US20100069405A1 - Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors - Google Patents

Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors Download PDF

Info

Publication number
US20100069405A1
US20100069405A1 US12/625,125 US62512509A US2010069405A1 US 20100069405 A1 US20100069405 A1 US 20100069405A1 US 62512509 A US62512509 A US 62512509A US 2010069405 A1 US2010069405 A1 US 2010069405A1
Authority
US
United States
Prior art keywords
group
compound
oxoethyl
formula
groups
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/625,125
Inventor
Ahmed Abouabdellah
Regine BARTSCH-LI
Christian Hoornaert
Antoine Ravet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Sanofi Aventis France
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Priority to US12/625,125 priority Critical patent/US20100069405A1/en
Publication of US20100069405A1 publication Critical patent/US20100069405A1/en
Assigned to SANOFI-AVENTIS reassignment SANOFI-AVENTIS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABOUABDELLAH, AHMED, HOORNAERT, CHRISTIAN, BARTSCH-LI, REGINE, RAVET, ANTOINE
Priority to US13/156,551 priority patent/US20110237595A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to compounds and compositions for the treatment of neurological diseases that cause neurogenic and neuropathic pain, inflammatory diseases, renal ischaemia, cardiovascular disease and other pathologies caused by the presence of endogenous cannabinoids and or other substrates resulting from the metabolic activities of fatty acid amido hydrolase (FAAH).
  • FAAH fatty acid amido hydrolase
  • Aryl- and -heteroarylalkylcarbamate derivatives are known to be useful in the treatment of numerous metabolic diseases in varying degrees. Their preparation and their application in therapeutics is also well documented.
  • Phenylalkylcarbamate and (dioxan-2-yl)alkylcarbamate derivatives are already known and are incorporated herein by reference.
  • the compounds of the present invention can readily achieve this objective.
  • the compounds of the invention correspond to the general formula (I):
  • A is chosen from one or more groups X, Y and/or Z;
  • X represents a methylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups;
  • Y represents either a C 2 -alkenylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups; or a C 2 -alkynylene group;
  • Z represents a group of formula:
  • m represents an integer ranging from 1 to 5; p and q represent integers and are defined such that p+q is a number ranging from 1 to 5; n represents an integer ranging from 1 to 7;
  • R 1 represents an R 2 group optionally substituted by one or more R 3 and/or R 4 groups;
  • R 2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
  • the compounds of general formula (I) can thus comprise several groups A which are identical to or different from one another.
  • A is chosen from one or more groups X and/or Y;
  • X represents a methylene group;
  • Y represents a C 2 -alkynylene group;
  • n represents an integer ranging from 1 to 5;
  • R 1 represents an R 2 group optionally substituted by one or more R 3 and/or R 4 groups;
  • R 2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
  • R 3 represents a group chosen from halogen atoms, more particularly chlorine and fluorine atom
  • A, X, Y, Z, m, p, q, n, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the general formula (I) or in the first subgroup as defined above, and R 2 represents a group chosen from a pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl or isoquinolinyl.
  • A, X, Y, Z, m, p, q, n, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the general formula (I) or in the subgroups as defined above;
  • R 7 represents a hydrogen atom;
  • R 8 represents a hydrogen atom or a C 1-6 -alkyl group, more particularly a methyl.
  • A is chosen from one or more groups X, Y and/or Z;
  • X represents a methylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups;
  • Y represents either a C 2 -alkenylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups; or a C 2 -alkynylene group;
  • Z represents a group of formula:
  • m represents an integer ranging from 1 to 5; p and q represent integers and are defined such that p+q is a number ranging from 1 to 5; n represents an integer ranging from 1 to 7;
  • R 1 represents an R 2 group optionally substituted by one or more R 3 and/or R 4 groups;
  • R 2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
  • A is chosen from one or more groups X and/or Y;
  • X represents a methylene group;
  • Y represents a C 2 -alkynylene group;
  • n represents an integer ranging from 1 to 5;
  • R 1 represents an R 2 group optionally substituted by one or more phenyl groups, more particularly by one phenyl;
  • R 2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
  • R 7 represents a hydrogen atom or a C 1-6 -alkyl group;
  • R 8 represents a hydrogen atom
  • R 7 represents a hydrogen atom
  • R 8 represents a hydrogen atom or a C 1-6 -alkyl group, more particularly a methyl.
  • the compounds of general formula (I) can comprise one or more asymmetric carbons. They can exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, including the racemic mixtures, form part of the invention.
  • the compounds of formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids, of use, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.
  • the compounds of general formula (I) can exist in the form of hydrates or of solvates, namely in the form of combinations or of associations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.
  • the compounds of the invention can be prepared according to various methods illustrated by the schemes which follow.
  • a first method (Scheme 1) for producing the compounds of general formula (I) consists in reacting an amine of general formula (II), in which R 1 , A and n are as defined in the general formula (I), with a carbonate of general formula (III) in which V represents a hydrogen atom or a nitro group, R 7 is as defined in the general formula (I) and R represents a methyl or ethyl group.
  • the carbamate-ester of general formula (IV) thus obtained is subsequently converted to the compound of general formula (I) by aminolysis using an amine of general formula R 8 NH 2 , where R 8 is as defined in the general formula (I).
  • the aminolysis reaction can be carried out in a solvent, such as methanol or ethanol, or a mixture of solvents, such as methanol and tetrahydrofuran.
  • Scheme 2 Another method for producing the compounds of general formula (I) consists in reacting a derivative of general formula (V), in which R 1 , n and A are as defined in the general formula (I) and W represents a hydroxyl, mesylate or tosylate group or a chlorine, bromine or iodine atom, with an oxazolidinedione of general structure (VI), in which R 7 is as defined in the general formula (I), to provide the oxazolidinedione derivative of general structure (VII).
  • the reaction can be carried out according to the conditions of Mitsunobu (Synthesis, 1981, 1-28), for example, by the action of diethyl or diisopropyl azodicarboxylate in the presence of triphenylphosphine.
  • the reaction can be carried out in the presence of a base, such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide, in a solvent, such as tetrahydrofuran, acetonitrile or dimethylformamide, at a temperature of between 0° C. and 80° C.
  • a base such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide
  • a solvent such as tetrahydrofuran, acetonitrile or dimethylformamide
  • R 1 represents a group of aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type
  • R 2 is substituted by a chlorine, bromine or iodine atom or by a triflate group in the position where the R 4 group has to be introduced with an aryl- or heteroarylboronic acid derivative according to the Suzuki reaction conditions (Chem. Rev., 1995, 95, 2457-2483) or with an aryl- or heteroaryltrialkylstannane derivative according to the Stille reaction conditions (Angew. Chem. Int. Ed., 1986, 25, 504-524).
  • the carbonates of general formula (III) can be prepared according to any method described in the literature, for example by reaction of an alcohol of general formula HOCHR 7 COOR, where R represents a methyl or ethyl group, with phenyl or 4-nitrophenyl chloroformate in the presence of a base, such as triethylamine or diisopropylethylamine.
  • a base such as triethylamine or diisopropylethylamine.
  • the compounds of general formula (IV) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
  • the compounds of general formula (VII) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
  • a subgroup of compounds of general formula (VII) is composed of the compounds for which:
  • n, A, R 1 and R 7 are as defined in the general formula (I) provided that:
  • a solution of 3.12 g (12.80 mmol) of 9-borabicyclo[3.3.1]nonane (BBN) in 100 ml of tetrahydrofuran is added dropwise, under an inert atmosphere, to a solution, cooled to approximately ⁇ 10° C., of 4.5 g (25.60 mmol) of phenylmethyl ethenylcarbamate (Org. Proc. Res. & Develop.; 2002, 6, 74-77) in 25 ml of tetrahydrofuran while keeping the temperature of the reaction medium below ⁇ 10° C. Stirring is continued at ⁇ 10° C. for 1 hour and then at ambient temperature for 4 hours.
  • BBN 9-borabicyclo[3.3.1]nonane
  • the aqueous phase is separated and is then extracted three times with dichloromethane.
  • the organic phases are combined and are washed successively with water and a saturated aqueous sodium chloride solution.
  • the organic phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure.
  • the residue thus obtained is purified by chromatography on silica gel, elution being carried out with a 20/80 mixture of ethyl acetate and of cyclohexane.
  • the residue is taken up in water and ethyl acetate.
  • the aqueous phase is separated and extracted twice with ethyl acetate, the combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure.
  • the residue thus obtained is purified by chromatography on silica gel, elution being carried out with a 1/99 mixture of ethyl acetate and of cyclohexane.
  • the mixture is concentrated under reduced pressure.
  • the residue is taken up in ethyl acetate and water, the aqueous phase is separated and extracted twice with ethyl acetate, and the combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, elution being carried out with a 10/90 and then 20/80 mixture of ethyl acetate and of cyclohexane.
  • the mixture is stirred at ambient temperature for 3 hours, 4 g of silica are then added and the mixture is evaporated to dryness.
  • the product is purified by chromatography on silica gel, elution being carried out with an 80/20 and then 60/40 mixture of cyclohexane and of ethyl acetate, to produce 1.22 g of product in the form of a yellow oil.
  • the organic phase is separated by settling and is washed with 25 ml of water and then with 25 ml of a saturated aqueous sodium chloride solution. It is dried over magnesium sulfate and evaporated to dryness to produce 1.68 g of product in the form of an orange oil used directly in the following stage.
  • the residue is purified by chromatography on silica gel, elution being carried out with a 90/10 and then 80/20 and 70/30 mixture of cyclohexane and of ethyl acetate, to produce 1.33 g of product in the form of a white solid.
  • the organic phases are subsequently washed with 2 times 70 ml of water and then with 70 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.
  • the residue is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and of ethyl acetate, to produce 1.3 g (5.47 mmol) of product in the form of a white solid.
  • the residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 95/5 and 90/10 mixture of dichloromethane and of methanol.
  • the product is recrystallized from a mixture of ethyl acetate and of methanol to produce 0.49 g (1.4 mmol) of white crystals.
  • the organic phase is separated by settling, washed with 200 ml of water and 200 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.
  • the residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 3.22 g (9.67 mmol) of product in the form of a yellowish oil.
  • 6-(4-Cl-phenyl)pyrimidin-4-yl (CH 2 ) 2 H CH 3 139-141 8.
  • 6-(4-Cl-phenyl)-2- (CH 2 ) 2 H CH 3 140-142 methylpyrimidin-4-yl 9.
  • 6-(4-Cl-phenyl)-2- (CH 2 ) 2 H CH 3 131-133 (dimethylamino)- pyrimidin-4-yl 10. isoquinolin-7-yl (CH 2 ) 2 H CH 3 134-136 11.
  • 4-phenylimidazol-1-yl (CH 2 ) 2 H CH 3 111-113 12.
  • 2-phenyloxazol-4-yl (CH 2 ) 2 H CH 3 94-98 13.
  • 6-(4-Cl-phenyl)pyrimidin-4-yl (CH 2 ) 3 H CH 3 147-149 21. 6-(4-Cl-phenyl)-2- (CH 2 ) 3 H CH 3 (377) methylpyrimidin-4-yl 22. 6-(4-Cl-phenyl)-2- (CH 2 ) 3 H CH 3 150-152 (dimethylamino)- pyrimidin-4-yl 23. quinolin-2-yl (CH 2 ) 3 H H 117-119 24. quinolin-4-yl (CH 2 ) 3 H H 150-152 25. isoquinolin-1-yl (CH 2 ) 3 H H 123-124 26.
  • pyrid-4-yl (CH 2 ) 4 H H 124-126 38.
  • pyrimidin-5-yl (CH 2 ) 4 H H 139-141 39.
  • 6-(4-Cl-phenyl)pyrimidin-4-yl (CH 2 ) 4 H CH 3 101-103 40.
  • the inhibitory activity was demonstrated in a radioenzymatic test based on the measurement of the product of hydrolysis ((1- 3 H)ethanolamine) of ((1- 3 H)ethanolamine)-anandamide by FAAH ( Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734).
  • mouse brains minus the cerebellum
  • the membrane homogenates are prepared at the time of use by homogenization of the tissues with a Polytron in a 10 mM Tris-HCl buffer (pH 8.0) comprising 150 mM NaCl and 1 mM EDTA.
  • the enzymatic reaction is subsequently carried out in 70 ⁇ A of buffer comprising bovine serum albumin free from fatty acids (1 mg/ml).
  • the test compounds at various concentrations, the ((1- 3 H)ethanolamine)-anandamide (specific activity of 15-20 Ci/mmol), diluted to 10 ⁇ M with non-radiolabelled anandamide, and the membrane preparation (400 ⁇ g of frozen tissue per assay) are successively added.
  • the enzymatic reaction is halted by addition of 140 ⁇ l of chloroform/methanol (2:1). The mixture is stirred for 10 minutes and is then centrifuged at 3500 g for 15 minutes. An aliquot (30 ⁇ l) of the aqueous phase comprising the (1- 3 H)ethanolamine is counted by liquid scintillation.
  • the most active compounds of the invention exhibit IC 50 values (concentration which inhibits the control enzymatic activity of FAAH by 50%) of between 0.001 and 1 ⁇ M.
  • compound No. 68 in the table exhibits an IC 50 of 0.267 ⁇ M.
  • the in vivo activity of the compounds of the invention was evaluated in a test for analgesia.
  • PBQ phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solution comprising 5% of ethanol
  • the test compounds are administered, orally (p.o.) or intraperitoneally (i.p.) in suspension in 0.5% Tween 80, 60 minutes or 120 minutes before the administration of PBQ.
  • Tween 80 60 minutes or 120 minutes before the administration of PBQ.
  • the most powerful compounds of the invention reduce by 35 to 70% the number of fractions induced by the PBQ, within a range of doses of between 1 and 30 mg/kg.
  • compound No. 48 in the table reduces by 53% and by 62% the number of tractions induced by the PBQ, at a dose of 10 mg/kg p.o., at 60 minutes and at 120 minutes respectively.
  • the enzyme FAAH ( Chemistry and Physics of Lipids , (2000), 108, 107-121) catalyses the hydrolysis of endogenous derivatives of amides and esters of various fatty acids, such as N-arachidonoylethanolamine(anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives have various pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors.
  • the compounds of the invention block this decomposition pathway and increase the tissue level of these endogenous substances. They can therefore be used in the prevention and treatment of pathologies in which endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH are involved.
  • Pain, in particular acute or chronic pain of neurogenic type migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness, vomiting, nausea, in particular resulting from chemotherapy; eating disorders, in particular anorexia and cachexia of various natures; neurological and psychiatric pathologies: tremors, dyskinesias, dystonias, spasticity, obsessive-compulsive behavior, Tourette's syndrome, all forms of depression and of anxiety of any nature and origin, mood disorders, psychoses; acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions related to cerebral ischaemia and to cranial and medullary trauma; epilepsy; sleep disorders, including
  • Another subject-matter of the invention is medicaments which comprise a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (I). These medicaments are used in therapeutics, in particular in the treatment of the abovementioned pathologies.
  • the present invention relates to pharmaceutical compositions including, as active principle, at least one compound according to the invention.
  • These pharmaceutical compositions comprise an effective dose of a compound according to the invention or a pharmaceutically acceptable salt, hydrate or solvate of the said compound and optionally one or more pharmaceutically acceptable excipients.
  • excipients are chosen, depending on the pharmaceutical form and the method of administration desired, from the usual excipients which are known to a person skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration the active principle of formula (I) above or its optional salt, solvate or hydrate can be administered in a single-dose administration form, as a mixture with conventional pharmaceutical excipients, to animals and to man for the prophylaxis or the treatment of the above disorders or diseases.
  • Appropriate single-dose administration forms comprise oral forms, such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular or intranasal administration or for administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration.
  • oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions
  • forms for sublingual, buccal, intratracheal, intraocular or intranasal administration or for administration by inhalation forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration.
  • the compounds according to the invention can be used in creams, ointments or lotions.
  • a single-dose administration form of a compound according to the invention in the form of a tablet can comprise the following components:
  • the dosage appropriate to each patient is determined by the doctor according to the method of administration, the weight and the response of the said patient.
  • the invention also relates to a method for the treatment of the pathologies indicated above which comprises the administration of an effective dose of a compound according to the invention, of one of its pharmaceutically acceptable salts or of a solvate or of a hydrate of the said compound.

