophosphate
DAST-(diethyl amino)sulphur trifluoride
DlEA - ΛζN-diisopropylethylamine t triplet
S singlet d doublet q quartet qvint quintet m multiplet br broad bs broad singlet dm doublet of multiplet bt broad triplet dd doublet of doublet General Experimental Procedures
Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass
LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS). 1H NMR measurements were performed on either a Varian Mercury 300 or a Varian Inova 500, operating at 1H frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDCl3 as internal standard. CDCl3 is used as the solvent for NMR unless otherwise stated. Purification was performed on a semipreparative HPLC with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M NH4Ac :acetonitrile 95:5).
For isolation of isomers, a Kromasil CN E9344 (250 x 20 mm i.d.) column was used. Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1 ml/min). Fraction collection was guided using a UV-detector (330 nm).
Examples of the Invention
Example 1 a) l,2-bis(4-chlorophenyl)-2-hvdroxyethanone
To 4-chlorobenzaldehyde (140.6 g, 1 mol) in ethanol (130 ml) was added a solution of sodium cyanide (10.6 g, 0.216 mol) in water (105 ml). The mixture was heated at reflux for 2.5 h and then extracted with DCM. The organic phase was washed with sodium bisulfite solution and the solvent was evaporated in vacuo. The compound was isolated by crystallization from diethyl ether/heptane. 48 g, 34%.
1H NMR (400 MHz) δ 7.82 (d, 2H), 7.38 (d, 2H), 7.30 (d, 2H), 7.24 (d, 2H), 5.87 (s, IH), 4.47 (s, IH). MS m/z 279, 281 (M-H)'.
b) 1 ,2-bis(4-chlorophenyl)ethane- 1 ,2-dione l,2-bis(4-chlorophenyl)-2-hydroxyethanone, (90 g, 0.320 mol) and nitric acid (170 ml) were heated at 100°C until the evolution of nitrogen oxides ceased after 4 hours. The reaction mixture was cooled, and water (250 ml) was carefully added. The crude product was filtered, washed several times with water and dried under reduced pressure to give a yellow solid (40.4 g, 45%).
1H NMR (500 MHz) 6 7.94 (d, 4H), 7.53 (d, 4H).
c) 5,6-bis(4-chlorophenyl)pyrazine-2,3-dicarbonitrile l,2-bis(4-chlorophenyl)ethane-l,2-dione, (20 g, 71.65 mmol), diaminomaleonitrile (8.5 g, 78.82 mmol) and acetic acid (6 ml) in ethanol (140 ml) and water (93 ml) were heated at 75 0C overnight. The reaction mixture was cooled, and water was added. The precipitate was filtered and washed with ethanol and then ether. The crude product was dissolved in DCM and treated with activated charcoal, then filtered through celite. After evaporation, a solid was formed and recrystallized from DCM/ethanol to give a pale yellow solid (17.3 g, 69%).
1R NMR (400 MHz) 6 7.49 (d, 4H), 7.38 (d, 4H).
d) 5,6-bis(4-chlorophenyl)pyrazine-2,3-dicarboxylic acid
To 5,6-bis(4-chlorophenyl)pyrazine-2,3-dicarbonitrile, (16.3 g, 46.28 mmol) and KOH (26 g, 463 mmol) in water (84 ml) was added hydrogen peroxide (35%, 19 ml) followed by a few drops of nonanol to reduce foaming. The reaction mixture was heated at reflux for 2h, cooled and washed once with diehtyl ether and acidified to pH 4 with 2M HCl. The precipitate was collected through a filter, washed with water and dried under reduced pressure to give the crude product. The crude product was convertd to dimethyl ester by refluxing with hydrogen chloride/methanol (100 ml) and purified by HPLC, giving 12.85 g of the methyl ester. The resulting methyl ester was treated with lithium hydroxide (2.95 g, 0.123 mmol) in acetonitrile (140 ml) and water (90 ml) at ambient temperature for 1.5 h. The acetonitrile was removed under reduced pressure and the aqueous solution was washed once with diethyl ether. Acidification with hydrochloric acid (2M) and filtration gave the title compound (11.8 g, 66% mmol) as a pale yellow solid.
1E NMR (400 MHz) δ 7.51 (d, 4H), 7.41 (d, 4H). MS m/z 389, 391 (M+H)+. e) 2,3-bis(4-chlorophenyl')furor3.4-blpyrazine-5,7-dione
5,6-bis(4-chlorophenyl)pyrazine-2,3-dicarboxylic acid (6.7 g, 17.30 mmol) and acetyl chloride (20 ml) were boiled under reflux overnight. The acetyl chloride was removed under reduced pressure to give the title compound (6.2 g, 97%) as a pale yellow solid. s 1H NMR (400 MHz) δ 7.51 (d, 4H), 7.41 (d, 4H).
f) 5,6-bis(4-chlorophenyl)-3-(piperidin-l-ylcarbonyl)pyrazine-2-carboxylic acid
Piperidine (57 mg, 0.67 mmol) was mixed with 2,3-bis(4-chlorophenyl)furo[3,4- o b]pyrazine-5,7-dione (238 mg, 0.64 mmol) in acetonitrile (10 ml). After 10 minutes the solvent was removed in vacuo to give the title compound (262 mg, 90%).