Abstract

The present invention is directed to compounds and compositions for the treatment of neurological diseases that cause neurogenic and neuropathic pain, inflammatory diseases, renal ischaemia, cardiovascular disease and other pathologies caused by the presence of endogenous cannabinoids and or other substrates resulting from the metabolic activities of fatty acid amido hydrolase (FAAH). These compounds are represented by the formula (I):
Figure US20100069405A1-20100318-C00001
wherein A, n, R1, R7 and R8 are as defined herein.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 11/464,355, filed Aug. 14, 2006, now allowed, which is a continuation of International Application No. PCT/FR2005000451 filed on Feb. 25, 2005; both of which are incorporated herein by reference in their entirety; which claims the benefit of priority of French Patent Application No. 04/01949 filed on Feb. 26, 2004.
    • FIELD OF THE INVENTION
  • The present invention relates generally to compounds and compositions for the treatment of neurological diseases that cause neurogenic and neuropathic pain, inflammatory diseases, renal ischaemia, cardiovascular disease and other pathologies caused by the presence of endogenous cannabinoids and or other substrates resulting from the metabolic activities of fatty acid amido hydrolase (FAAH).
    • BACKGROUND OF THE INVENTION
  • Aryl- and -heteroarylalkylcarbamate derivatives are known to be useful in the treatment of numerous metabolic diseases in varying degrees. Their preparation and their application in therapeutics is also well documented.
  • Phenylalkylcarbamate and (dioxan-2-yl)alkylcarbamate derivatives, disclosed respectively in the documents FR 2850377 A and WO 2004/020430 A2, which are inhibitors of the enzyme FAAH (Fatty Acid Amido Hydrolase) are already known and are incorporated herein by reference.
  • However, there still exists a need to find and develop products which are inhibitors of the enzyme FAAH. The compounds of the present invention can readily achieve this objective. The compounds of the invention correspond to the general formula (I):
  • Figure US20100069405A1-20100318-C00002
  • in which:
    A is chosen from one or more groups X, Y and/or Z;
    X represents a methylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups;
    Y represents either a C2-alkenylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene group;
    Z represents a group of formula:
  • Figure US20100069405A1-20100318-C00003
  • m represents an integer ranging from 1 to 5;
    p and q represent integers and are defined such that p+q is a number ranging from 1 to 5;
    n represents an integer ranging from 1 to 7;
    R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
    R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl or isothiazolopyridyl;
    R3 represents a group chosen from halogen atoms or cyano, nitro, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl, NR5R6, NR5COR6, NR5CO2R6, NR5SO2R6, COR5, CO2R5, CONR5R6, SO2R5, SO2NR5R6, —O—(C1-3-alkylene)-O— or phenyl groups, the phenyl group optionally being substituted by one or more halogen atoms;
    R4 represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
    R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group or form, with the atom or atoms which carry them, a ring chosen from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C1-6-alkyl or benzyl group;
    R7 represents a hydrogen atom or a C1-6-alkyl group;
    R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
  • In the context of the invention, the compounds of general formula (I) can thus comprise several groups A which are identical to or different from one another.
  • Among the compounds of general formula (I), a first subgroup of compounds are those in which:
  • A is chosen from one or more groups X and/or Y;
    X represents a methylene group;
    Y represents a C2-alkynylene group;
    n represents an integer ranging from 1 to 5;
    R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
    R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
    R3 represents a group chosen from halogen atoms, more particularly chlorine and fluorine atoms, or C1-6-alkyl, more particularly methyl, C3-7-cycloalkyl, more particularly cyclopropyl, C1-6-alkoxy, more particularly methoxy, NR5R6 or phenyl groups;
    R4 represents a group chosen from phenyl, naphthyl or pyridyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
    R5 and R6 represent, independently of one another, a C1-6-alkyl group, more particularly a methyl;
    R7 represents a hydrogen atom or a C1-6-alkyl group;
    R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
  • Among the compounds of general formula (I), a second subgroup of compounds are those in which:
  • A, X, Y, Z, m, p, q, n, R1, R3, R4, R5, R6, R7 and R8 are as defined in the general formula (I) or in the first subgroup as defined above,
    and R2 represents a group chosen from a pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl or isoquinolinyl.
  • Among the compounds of general formula (I), a third subgroup of compounds are those in which:
  • A, X, Y, Z, m, p, q, n, R1, R2, R3, R4, R5 and R6 are as defined in the general formula (I) or in the subgroups as defined above;
    R7 represents a hydrogen atom;
    R8 represents a hydrogen atom or a C1-6-alkyl group, more particularly a methyl.
  • The following compounds may be mentioned among the compounds of the subgroups defined above:
    • 2-(methylamino)-2-oxoethyl (5-phenylpyrid-2-yl)methylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(5-phenylpyrid-2-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(2-phenylpyrimidin-5-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(5-phenylpyrimidin-2-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)pyrimidin-4-yl]ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(isoquinolin-7-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(2-phenyl-1,3-oxazol-4-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-[5-(4-chlorophenyl)isoxazol-3-yl]ethylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-2-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-3-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-4-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrimidin-5-yl)propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]propylcarbamate
    • 2-amino-2-oxoethyl 3-(quinolin-2-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(quinolin-4-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(isoquinolin-1-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(isoquinolin-4-yl)propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[5-(4-chlorophenyl)isoxazol-3-yl]propylcarbamate
    • 2-amino-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[3-(4-phenylphenyl)isoxazol-5-yl]propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-[3-(naphth-2-yl)isoxazol-5-yl]propylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-2-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-3-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-4-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrimidin-5-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)pyrimidin-4-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-methylpyrimidin-4-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-cyclopropylpyrimidin-4-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[6-(4-chlorophenyl)-2-(dimethylamino)pyrimidin-4-yl]butylcarbamate
    • 2-amino-2-oxoethyl 4-(quinolin-2-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(quinolin-4-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(isoquinolin-1-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(isoquinolin-4-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[5-(4-chlorophenyl)isoxazol-3-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[3-(4-chlorophenyl)isoxazol-5-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[3-(4-phenylphenyl)isoxazol-5-yl]butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-[3-(naphth-2-yl)isoxazol-5-yl]butylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrid-2-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrid-4-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrimidin-5-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(quinolin-2-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(quinolin-4-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(isoquinolin-1-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(isoquinolin-4-yl)pentylcarbamate
    • 2-amino-2-oxo ethyl[3-(naphth-1-yl)prop-2-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[3-(naphth-1-yl)prop-2-yn-1-yl]carbamate
    • 2-amino-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[5-(4-fluoronaphth-1-yl)pent-4-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[3-(pyrid-3-yl)isoxazol-5-ylpropyl]carbamate
    • 2-(methylamino)-2-oxoethyl[3-(4-methoxynaphth-1-yl)isoxazol-5-ylpropyl]carbamate.
  • Among the compounds of general formula (I), one subfamily of compounds correspond to the general formula (I′):
  • Figure US20100069405A1-20100318-C00004
  • in which
    A is chosen from one or more groups X, Y and/or Z;
    X represents a methylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups;
    Y represents either a C2-alkenylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene group;
    Z represents a group of formula:
  • Figure US20100069405A1-20100318-C00005
  • m represents an integer ranging from 1 to 5;
    p and q represent integers and are defined such that p+q is a number ranging from 1 to 5;
    n represents an integer ranging from 1 to 7;
    R1 represents an R2 group optionally substituted by one or more R3 and/or R4 groups;
    R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl or isothiazolopyridyl;
    R3 represents a group chosen from halogen atoms or cyano, nitro, C1-6-alkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl, NR5R6, NR5COR6, NR5CO2R6, NR5SO2R6, COR5, CO2R5, CONR5R6, SO2R5, SO2NR5R6 or —O—(C1-3-alkylene)-O— groups;
    R4 represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
    R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group or form, with the atom or atoms which carry them, a ring chosen from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C1-6-alkyl or benzyl group;
    R7 represents a hydrogen atom or a C1-6-alkyl group;
    R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
  • Among the compounds of general formula (I′), a first subgroup of compounds are those in which:
  • A is chosen from one or more groups X and/or Y;
    X represents a methylene group;
    Y represents a C2-alkynylene group;
    n represents an integer ranging from 1 to 5;
    R1 represents an R2 group optionally substituted by one or more phenyl groups, more particularly by one phenyl;
    R2 represents a group chosen from a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl or pyrrolopyridyl;
    R7 represents a hydrogen atom or a C1-6-alkyl group;
    R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group.
  • Among the compounds of general formula (I′), a second subgroup of compounds are those in which:
  • A, n and R1 are as defined in the first subgroup defined above;
    R7 represents a hydrogen atom;
    R8 represents a hydrogen atom or a C1-6-alkyl group, more particularly a methyl.
  • Mention may be made, among the compounds of general formula (I′), of the following compounds:
    • 2-(methylamino)-2-oxoethyl (5-phenylpyrid-2-yl)methylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(5-phenylpyrid-2-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(6-phenylpyridazin-3-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(2-phenylpyrimidin-5-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(5-phenylpyrimidin-2-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(isoquinolin-7-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(4-phenyl-1H-imidazol-1-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(2-phenyl-1,3-oxazol-4-yl)ethylcarbamate
    • 2-(methylamino)-2-oxoethyl 2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-2-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-3-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrid-4-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(pyrimidin-5-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(quinolin-2-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(quinolin-4-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(isoquinolin-1-yl)propylcarbamate
    • 2-amino-2-oxoethyl 3-(isoquinolin-4-yl)propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-(4-phenyl-1H-imidazol-1-yl)propylcarbamate
    • 2-(methylamino)-2-oxoethyl 3-(1H-benzimidazol-1-yl)propylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-2-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-3-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrid-4-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(pyrimidin-5-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(quinolin-2-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(quinolin-4-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(isoquinolin-1-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(isoquinolin-4-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-(1H-benzimidazol-1-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(1H-pyrrolo[2,3-b]pyrid-1-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-(1H-pyrrolo[2,3-b]pyrid-1-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-(3,4-dihydroisoquinolin-2(1H)-yl)butylcarbamate
    • 2-amino-2-oxoethyl 4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)butylcarbamate
    • 2-(methylamino)-2-oxoethyl 4-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)butylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrid-2-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrid-4-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(pyrimidin-5-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(quinolin-2-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(quinolin-4-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(isoquinolin-1-yl)pentylcarbamate
    • 2-amino-2-oxoethyl 5-(isoquinolin-4-yl)pentylcarbamate
    • 2-amino-2-oxoethyl[3-(naphth-1-yl)prop-2-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[3-(naphth-1-yl)prop-2-yn-1-yl]carbamate
    • 2-amino-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate
    • 2-(methylamino)-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate.
  • The compounds of general formula (I) can comprise one or more asymmetric carbons. They can exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, including the racemic mixtures, form part of the invention.
  • The compounds of formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.
  • These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids, of use, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.
  • The compounds of general formula (I) can exist in the form of hydrates or of solvates, namely in the form of combinations or of associations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.
  • In the context of the invention:
      • Ct-z, where t and z can take the values from 1 to 7, is understood to mean a carbon chain which can have from t to z carbon atoms, for example C1-3 a carbon chain which can have from 1 to 3 carbon atoms;
      • alkyl is understood to mean a saturated, linear or branched, aliphatic group; for example a C1-6-alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;
      • alkylene is understood to mean a saturated, linear or branched, divalent alkyl group, for example a C1-3-alkylene group represents a linear or branched divalent carbon chain of 1 to 3 carbon atoms, more particularly a methylene, ethylene, 1-methylethylene or propylene;
      • cycloalkyl is understood to mean a cyclic alkyl group, for example a C3-7-cycloalkyl group represents a cyclic carbon group of 3 to 7 carbon atoms, more particularly a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
      • alkenylene is understood to mean an unsaturated divalent aliphatic group comprising 2 carbons, more particularly an ethenylene;
      • C2-alkynylene is understood to mean a —C≡C— group;
      • alkoxy is understood to mean an —O-alkyl group comprising a saturated, linear or branched, aliphatic chain;
      • thioalkyl is understood to mean an —S-alkyl group comprising a saturated, linear or branched, aliphatic chain;
      • fluoroalkyl is understood to mean an alkyl group, one or more hydrogen atoms of which have been substituted by a fluorine atom;
      • fluoroalkoxy is understood to mean an alkoxy group, one or more hydrogen atoms of which have been substituted by a fluorine atom;
      • fluorothioalkyl is understood to mean a thioalkyl group, one or more hydrogen atoms of which have been substituted by a fluorine atom;
      • halogen is understood to mean a fluorine, a chlorine, a bromine or an iodine.
  • The compounds of the invention can be prepared according to various methods illustrated by the schemes which follow.
  • Figure US20100069405A1-20100318-C00006
  • A first method (Scheme 1) for producing the compounds of general formula (I) consists in reacting an amine of general formula (II), in which R1, A and n are as defined in the general formula (I), with a carbonate of general formula (III) in which V represents a hydrogen atom or a nitro group, R7 is as defined in the general formula (I) and R represents a methyl or ethyl group. The carbamate-ester of general formula (IV) thus obtained is subsequently converted to the compound of general formula (I) by aminolysis using an amine of general formula R8NH2, where R8 is as defined in the general formula (I). The aminolysis reaction can be carried out in a solvent, such as methanol or ethanol, or a mixture of solvents, such as methanol and tetrahydrofuran.
  • Another method (Scheme 2) for producing the compounds of general formula (I) consists in reacting a derivative of general formula (V), in which R1, n and A are as defined in the general formula (I) and W represents a hydroxyl, mesylate or tosylate group or a chlorine, bromine or iodine atom, with an oxazolidinedione of general structure (VI), in which R7 is as defined in the general formula (I), to provide the oxazolidinedione derivative of general structure (VII).
  • In the case where W represents a hydroxyl group, the reaction can be carried out according to the conditions of Mitsunobu (Synthesis, 1981, 1-28), for example, by the action of diethyl or diisopropyl azodicarboxylate in the presence of triphenylphosphine. In the case where W represents a chlorine, bromine or iodine atom or a mesylate or tosylate group, the reaction can be carried out in the presence of a base, such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide, in a solvent, such as tetrahydrofuran, acetonitrile or dimethylformamide, at a temperature of between 0° C. and 80° C. The oxazolidinedione derivative of general formula (VII) thus obtained is subsequently converted to the compound of general formula (I) by aminolysis using an amine of general formula R8NH2, where R8 is as defined in the general formula (I).
  • Figure US20100069405A1-20100318-C00007
  • The compounds of general formula (I), (IV) and (VII) in which R1 represents a group of aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type can also be prepared by reaction of the corresponding compounds of general formula (I), (IV) or (VII) for which R2 is substituted by a chlorine, bromine or iodine atom or by a triflate group in the position where the R4 group has to be introduced with an aryl- or heteroarylboronic acid derivative according to the Suzuki reaction conditions (Chem. Rev., 1995, 95, 2457-2483) or with an aryl- or heteroaryltrialkylstannane derivative according to the Stille reaction conditions (Angew. Chem. Int. Ed., 1986, 25, 504-524).
  • The carbonates of general formula (III) can be prepared according to any method described in the literature, for example by reaction of an alcohol of general formula HOCHR7COOR, where R represents a methyl or ethyl group, with phenyl or 4-nitrophenyl chloroformate in the presence of a base, such as triethylamine or diisopropylethylamine.
  • The compounds of general formulae (II), (V) and (VI) and the amines of general formula R8NH2, when their method of preparation is not described, are commercially available or are described in the literature or can be prepared according to various methods described in the literature or known to a person skilled in the art.
  • The compounds of general formula (IV) in which n, A, R1 and R7 are as defined in the general formula (I) and R represents a methyl or ethyl group are novel and also form part of the invention, the following compounds being excluded:
    • ethyl 2-[({[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino}carbonyl)oxy]propanoate;
    • ethyl 2-[({[2-[5-(phenylmethoxy)-1H-indol-3-yl]ethyl]amino}carbonyl)oxy]propanoate.
  • The compounds of general formula (IV) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
  • The compounds of general formula (VII) in which n, A, R1 and R7 are as defined in the general formula (I) are novel and also form part of the invention, the following compounds being excluded:
    • 2-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-1-methylpyridinium iodide;
    • 2-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-5-ethyl-1-methylpyridinium iodide;
    • 4-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-1-methylpyridinium iodide;
    • 5-methyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione hydrochloride;
    • 5-methyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione hydrochloride;
    • 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]-2,4-oxazolidinedione;
    • 3-[2-(5-methyl-4-thiazolyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(1H-pyrrol-2-yl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 3-[3-(2-thienyl)propyl]-2,4-oxazolidinedione;
    • 3-[4-(2-thienyl)butyl]-2,4-oxazolidinedione;
    • 5-methyl-3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 5-ethyl-3-[2-(2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(3-thienyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-methyl-2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-acetyl-2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-bromo-2-thienyl)ethyl]-2,4-oxazolidinedione;
    • 5-[2-(2,4-dioxo-3-oxazolidinyl)ethyl]-2-thiophenecarbaldehyde;
    • 3-[3-(1-indolinyl)propyl]-2,4-oxazolidinedione;
    • 3-[3-(1-indolinyl)propyl]-5-methyl-2,4-oxazolidinedione;
    • 3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-ethyl-2-pyridyl)ethyl]-5-methyl-2,4-oxazolidinedione;
    • 5-ethyl-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-ethyl-2-pyridyl)ethyl]-5-isopropyl-2,4-oxazolidinedione;
    • 3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 5-ethyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 5-ethyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 5-isopropyl-3-[2-(4-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 5-isopropyl-3-[2-(2-pyridyl)ethyl]-2,4-oxazolidinedione;