1H NMR (400 MHz) 67.48-7.38 (m, 4H), 7.37-7.28 (m, 4H), 3.86-3.76 (m, 2H), 3.35-3.23
(m, 2H), 1.83-1.65 (m, 4H), 1.64-1.53 (m, 2H).
MS m/z 456, 458 (M+H)+ , 454, 456 (M-H)". 5 This compound is believed to be a novel intermediate and is herein claimed as another aspect of the present invention.
g) 5 , 6-bis(4-chlorophenyl)-N-piperidin- 1 -yl-3 -("piperidin- 1 -ylcarbonvDp yrazine-2- carboxamide 0 Oxalyl chloride (1 ml), DMF (2 drops), and 5,6-bis(4-chlorophenyl)-3-(piperidin-l- ylcarbonyl)pyrazine-2-carboxylic acid, (246 mg, 0.54 mmol) were mixed in DCM (3 ml). After 30 minutes the solvent and excess oxalyl chloride was removed in vacuo with the aid of toluene. The residue was dissolved in toluene (15 ml) and piperidin- 1 -amine (135 mg, 1.35 mmol) was added. After 24 h the solution was diluted with toluene and washed with 5 hydrochloric acid, sodium carbonate solution, and brine. Drying (magnesium sulfate) and evaporation of the solvent gave a residue that was purified by preparative HPLC to give the target compound. 1H NMR (400 MHz) 6 8.29 (s, IH), 7.45-7.40 (d, 2H), 7.40-7.33 (m, 4H), 7.32-7.27 (d, 2H), 3.84-3.76 (m, 2H), 3.34-3.27 (m, 2H), 2.90-2.81 (m, 4H), 1.81-1.51 (m, 10H), 1.50- 1.39 (m, 2H). MS m/z calcd for [C28H30Cl2N5O2]H+ 538.1777, found 538.1729 (M+H)+
Pharmacological Activity
Compounds of the present invention are active against the receptor product of the CB 1 gene. The affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al, Molecular Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354. Alternatively, the assay may be performed as follows.
lOμg of membranes prepared from cells stably transfected with the CBl gene were suspended in 200μl of 10OmM NaCl, 5mM MgCl2, ImM EDTA, 5OmM HEPES (pH 7.4), ImM DTT, 0.1% BSA and lOOμM GDP. To this was added an EC80 concentration of agonist (CP55940), the required concentration of test compound and O.lμCi [35S]-GTPγS. The reaction was allowed to proceed at 30°C for 45 min. Samples were then transferred on to GF/B filters using a cell harvester and washed with wash buffer (5OmM Tris (pH 7.4), 5mM MgCl2, 5OmM NaCl). Filters were then covered with scintilant and counted for the amount of [35S]-GTPγS retained by the filter.
Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set as 0% and 100% activity respectively. At various concentrations of novel ligand, activity is calculated as a percentage of the maximum activity and plotted. The data are fitted using the equation y=A+((B-A)/l+((C/x) UD)) and the IC50 value determined as the concentration required to give half maximal inhibition of GTPγS binding under the conditions used.
The compounds of the present invention are active at the CBl receptor (IC50 <1 micromolar). Most preferred compounds have IC50 <200 nanomolar. 5,6-bis(4- chlorophenyl)-iV-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine-2-carboxamide and pharmaceutically acceptable salts thereof are selected because of their superior potency in vitro and/or higher affinity, leading to better in vivo efficacy. The compounds also have a better selectivity profile, which is expected to improve in vivo safety.
In addition the compounds of the present invention may have improved DMPK (Drag Metabolism and Pharmacokinetic) properties, for example improved metabolic stability in vitro or .bioavailability. The compounds also have an improved solubility and/or a promising toxicological profile.

Claims

Claims
1. 5 ,6-Bis(4-Chlorophenyl)-N-piperidin- 1 -yl-3-(piperidin- 1 -ylcarbonyl)pyrazine-2- carboxamide and/or pharmaceutically acceptable salts thereof.
2. 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2- carboxamide and/or pharmaceutically acceptable salts thereof for use as a medicament.
3. A pharmaceutical formulation comprising 5,6-bis(4-chlorophenyl)-N-piperidin-l-yl-3- (piperidin-l-yl-carbonyl)pyrazine-2-carboxamide and/or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.
4. Use of 5 ,6-bis(4-chlorophenyl)-N-piperidin- 1 -yl-3-(piperidin- 1 -yl-carbonyl)pyrazine- 2-carboxamide and/or pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders, Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and extended abuse, addiction and/or relapse indications.
5. A method of treating obesity, psychiatric disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, neurological disorders, neurological disorders, Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal system, and extended abuse, addiction and/or relapse indications, comprising administering a pharmacologically effective amount of 5,6-bis(4- chlorophenyl)-N-piperidin-l-yl-3-(piperidin-l-yl-carbonyl)pyrazine-2-carboxaniide and/or pharmaceutically acceptable salts thereof to a patient in need thereof.
6. A compound as defined in either claim 1 for use in the treatment of obesity.
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