    • 3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-oxazolidinedione.
  • The compounds of general formula (VII) are of use as synthetic intermediates for the preparation of the compounds of general formula (I).
  • A subgroup of compounds of general formula (VII) is composed of the compounds for which:
  • n, A, R1 and R7 are as defined in the general formula (I) provided that:
      • when R2 is a pyrrolyl, imidazo[1,2-a]pyridyl or indolinyl group, then R2 is substituted by one or more R3 and/or R4 groups;
      • when R2 is a pyridyl group, then R2 is substituted by one or more R3 and/or R4 groups where R3 is other than a methyl or than an ethyl;
      • when R2 is a thienyl group, then R2 is substituted by one or more R3 and/or R4 groups where R3 is other than a bromine, than a methyl or than a CHO or COCH3 group;
      • when R2 is a thioazolyl group substituted by an R3 group, then R3 is other than a methyl.
  • The examples which will follow illustrate the preparation of a few compounds of the invention. These examples are not limiting and only illustrate the invention. The microanalyses, the IR and NMR spectra and/or the LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirm the structures and the purities of the compounds obtained. M.p. (° C.) represents the melting point in degrees Celsius.
  • The numbers shown in brackets in the titles of the examples correspond to those in the 1st column in the table below.
    • EXAMPLE 1 Compound No. 3 2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate
  • Figure US20100069405A1-20100318-C00008
    • 1.1. phenylmethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate
  • A solution of 3.12 g (12.80 mmol) of 9-borabicyclo[3.3.1]nonane (BBN) in 100 ml of tetrahydrofuran is added dropwise, under an inert atmosphere, to a solution, cooled to approximately −10° C., of 4.5 g (25.60 mmol) of phenylmethyl ethenylcarbamate (Org. Proc. Res. & Develop.; 2002, 6, 74-77) in 25 ml of tetrahydrofuran while keeping the temperature of the reaction medium below −10° C. Stirring is continued at −10° C. for 1 hour and then at ambient temperature for 4 hours. 18 ml of an aqueous sodium hydroxide solution (3N) are added and stirring is continued for 1 hour. 4.0 g (17.1 mmol) of 5-bromo-2-phenylpyridine and 2.12 g (2.6 mmol) of PdCl2(dppf).CH2Cl2 (dppf: 1,1′-bis(diphenylphosphino)ferrocene) are subsequently added. Stirring is continued at ambient temperature for 18 hours. The reaction medium is cooled with a bath of ice-cold water and then 40 ml of a 2/1 mixture of a buffer solution (pH=7) and of 30% aqueous hydrogen peroxide solution are added dropwise. The mixture is left stirring at ambient temperature for 1 hour. The aqueous phase is separated and is then extracted three times with dichloromethane. The organic phases are combined and are washed successively with water and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, elution being carried out with a 20/80 mixture of ethyl acetate and of cyclohexane.
  • 2.9 g of product are obtained in the form of a white solid.
  • M.p. (° C.): 118° C.
    • 1.2. 2-(6-phenylpyrid-3-yl)ethanamine
  • 9 ml of 33% hydrobromic acid in acetic acid are added dropwise to a solution, cooled to approximately 0° C., of 1.8 g (5.42 mmol) of phenylmethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate, prepared in stage 1.1., in 50 ml of dichloromethane. Stirring is continued at ambient temperature for 2 hours. The mixture is concentrated under reduced pressure and the residue is taken up in dichloromethane and a saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is separated and is extracted twice with ethyl acetate. The combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure.
  • 0.86 g of product is obtained in the form of an oil used as is in the following stage.
    • 1.3. ethyl({[2-(6-phenylpyrid-3-yl)ethyl]amino}carbonyl)oxyacetate
  • A solution of 0.85 g (4.29 mmol) of 2-(6-phenylpyrid-3-yl)ethanamine, prepared in stage 1.2., and of 1.25 g (5.58 mmol) of ethyl[(phenyloxycarbonyl)oxy]acetate (J. Med. Chem., 1999, 42, 277-290) in 40 ml of toluene is heated at 60° C. for 12 hours. The mixture is allowed to return to ambient temperature, the insoluble material is separated by filtration and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, elution being carried out with a 30/70 mixture of ethyl acetate and of cyclohexane.
  • 1.06 g of product are thus obtained in the form of an oil.
    • 1.4. 2-(methylamino)-2-oxoethyl 2-(6-phenylpyrid-3-yl)ethylcarbamate
  • 4.6 ml (9.17 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.0 g (3.06 mmol) of ethyl({[2-(6-phenylpyrid-3-yl)ethyl]amino}carbonyl)-oxyacetate, obtained in stage 1.3., in 6 ml of methanol. Stirring is continued at ambient temperature for 4 hours.
  • After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, elution being carried out with a 95/5 mixture of dichloromethane and of methanol. A white solid is obtained and is recrystallized from ethyl acetate.
  • 0.510 g of product is obtained in the form of a white solid.
  • LC-MS: M+H=314
  • M.p. (° C.): 130-132° C.
  • 1H NMR (CDCl3) δ (ppm): 2.85 (d, 3H), 2.95 (t, 2H), 3.55 (q, 2H), 4.60 (s, 2H), 5.05 (broad s, 1H), 6.10 (broad s, 1H), 7.50 (m, 3H), 7.70 (m, 2H), 8.0 (d, 2H), 8.60 (s, 1H).
    • EXAMPLE 2 Compound No. 56 2-(methylamino)-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate
  • Figure US20100069405A1-20100318-C00009
    • 2.1. 1-(4-bromobutyl)-1H-indole
  • 0.96 g (17.07 mmol) of sodium hydroxide is added in small portions to a solution, cooled by a bath of ice-cold water, of 2 g (17.07 mmol) of 1H-indole and of 1.15 ml (51.22 mmol) of 1,4-dibromobutane in 80 ml of dimethylformamide. The bath is removed and stirring is continued at ambient temperature for 15 hours.
  • After concentrating under reduced pressure, the residue is taken up in water and ethyl acetate. The aqueous phase is separated and extracted twice with ethyl acetate, the combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, elution being carried out with a 1/99 mixture of ethyl acetate and of cyclohexane.
  • 3 g of product are obtained in the form of a yellow oil.
    • 2.2. 3-[4-(1H-indol-1-yl)butyl]-1,3-oxazolidine-2,4-dione
  • A solution of 3 g (11.90 mmol) of 1-(4-bromobutyl)-1H-indole, prepared in stage 2.1., of 2.41 g (23.80 mmol) of 1,3-oxazolidin-2,4-dione (J. Med. Chem., 1991, 34, 1538-1544) and of 2.74 g (23.80 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is brought to reflux for 14 hours under an inert atmosphere.
  • The mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and water, the aqueous phase is separated and extracted twice with ethyl acetate, and the combined organic phases are washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, elution being carried out with a 10/90 and then 20/80 mixture of ethyl acetate and of cyclohexane.
  • 2 g of product are obtained in the form of a white solid.
    • 2.3. 2-(methylamino)-2-oxoethyl 4-(1H-indol-1-yl)butylcarbamate
  • The procedure is as described in Example 1 (stage 1.4.). Starting from 0.90 g (3.31 mmol) of 3-[4-(1H-indol-1-yl)butyl]-1,3-oxazolidine-2,4-dione, obtained in stage 2.2., and from 5 ml (9.93 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and of methanol, 0.70 g of product is obtained in the form of an amorphous white solid.
  • LC-MS: M+H=304
  • M.p. (° C.): 64-67° C.
  • 1H NMR (CDCl3) δ (ppm): 1.50 (m, 2H), 1.90 (m, 2H), 2.80 (d, 3H), 3.20 (q, 2H), 4.20 (t, 2H), 4.55 (s, 2H), 5.95 (broad s, 1H), 6.10 (broad s, 1H), 6.50 (d, 1H), 7.20 (m, 3H), 7.40 (d, 1H), 7.70 (d, 1H).
    • EXAMPLE 3 Compound No. 71 2-amino-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate
  • Figure US20100069405A1-20100318-C00010
    • 3.1. 5-(naphth-1-yl)pent-4-yn-1-ol
  • A solution of 0.59 g (7 mmol) of 4-pentyn-1-ol in 3 ml of acetonitrile is added dropwise under an argon atmosphere to a suspension of 1.78 g (7 mmol) of 1-iodonaphthalene, of 1.48 ml (10.5 mmol) of triethylamine, of 0.066 g (0.35 mmol) of cuprous iodide and of 0.147 g (0.21 mmol) of di(triphenylphosphine)palladium dichloride (Ph3P)2PdCl2 in 4 ml of acetonitrile. The mixture is stirred at ambient temperature for 3 hours, 4 g of silica are then added and the mixture is evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with an 80/20 and then 60/40 mixture of cyclohexane and of ethyl acetate, to produce 1.22 g of product in the form of a yellow oil.
    • 3.2. 5-(naphth-1-yl)pent-4-yn-1-yl methanesulfonate
  • A solution of 0.85 g (7.42 mmol) of methanesulfonyl chloride in 5 ml of dichloromethane is added dropwise to a solution, cooled with an ice bath, of 1.2 g (5.71 mmol) of 5-(naphth-1-yl)pent-4-yn-1-ol, obtained in stage 3.1., and of 1.6 ml (11.4 mmol) of triethylamine in 12 ml of dichloromethane. The mixture is stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. 25 ml of water and 75 ml of dichloromethane are subsequently added. The organic phase is separated by settling and is washed with 25 ml of water and then with 25 ml of a saturated aqueous sodium chloride solution. It is dried over magnesium sulfate and evaporated to dryness to produce 1.68 g of product in the form of an orange oil used directly in the following stage.
    • 3.3. 3-[5-(naphth-1-yl)pent-4-yn-1-yl]-1,3-oxazolidine-2,4-dione
  • 1.64 g (5.70 mmol) of 5-(naphth-1-yl)pent-4-yn-1-yl methanesulfonate, obtained in stage 3.2., and 0.72 g (7.1 mmol) of 1,3-oxazolidine-2,4-dione are dissolved in 9 ml of tetrahydrofuran. 1.3 g (11.4 mmol) of 1,1,3,3-tetramethylguanidine in solution in 3 ml of tetrahydrofuran are added. The mixture is heated at reflux overnight. 25 ml of ethyl acetate and 6 g of silica are added. The mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, elution being carried out with a 90/10 and then 80/20 and 70/30 mixture of cyclohexane and of ethyl acetate, to produce 1.33 g of product in the form of a white solid.
  • M.p. (° C.): 99-101° C.
    • 3.4. 2-amino-2-oxoethyl[5-(naphth-1-yl)pent-4-yn-1-yl]carbamate
  • 0.75 g (2.56 mmol) of 3-[5-(naphth-1-yl)pent-4-yn-1-yl]-1,3-oxazolidine-2,4-dione, obtained in stage 3.3., is dissolved in 18 ml of a 7M solution of ammonia (126 mmol) in methanol. The mixture is left overnight at ambient temperature. 3 g of silica are subsequently added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 96/4 and 94/6 mixture of dichloromethane and of methanol. The product is subsequently recrystallized from a mixture of ethyl acetate and of diisopropyl ether to produce 0.59 g of product in the form of white crystals.
  • LC-MS: M+H=311
  • M.p. (° C.): 105-108° C.
  • 1H NMR (CDCl3) δ (ppm): 8.33 (d, 1H), 7.85 (m, 2H), 7.70-7.40 (m, 4H), 5.90 (broad m, 1H), 5.50 (broad m, 1H), 5.20 (broad m, 1H), 4.55 (s, 2H), 3.50 (m, 2H), 2.70 (t, 2H), 1.95 (m, 2H).
    • EXAMPLE 4 Compound No. 29 2-(methylamino)-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate
  • Figure US20100069405A1-20100318-C00011
    • 4.1. 3-[3-(4-chlorophenyl)isoxazol-5-yl]propan-1-ol
  • 1.6 ml (11.5 mmol) of triethylamine are added dropwise to a solution, cooled with an ice bath, of 1.18 ml (12.6 mmol) of pent-4-yn-1-ol and of 2.0 g (10.5 mmol) of 4-chloro-N-hydroxybenzenecarboximidoyl chloride (J. Med. Chem., 1998, 41, 4556-4566) in 30 ml of dichloromethane. Reaction is allowed to take place at ambient temperature overnight. 50 ml of dichloromethane and 70 ml of water are added. The organic phase is separated and the aqueous phase is extracted with 2 times 50 ml of dichloromethane. The organic phases are subsequently washed with 2 times 70 ml of water and then with 70 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and of ethyl acetate, to produce 1.3 g (5.47 mmol) of product in the form of a white solid.
  • M.p. (° C.): 60-62° C.
    • 4.2. 3-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}-1,3-oxazolidine-2,4-dione
  • 0.5 ml (6.0 mmol) of methanesulfonyl chloride is added dropwise to a solution, cooled with an ice bath, of 1.30 g (5.47 mmol) of 3-[3-(4-chlorophenyl)isoxazol-5-yl]propan-1-ol, prepared in stage 4.1., and of 0.9 ml (7.11 mmol) of triethylamine in 70 ml of dichloromethane. The mixture is subsequently stirred at room temperature for 2 hours. 70 ml of water are added and the organic phase is separated. The aqueous phase is extracted with 2 times 70 ml of dichloromethane. The organic phases are subsequently washed with 100 ml of water and 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.
  • The residue is redissolved in 60 ml of tetrahydrofuran, and 0.9 g (8.9 mmol) of 1,3-oxazolidine-2,4-dione and 1.1 ml (8.7 mmol) of 1,1,3,3-tetramethylguanidine are added. The mixture is heated at 65° C. overnight. It is taken up in a mixture of 100 ml of water and of 100 ml of ethyl acetate. The organic phase is separated and the aqueous phase is extracted with 2 times 80 ml of ethyl acetate. The organic phases are washed with 100 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 90.5/0.5 mixture of dichloromethane and of methanol, to produce 1.0 g (3.1 mmol) of product in the form of a white solid.
    • 4.3. 2-(methylamino)-2-oxoethyl 3-[3-(4-chlorophenyl)isoxazol-5-yl]propylcarbamate
  • 0.6 g (1.87 mmol) of 3-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}-1,3-oxazolidine-2,4-dione, prepared in stage 4.2., is dissolved in a mixture of 8 ml of tetrahydrofuran and of 15 ml of methanol. 2.8 ml of a 2M solution of methylamine (5.6 mmol) in tetrahydrofuran are added. Reaction is allowed to take place at ambient temperature overnight and then the mixture is evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 95/5 and 90/10 mixture of dichloromethane and of methanol. The product is recrystallized from a mixture of ethyl acetate and of methanol to produce 0.49 g (1.4 mmol) of white crystals.
  • LC-MS: M+H=352
  • M.p. (° C.): 158-160° C.
  • 1H NMR (CDCl3) δ (ppm): 7.75 (d, 2H), 7.45 (d, 2H), 6.35 (s, 1H), 6.10 (broad s, 1H), 5.00 (broad s, 1H), 4.60 (s, 2H), 3.35 (m, 2H), 2.85 (m+d, 5H), 2.05 (m, 2H).
    • EXAMPLE 5 Compound No. 20 2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propylcarbamate
  • Figure US20100069405A1-20100318-C00012
    • 5.1. 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-ol
  • 61.5 ml of 1.6M solution of n-butyllithium (98.4 mmol) in hexane are added dropwise to a solution, cooled to −78° C. under argon, of 13.25 g (78.8 mmol) of 2-(pent-4-yn-1-yloxy)tetrahydro-2H-pyran in 130 ml of anhydrous tetrahydrofuran. Stirring is continued at −78° C. for 1 hour and then a solution of 12.18 g (86.6 mmol) of 4-chlorobenzaldehyde in 40 ml of tetrahydrofuran is added dropwise. Stirring is continued at −78° C. for 2 hours and then the solution is reheated to 0° C. and is poured onto 300 ml of a saturated aqueous ammonium chloride solution. Extraction is carried out with 450 ml of ethyl acetate. The organic phase is washed with 50 ml of water and then with 50 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 16.64 g (53.88 mmol) of product in the form of a colorless oil.
    • 5.2. 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-one
  • A solution of 16.60 g (53.7 mmol) of 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-ol, prepared in stage 5.1., is added dropwise to a suspension, cooled with an ice bath, of 93 g (1.07 mol) of manganese dioxide in 500 ml of dichloromethane. Stirring is continued for 1.5 hours, then the mixture is filtered through celite and the filter cake is rinsed with dichloromethane. The filtrates are evaporated to produce 16.3 g (53.1 mmol) of product in the form of a yellowish oil.
    • 5.3. 4-(4-chlorophenyl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]pyrimidine
  • A mixture of 3.60 g (11.73 mmol) of 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-one, prepared in stage 5.2., of 9.45 g (117 mmol) of formamidine hydrochloride and of 25 g (234 mmol) of sodium carbonate in suspension in 108 ml of acetonitrile and 0.1 ml of water is stirred at 40° C. for 5 hours. The mixture is subsequently taken up in 600 ml of water and 400 ml of a saturated aqueous sodium carbonate solution. The organic phase is separated by settling, washed with 200 ml of water and 200 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 3.22 g (9.67 mmol) of product in the form of a yellowish oil.
    • 5.4.3-[6-(4-chlorophenyl)pyrimidin-4-yl]propan-1-ol
  • 3.22 g (9.67 mmol) of 4-(4-chlorophenyl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]pyrimidine, prepared in stage 5.3., are dissolved in 32 ml of methanol, and 16 ml of a 4N solution of hydrochloric acid in dioxane are added. The mixture is stirred at ambient temperature for 1.5 hours and then 150 ml of a half-saturated aqueous sodium hydrogencarbonate solution are added portionwise. Extraction is carried out with 350 ml of ethyl acetate. The organic phase is washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to produce 2.33 g (9.36 mmol) of product in the form of a white solid.
  • M.p. (° C.): 75-76° C.
    • 5.5. 3-{3-[6-(4-chlorophenyl)pyrimidin-4-yl]propyl}-1,3-oxazolidine-2,4-dione
  • 0.4 ml of a 40% solution of diethyl azodicarboxylate (0.9 mmol) in toluene is added to a solution, cooled with an ice bath, of 0.111 g (0.44 mmol) of 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propan-1-ol, prepared in stage 5.4., of 0.077 g (0.76 mmol) of 1,3-oxazolidine-2,4-dione and of 0.235 g (0.89 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran. The mixture is subsequently stirred at ambient temperature overnight. It is taken up in a mixture of ethyl acetate and of water. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 97/3 mixture of dichloromethane and of methanol, to produce 0.117 g (0.35 mmol) of product in the solid form.
    • 5.6. 2-(methylamino)-2-oxoethyl 3-[6-(4-chlorophenyl)pyrimidin-4-yl]propylcarbamate
  • 0.113 g (0.34 mmol) of 3-{3-[6-(4-chlorophenyl)pyrimidin-4-yl]propyl}-1,3-oxazolidine-2,4-dione, prepared in stage 5.5., is redissolved in a mixture of 4 ml of ethanol, 1 ml of methanol and 1 ml of dichloromethane. 2 ml of an 8M solution of methylamine (16 mmol) in ethanol are added. The mixture is stirred at ambient temperature for 2 hours and is then evaporated. The solid residue is taken up in diethyl ether to produce 0.127 g (0.34 mmol) of product in the form of a white solid.
  • LC-MS: M+H=363
  • M.p. (° C.): 147-149° C.
  • 1H NMR (CDCl3) δ (ppm): 9.15 (s, 1H), 8.05 (d, 2H), 7.65 (s, 1H), 7.55 (d, 2H), 6.15 (broad s, 1H), 5.30 (broad s, 1H), 4.55 (s, 2H), 3.35 (m, 2H), 2.85 (m+d, 5H), 2.10 (m, 2H).
  • The chemical structures and the physical properties of a few compounds according to the invention are illustrated in the following Table 1.
  • In this table:
      • all the compounds are in the free base form,
      • isopropyl, n-butyl and t-butyl respectively represent isopropyl, linear butyl and tert-butyl groups.
  • TABLE 1
    (I)
    Figure US20100069405A1-20100318-C00013
    M.p.
    (°C.)
    (M +
    No. R1 [A]n R7 R8 H)
    1. 5-phenylpyrid-2-yl CH2 H CH3 136-138
    2. 5-phenylpyrid-2-yl (CH2)2 H CH3 (314)
    3. 6-phenylpyrid-3-yl (CH2)2 H CH3 130-132
    4. 6-phenylpyridazin-3-yl (CH2)2 H CH3 159-161
    5. 2-phenylpyrimidin-5-yl (CH2)2 H CH3 125-127
    6. 5-phenylpyrimidin-2-yl (CH2)2 H CH3 150-152
    7. 6-(4-Cl-phenyl)pyrimidin-4-yl (CH2)2 H CH3 139-141
    8. 6-(4-Cl-phenyl)-2- (CH2)2 H CH3 140-142
    methylpyrimidin-4-yl
    9. 6-(4-Cl-phenyl)-2- (CH2)2 H CH3 131-133
    (dimethylamino)-
    pyrimidin-4-yl
    10. isoquinolin-7-yl (CH2)2 H CH3 134-136
    11. 4-phenylimidazol-1-yl (CH2)2 H CH3 111-113
    12. 2-phenyloxazol-4-yl (CH2)2 H CH3 94-98
    13. 5-(4-Cl-phenyl)isoxazol-3-yl (CH2)2 H CH3 150-152
    14. 3-(4-Cl-phenyl)-1-methyl-1H- (CH2)2 H CH3 125-127
    pyrazol-5-yl
    15. 5-phenyl-1,2,4-oxadiazol-3-yl (CH2)2 H CH3 131-135
    16. pyrid-2-yl (CH2)3 H H 114-115
    17. pyrid-3-yl (CH2)3 H H 105-107
    18. pyrid-4-yl (CH2)3 H H 161-162
    19. pyrimidin-5-yl (CH2)3 H H 119-121
    20. 6-(4-Cl-phenyl)pyrimidin-4-yl (CH2)3 H CH3 147-149
    21. 6-(4-Cl-phenyl)-2- (CH2)3 H CH3 (377)
    methylpyrimidin-4-yl
    22. 6-(4-Cl-phenyl)-2- (CH2)3 H CH3 150-152
    (dimethylamino)-
    pyrimidin-4-yl
    23. quinolin-2-yl (CH2)3 H H 117-119
    24. quinolin-4-yl (CH2)3 H H 150-152
    25. isoquinolin-1-yl (CH2)3 H H 123-124
    26. isoquinolin-4-yl (CH2)3 H H 154-156
    27. 5-(4-Cl-phenyl)isoxazol-3-yl (CH2)3 H CH3 138-140
    28. 3-(4-Cl-phenyl)isoxazol-5-yl (CH2)3 H H 176-178
    29. 3-(4-Cl-phenyl)isoxazol-5-yl (CH2)3 H CH3 158-160
    30. 3-(4-phenylphenyl)isoxazol- (CH2)3 H CH3 198-200
    5-yl
    31. 3-(naphth-2-yl)isoxazol-5-yl (CH2)3 H CH3 143-145
    32. 3-(4-Cl-phenyl)-1-methyl-1H- (CH2)3 H CH3 (365)
    pyrazol-5-yl
    33. 4-phenylimidazol-1-yl (CH2)3 H CH3 96-98
    34. benzimidazol-1-yl (CH2)3 H CH3 154-156
    35. pyrid-2-yl (CH2)4 H H 141-143
    36. pyrid-3-yl (CH2)4 H H 131-133
    37. pyrid-4-yl (CH2)4 H H 124-126
    38. pyrimidin-5-yl (CH2)4 H H 139-141
    39. 6-(4-Cl-phenyl)pyrimidin-4-yl (CH2)4 H CH3 101-103
    40. 6-(4-Cl-phenyl)-2- (CH2)4 H CH3 118-120
    methylpyrimidin-4-yl
    41. 6-(4-Cl-phenyl)-2- (CH2)4 H CH3 118-120
    cyclopropyl-pyrimidin-4-yl
    42. 6-(4-Cl-phenyl)-2- (CH2)4 H CH3 120-122
    (dimethylamino)-pyrimidin-
    4-yl
    43. quinolin-2-yl (CH2)4 H H 131-133
    44. quinolin-4-yl (CH2)4 H H (302)
    45. isoquinolin-1-yl (CH2)4 H H 119-121
    46. isoquinolin-4-yl (CH2)4 H H 154-156
    47. 5-(4-Cl-phenyl)isoxazol-3-yl (CH2)4 H CH3 130-132
    48. 3-(4-Cl-phenyl)isoxazol-5-yl (CH2)4 H CH3 138-140
    49. 3-(4-phenylphenyl)isoxazol- (CH2)4 H CH3 193-195
    5-yl
    50. 3-(naphth-2-yl)isoxazol-5-yl (CH2)4 H CH3 158-160
    51. 3-(4-Cl-phenyl)-1-methyl-1H- (CH2)4 H CH3 144-146
    pyrazol-5-yl
    52. 4-phenylimidazol-1-yl (CH2)4 H H 113-115
    53. 4-phenylimidazol-1-yl (CH2)4 H CH3 109-111
    54. benzimidazol-1-yl (CH2)4 H CH3 114-116
    55. indol-1-yl (CH2)4 H H 100-102
    56. indol-1-yl (CH2)4 H CH3 64-67
    57. pyrrolo[2,3-b]pyrid-1-yl (CH2)4 H H 102-104
    58. pyrrolo[2,3-b]pyrid-1-yl (CH2)4 H CH3 52-54
    59. tetrahydroisoquinolin-2-yl (CH2)4 H CH3 (320)
    60. 2-oxo-3,4- (CH2)4 H H (320)
    dihydroquinolin-1(2H)-yl
    61. 2-oxo-3,4- (CH2)4 H CH3 (334)
    dihydroquinolin-1(2H)-yl
    62. pyrid-2-yl (CH2)5 H H 77-79
    63. pyrid-4-yl (CH2)5 H H 155-157
    64. pyrimidin-5-yl (CH2)5 H H 115-117
    65. quinolin-2-yl (CH2)5 H H (316)
    66. quinolin-4-yl (CH2)5 H H 115-117
    67. isoquinolin-1-yl (CH2)5 H H 134-135
    68. isoquinolin-4-yl (CH2)5 H H (316)
    69. naphth-1-yl C≡CCH2 H H 132-134
    70. naphth-1-yl C≡CCH2 H CH3 107-109
    71. naphth-1-yl C≡C(CH2)3 H H 105-108
    72. naphth-1-yl C≡C(CH2)3 H CH3 73-76
    73. 4-F-naphth-1-yl C≡C(CH2)3 H CH3 96-98
    74. 3-(pyrid-3-yl)isoxazol-5-yl (CH2)3 H CH3 133-135
    75. 3-(4-methoxynaphth- (CH2)3 H CH3 95-97
    1-yl)isoxazol-5-yl

    The compounds of the invention have formed the subject of pharmacological trials which make it possible to determine their inhibitory effect on the enzyme FAAH (Fatty Acid amido Hydrolase).
  • The inhibitory activity was demonstrated in a radioenzymatic test based on the measurement of the product of hydrolysis ((1-3H)ethanolamine) of ((1-3H)ethanolamine)-anandamide by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). Thus, mouse brains (minus the cerebellum) are removed and stored at −80° C. The membrane homogenates are prepared at the time of use by homogenization of the tissues with a Polytron in a 10 mM Tris-HCl buffer (pH 8.0) comprising 150 mM NaCl and 1 mM EDTA. The enzymatic reaction is subsequently carried out in 70 μA of buffer comprising bovine serum albumin free from fatty acids (1 mg/ml). The test compounds, at various concentrations, the ((1-3H)ethanolamine)-anandamide (specific activity of 15-20 Ci/mmol), diluted to 10 μM with non-radiolabelled anandamide, and the membrane preparation (400 μg of frozen tissue per assay) are successively added. After 15 minutes at 25° C., the enzymatic reaction is halted by addition of 140 μl of chloroform/methanol (2:1). The mixture is stirred for 10 minutes and is then centrifuged at 3500 g for 15 minutes. An aliquot (30 μl) of the aqueous phase comprising the (1-3H)ethanolamine is counted by liquid scintillation.
  • Under these conditions, the most active compounds of the invention exhibit IC50 values (concentration which inhibits the control enzymatic activity of FAAH by 50%) of between 0.001 and 1 μM.
  • For example, compound No. 68 in the table exhibits an IC50 of 0.267 μM.
  • It is therefore apparent that the compounds according to the invention have an inhibitory activity on the enzyme FAAH.
  • The in vivo activity of the compounds of the invention was evaluated in a test for analgesia. Thus, the intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solution comprising 5% of ethanol) to male OF1 mice weighing 25 to 30 g causes abdominal tractions, on average 30 twisting or contracting motions during the period from 5 to 15 minutes after injection. The test compounds are administered, orally (p.o.) or intraperitoneally (i.p.) in suspension in 0.5% Tween 80, 60 minutes or 120 minutes before the administration of PBQ. Under these conditions, the most powerful compounds of the invention reduce by 35 to 70% the number of fractions induced by the PBQ, within a range of doses of between 1 and 30 mg/kg.
  • For example, compound No. 48 in the table reduces by 53% and by 62% the number of tractions induced by the PBQ, at a dose of 10 mg/kg p.o., at 60 minutes and at 120 minutes respectively.
  • The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyses the hydrolysis of endogenous derivatives of amides and esters of various fatty acids, such as N-arachidonoylethanolamine(anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives have various pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors.
  • The compounds of the invention block this decomposition pathway and increase the tissue level of these endogenous substances. They can therefore be used in the prevention and treatment of pathologies in which endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH are involved.
  • Mention may be made, for example, of the following diseases and conditions:
  • Pain, in particular acute or chronic pain of neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes;
    acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
    acute or chronic peripheral pain;
    dizziness, vomiting, nausea, in particular resulting from chemotherapy;
    eating disorders, in particular anorexia and cachexia of various natures;
    neurological and psychiatric pathologies: tremors, dyskinesias, dystonias, spasticity, obsessive-compulsive behavior, Tourette's syndrome, all forms of depression and of anxiety of any nature and origin, mood disorders, psychoses;
    acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions related to cerebral ischaemia and to cranial and medullary trauma;
    epilepsy;
    sleep disorders, including sleep apnea;
    cardiovascular diseases, in particular hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischaemia;
    renal ischaemia;
    cancers: benign skin tumors, brain tumors and papillomas, prostate tumors, cerebral tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, plexus tumor, neuroepitheliomas, epiphyseal tumor, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas);
    disorders of the immune system, in particular autoimmune diseases; psoriasis, lupus erythematosus, diseases of the connective tissue or collagen diseases, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, graft rejection, diseases affecting the plasmocytic line;
    allergic diseases; immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis;
    parasitic, viral or bacterial infectious diseases: AIDS, meningitis;
    inflammatory diseases, in particular joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
    osteoporosis;
    eye conditions: ocular hypertension, glaucoma;
    pulmonary conditions: diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema;
    gastrointestinal diseases: irritable bowel syndrome, inflammatory intestinal disorders, ulcers, diarrhea;
    urinary incontinence and bladder inflammation.
  • The use of a compound of formula (I), in the base or pharmaceutically acceptable salt, hydrate or solvate form, in the preparation of a medicament intended to treat the abovementioned pathologies forms an integral part of the invention.
  • Another subject-matter of the invention is medicaments which comprise a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (I). These medicaments are used in therapeutics, in particular in the treatment of the abovementioned pathologies.
  • According to another of its aspects, the present invention relates to pharmaceutical compositions including, as active principle, at least one compound according to the invention. These pharmaceutical compositions comprise an effective dose of a compound according to the invention or a pharmaceutically acceptable salt, hydrate or solvate of the said compound and optionally one or more pharmaceutically acceptable excipients.
  • The said excipients are chosen, depending on the pharmaceutical form and the method of administration desired, from the usual excipients which are known to a person skilled in the art.
  • In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of formula (I) above or its optional salt, solvate or hydrate can be administered in a single-dose administration form, as a mixture with conventional pharmaceutical excipients, to animals and to man for the prophylaxis or the treatment of the above disorders or diseases.
  • Appropriate single-dose administration forms comprise oral forms, such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular or intranasal administration or for administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
  • By way of example, a single-dose administration form of a compound according to the invention in the form of a tablet can comprise the following components:
  •
    Compound according to the invention 50.0 mg
    Mannitol 223.75 mg
    Croscarmellose sodium 6.0 mg
    Maize starch 15.0 mg
    Hydroxypropylmethylcellulose 2.25 mg
    Magnesium stearate 3.0 mg

    The said single-dose forms comprise a dose which makes possible a daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending upon the pharmaceutical dosage form.
  • There may be specific cases where higher or lower dosages are appropriate; such dosages also come within the invention. According to the usual practice, the dosage appropriate to each patient is determined by the doctor according to the method of administration, the weight and the response of the said patient.
  • According to another of its aspects, the invention also relates to a method for the treatment of the pathologies indicated above which comprises the administration of an effective dose of a compound according to the invention, of one of its pharmaceutically acceptable salts or of a solvate or of a hydrate of the said compound.

Claims (14)

1. A compound according to the formula (I):
Figure US20100069405A1-20100318-C00014
wherein A is selected from the group consisting of X, Y and Z; wherein
X represents a methylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups;
Y represents either a C2-alkenylene group optionally substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene group;
Z represents a group of formula:
Figure US20100069405A1-20100318-C00015
m represents an integer ranging from 1 to 5;
p and q represent integers and are defined such that p+q is a number ranging from 1 to 5;
n represents an integer ranging from 1 to 7;
R1 represents an R2 group optionally substituted by one or more R3 and R4 groups;
R2 represents a group chosen from a pyridyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl and isothiazolopyridyl;
R3 represents a group chosen from halogen atoms, cyano, nitro, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl, NR5R6, NR5COR6, NR5CO2R6, NR5SO2R6, COR5, CO2R5, CONR5R6, SO2R5, SO2NR5R6, —O—(C1-3-alkylene)-O— and phenyl group, the phenyl group optionally being substituted by one or more halogen atoms;
R4 represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group or, with the atom or atoms which carry them, form a ring chosen from the group consisting of an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C1-6-alkyl or benzyl group;
R7 represents a hydrogen atom or a C1-6-alkyl group, and
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group; or a salt thereof.
2. The compound as recited in claim 1, wherein:
A is chosen from one or more groups X or Y;
X represents a methylene group;
Y represents a C2-alkynylene group;
n represents an integer ranging from 1 to 5;
R2 represents a group chosen from a pyridyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl and pyrrolopyridyl;
R3 represents a group chosen from halogen atoms or C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl groups;
R4 represents a group chosen from phenyl, naphthyl and pyridyl groups; it being possible for the R4 group or groups to be substituted by one or more R3 groups which are identical to or different from one another;
R5 and R6 represent, independently of one another, a C1-6-alkyl group;
R7 represents a hydrogen atom or a C1-6-alkyl group; and
R8 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group;
a salt thereof.
3. The compound as recited in claim 2 wherein R2 is selected from the group consisting of pyridyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl and isoquinolinyl.
4. The compound as recited in claim 3 wherein:
R7 represents a hydrogen atom; and
R8 represents a hydrogen atom or a C1-6-alkyl group; or
a salt thereof.
5. A process for the preparation of the compound of formula (I) as recited in claim 1 comprising converting the carbamate ester of formula (IV):
Figure US20100069405A1-20100318-C00016
to the compound of formula (I) by aminolysis using an amine of formula R8NH2, in which A, n, R1 and R7 and R8 are as defined in claim 1.
6. A process for the preparation of the compound of formula (I) as recited in claim 1 comprising converting the oxazolidinedione derivative of formula (VII):
Figure US20100069405A1-20100318-C00017
to the compound of formula (I) by aminolysis, using an amine of formula R8NH2, in which A, n, R1, R7 and R8 are as defined in claim 1.
7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
8. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
9. A pharmaceutical composition comprising the compound of claim 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
11. A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
12. A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof.
13. A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof.
14. A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof.
US12/625,125 2004-02-26 2009-11-24 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors Abandoned US20100069405A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/625,125 US20100069405A1 (en) 2004-02-26 2009-11-24 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
US13/156,551 US20110237595A1 (en) 2004-02-26 2011-06-09 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR0401949A FR2866886B1 (en) 2004-02-26 2004-02-26 ARYL-AND HETEROARYL-AKYLCARBAMATES DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR0401949 2004-02-26
PCT/FR2005/000451 WO2005090292A1 (en) 2004-02-26 2005-02-25 Derivatives of heteroaryl-alkylcarbamates, preparation method thereof and use of same as faah enzyme inhibitors
US11/464,355 US7645757B2 (en) 2004-02-26 2006-08-14 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
US12/625,125 US20100069405A1 (en) 2004-02-26 2009-11-24 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US11/464,355 Division US7645757B2 (en) 2004-02-26 2006-08-14 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/156,551 Division US20110237595A1 (en) 2004-02-26 2011-06-09 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Publications (1)

Publication Number Publication Date
US20100069405A1 true US20100069405A1 (en) 2010-03-18

Family

ID=34834066

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/464,355 Expired - Fee Related US7645757B2 (en) 2004-02-26 2006-08-14 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
US12/625,125 Abandoned US20100069405A1 (en) 2004-02-26 2009-11-24 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
US13/156,551 Abandoned US20110237595A1 (en) 2004-02-26 2011-06-09 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/464,355 Expired - Fee Related US7645757B2 (en) 2004-02-26 2006-08-14 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/156,551 Abandoned US20110237595A1 (en) 2004-02-26 2011-06-09 Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Country Status (29)

Country Link
US (3) US7645757B2 (en)
EP (2) EP1720829B1 (en)
JP (1) JP4824668B2 (en)
KR (1) KR20070011297A (en)
CN (1) CN1926097B (en)
AR (1) AR047973A1 (en)
AT (1) ATE445592T1 (en)
AU (1) AU2005223423B2 (en)
BR (1) BRPI0508193A (en)
CA (1) CA2554609A1 (en)
CY (1) CY1109716T1 (en)
DE (1) DE602005017122D1 (en)
DK (1) DK1720829T3 (en)
ES (1) ES2334449T3 (en)
FR (1) FR2866886B1 (en)
HK (1) HK1101759A1 (en)
HR (1) HRP20100017T1 (en)
IL (1) IL177329A (en)
MA (1) MA28367A1 (en)
NO (1) NO20064329L (en)
NZ (1) NZ550008A (en)
PL (1) PL1720829T3 (en)
PT (1) PT1720829E (en)
RS (1) RS51246B (en)
RU (1) RU2364586C2 (en)
SI (1) SI1720829T1 (en)
TW (1) TW200533637A (en)
WO (1) WO2005090292A1 (en)
ZA (1) ZA200606724B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2866884B1 (en) * 2004-02-26 2007-08-31 Sanofi Synthelabo ARYL-AND HETEROARYL-PIPERIDINECARBOXYLATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2866885B1 (en) * 2004-02-26 2007-08-31 Sanofi Synthelabo PIPERIDINYLALKYLCARBAMATES DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF
MX2009011511A (en) 2007-04-26 2009-11-12 Takeda Pharmaceutical Bicyclic compound and pharmaceutical use thereof.
WO2009070497A1 (en) * 2007-11-28 2009-06-04 Smithkline Beecham Corporation SEH AND 11 β-HSD1 INHIBITORS AND THEIR USE
KR101799429B1 (en) * 2010-05-03 2017-11-21 에스케이바이오팜 주식회사 Pharmaceutical composition for inhibiting apoptosis of neuron or neurodegeneration

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2866734A (en) * 1956-12-05 1958-12-30 Us Vitamin Corp 3-pyridylethyl 2, 4-oxazolidinediones and process
US3054794A (en) * 1958-01-17 1962-09-18 Us Vitamin Pharm Corp Process for preparing 3-(aminoalkyl)-oxazolidine-2, 4-diones
US3876661A (en) * 1971-03-02 1975-04-08 Anthony J Verbiscar Carbamate esters of serotonin and analogs
US20020115693A1 (en) * 2000-01-18 2002-08-22 Stanislaw Rachwal Substituted imidazoles as selective modulators of bradykinin B2 receptors
US20070167491A1 (en) * 2004-03-03 2007-07-19 Mansfield Darren J 2-Pyridinylethylcarboxamide derivatives and their use as fungicides
US7309701B2 (en) * 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3742022A (en) * 1967-05-08 1973-06-26 A Verbiscar Carbamate esters of physiologically active ph enenthylamines
JP2001523695A (en) * 1997-11-24 2001-11-27 ザ スクリップス リサーチ インスティテュート Inhibitors of gap junction communication
JP2004532229A (en) * 2001-04-27 2004-10-21 ブリストル−マイヤーズ　スクイブ　カンパニー Fatty acid amide hydrolase inhibitor
JP4567439B2 (en) * 2002-04-27 2010-10-20 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Carboxylic acid amide
FR2843964B1 (en) * 2002-08-29 2004-10-01 Sanofi Synthelabo DIOXANE-2-ALKYLCARBAMATES DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
US7176201B2 (en) * 2002-10-07 2007-02-13 The Regents Of The University Of California Modulation of anxiety through blockade of anandamide hydrolysis
MXPA05003762A (en) * 2002-10-08 2005-07-22 Scripps Research Inst Inhibitors of fatty acid amide hydrolase.
FR2850377B1 (en) * 2003-01-23 2009-02-20 Sanofi Synthelabo ARYLALKYLCARBAMATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2854633B1 (en) * 2003-05-07 2005-06-24 Sanofi Synthelabo PIPERIDINYL-AND PIPERAZINYL-ALKYLCARBAMATES DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
UA82695C2 (en) * 2003-06-06 2008-05-12 Нисан Кемикал Индастриз, Лтд. Heteroaromatic compounds as thrombopoietin receptor activators
WO2005002525A2 (en) * 2003-07-01 2005-01-13 Microbia, Inc. Cox-2 and faah inhibitors
JP2007509044A (en) * 2003-10-08 2007-04-12 バーテックス　ファーマシューティカルズ　インコーポレイテッド Modulator of ATP binding cassette transporter containing cycloalkylpyranyl group
FR2866885B1 (en) * 2004-02-26 2007-08-31 Sanofi Synthelabo PIPERIDINYLALKYLCARBAMATES DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF
US20100152188A1 (en) * 2005-08-05 2010-06-17 Akella Satya Surya Visweswara Srinivas Novel Heterocyclic Compounds
AU2006293635A1 (en) * 2005-09-22 2007-03-29 Sanofi-Aventis Amino-alkyl-amide derivatives as CCR3 receptor liquids
FR2894578B1 (en) * 2005-12-12 2008-02-01 Sanofi Aventis Sa HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE.
TW200806641A (en) * 2006-01-25 2008-02-01 Synta Pharmaceuticals Corp Substituted aromatic compounds for inflammation and immune-related uses
JO2754B1 (en) * 2006-12-21 2014-03-15 استرازينكا ايه بي Indazolyl amide derivatives for the treatment of glucocorticoid receptor mediated disorders
US9549982B2 (en) * 2009-11-23 2017-01-24 Foundational Biosystems, Llc Ultra low dose nutraceutical compositions for enhancing sleep quality and treating sleep disorders

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2866734A (en) * 1956-12-05 1958-12-30 Us Vitamin Corp 3-pyridylethyl 2, 4-oxazolidinediones and process
US3054794A (en) * 1958-01-17 1962-09-18 Us Vitamin Pharm Corp Process for preparing 3-(aminoalkyl)-oxazolidine-2, 4-diones
US3876661A (en) * 1971-03-02 1975-04-08 Anthony J Verbiscar Carbamate esters of serotonin and analogs
US20020115693A1 (en) * 2000-01-18 2002-08-22 Stanislaw Rachwal Substituted imidazoles as selective modulators of bradykinin B2 receptors
US7309701B2 (en) * 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
US20070167491A1 (en) * 2004-03-03 2007-07-19 Mansfield Darren J 2-Pyridinylethylcarboxamide derivatives and their use as fungicides

Also Published As

Publication number Publication date
TW200533637A (en) 2005-10-16
DK1720829T3 (en) 2010-03-01
US20110237595A1 (en) 2011-09-29
FR2866886B1 (en) 2007-08-31
EP2251324A1 (en) 2010-11-17
RU2364586C2 (en) 2009-08-20
DE602005017122D1 (en) 2009-11-26
AR047973A1 (en) 2006-03-15
JP4824668B2 (en) 2011-11-30
KR20070011297A (en) 2007-01-24
RU2006134026A (en) 2008-04-10
JP2007524705A (en) 2007-08-30
ATE445592T1 (en) 2009-10-15
IL177329A0 (en) 2006-12-10
CN1926097A (en) 2007-03-07
NO20064329L (en) 2006-09-25
PL1720829T3 (en) 2010-03-31
RS51246B (en) 2010-12-31
AU2005223423B2 (en) 2011-04-14
BRPI0508193A (en) 2007-08-14
FR2866886A1 (en) 2005-09-02
ZA200606724B (en) 2007-12-27
SI1720829T1 (en) 2010-02-26
CY1109716T1 (en) 2014-08-13
EP1720829A1 (en) 2006-11-15
EP1720829B1 (en) 2009-10-14
PT1720829E (en) 2010-01-13
HK1101759A1 (en) 2007-10-26
CN1926097B (en) 2011-06-08
CA2554609A1 (en) 2005-09-29
HRP20100017T1 (en) 2010-02-28
WO2005090292A1 (en) 2005-09-29
US7645757B2 (en) 2010-01-12
AU2005223423A1 (en) 2005-09-29
NZ550008A (en) 2010-06-25
ES2334449T3 (en) 2010-03-10
US20070021426A1 (en) 2007-01-25
MA28367A1 (en) 2006-12-01
IL177329A (en) 2012-01-31

Similar Documents

Publication Publication Date Title
US7973042B2 (en) Derivatives of alkylpiperazine- and alkylhomopiperazine-carboxylates, preparation method thereof and use of same as fatty acid amido hydrolase enzyme inhibitors
US7781590B2 (en) Piperidinylalkylcarbamate derivatives, methods for their preparation and the therapeutic use thereof as fatty acid amido hydrolase enzyme inhibitors
US7214798B2 (en) Derivatives of piperidinyl-and piperazinyl-alkyl carbamates, preparation methods thereof and application of same in therapeutics
US8026258B2 (en) Aryloxyalkylcarbamate-type derivatives, preparation method thereof and use of same in therapeutics
US20070021405A1 (en) Aryl- and heteroarylpiperidinecarboxylate-derivatives methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
JP5452594B2 (en) Alkyl thiazole carbamate derivatives, their preparation, and their use as FAAH enzyme inhibitors
EP2429998B1 (en) 5-membered heterocyclic compound cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation thereof, and therapeutic use thereof
US20110237595A1 (en) Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors
JP2006517218A (en) Preparation of arylalkyl carbamate derivatives and their therapeutic use
AU2011204768A1 (en) Derivatives of heteroaryl-alkylcarbamates, preparation method thereof and use of same as FAAH enzyme inhibitors
MXPA06009396A (en) Derivatives of heteroaryl-alkylcarbamates, preparation method thereof and use of same as faah enzyme inhibitors
MXPA06009626A (en) Derivatives of piperidinylalkylcarbamates, preparation method thereof and use of same as faah enzyme inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: SANOFI-AVENTIS,FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ABOUABDELLAH, AHMED;BARTSCH-LI, REGINE;HOORNAERT, CHRISTIAN;AND OTHERS;SIGNING DATES FROM 20060919 TO 20060922;REEL/FRAME:024509/0742

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE