US20070021390A1 - Derivatives of heterocycles with 5 members, their preparation and their use as medicaments - Google Patents

Derivatives of heterocycles with 5 members, their preparation and their use as medicaments Download PDF

Info

Publication number
US20070021390A1
US20070021390A1 US11/256,901 US25690105A US2007021390A1 US 20070021390 A1 US20070021390 A1 US 20070021390A1 US 25690105 A US25690105 A US 25690105A US 2007021390 A1 US2007021390 A1 US 2007021390A1
Authority
US
United States
Prior art keywords
alkyl
group
radical
independently
hydrogen
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
US11/256,901
Other languages
English (en)
Inventor
Pierre Chabrier de Lassauniere
Jeremiah Harnett
Denis Bigg
Jacuqes Pommier
Jacques Lannoy
Anne-Marie Liberatore
Christophe Thurieau
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.)
Ipsen Pharma SAS
Original Assignee
Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
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
Priority claimed from FR9912643A external-priority patent/FR2799461B1/fr
Priority claimed from FR0010151A external-priority patent/FR2812546B1/fr
Application filed by Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS filed Critical Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Priority to US11/256,901 priority Critical patent/US20070021390A1/en
Publication of US20070021390A1 publication Critical patent/US20070021390A1/en
Priority to US11/708,531 priority patent/US20070179153A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • 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
    • 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
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to the use of compounds of general formula (I) for preparing a medicament intended to inhibit monoamine oxydases (MAO) and/or lipidic peroxidation and/or to act as modulators of the sodium channels.
  • a subject of the invention is also, as medicaments, the compounds of general formula (II) defined hereafter.
  • it relates to new compounds of general formula (III).
  • the advantage of a combination of the inhibitory activities of MAO and inhibition of lipidic peroxidation is for example well illustrated in Parkinson's disease.
  • This pathology is characterized by a loss of dopaminergic neurons of the nigrostriatal route the cause of which would in part be linked to an oxidizing stress due to ROS's.
  • the exogenic dopamine from L Dopa is used in therapeutics in order to maintain sufficient levels of dopamine.
  • MAO inhibitors are also used with L Dopa to avoid its metabolic degradation but do not act on the ROS's. Compounds which act both on MAO's and ROS's will therefore have a certain advantage.
  • the character of the modulator of the sodium channels is very useful for therapeutic indications such as:
  • the European Patent Application EP 432 740 describes derivatives of hydroxyphenylthiazoles, which can be used in the treatment of inflammatory diseases, in particular rheumatic diseases. These derivatives of hydroxyphenylthiazoles show properties of trapping free radicals and inhibitors of the metabolism of arachidonic acid (they inhibit lipoxygenase and cyclooxygenase).
  • R1 represents one of the aryl, heteroaryl, aralkyl or cycloalkyl radicals optionally substituted by one to three substituents chosen independently from a halogen atom, the CF 3 , CN, OH, alkyl or alkoxy radical, SO 2 R9 with R9 representing NH 2 or NHCH 3
  • X represents NR2, R2 representing H or alkyl
  • Y represents N or CR3
  • Z represents CR3 or N; on the condition however that Y and Z are not both CR3 or N at the same time
  • R3 represents H, alkyl, halogen, hydroxyalkyl or phenyl optionally substituted by 1 to 3 substituents chosen from H, CF 3 , CN, SO 2 NH 2 , OH, alkyl or alkoxy
  • m represents 0, 1 or 2
  • R4 represents H or alkyl; when Z represents CR3, then R3 and R4 can also represent together —
  • R1 represents in particular an alkyl, optionally substituted phenyl or optionally substituted heterocyclic aryl radical
  • R2 represents H or phenylalkyl
  • R4 represents H, quinolyl, 3-4-methylenedioxyphenyl or one of the phenyl or pyridyl radicals optionally substituted, by a radical or radicals chosen in particular from alkyl, alkoxy, alkylthio, optionally protected hydroxy, amino, alkylamino, dialkylamino
  • R5 represents H or an imidazolyl, phenyl, nitrophenyl, phenylalkyl radical, or also a —CO—N(R7)(R8) radical, in which R7 and R8 represent independently H, phenyl, phenylalkyl, alkyl or alkoxy; or R4 and R5 in combination form a
  • the compounds corresponding to general formula (I) in racemic, enantiomeric form or any combination of these forms in which Het is a heterocycle with 5 members comprising 2 heteroatoms and such that general formula (I) corresponds exclusively to one of the following sub-formulae: in which A represents either a radical in which R 3 represents a hydrogen atom, the OH group or an alkoxy or alkyl radical, or a radical in which R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitro or NR 10 R 11 radical, R 10 and R 11 representing, independently, a hydrogen atom, an alkyl radical or a —COR 12 group, or R 10 and R 11 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from
  • ⁇ representing a linear or branched alkylene radical containing 1 to 6 carbon atoms
  • —R 34 and R 35 representing, independently, a hydrogen atom or an alkyl radical
  • R 36 and R 37 representing, independently, a hydrogen atom or a carbocyclic or heterocyclic aryl radical optionally substituted by one or more substituents chosen from the alkyl, OH, halogen, nitro, alkoxy or NR 10 R 11 radicals,
  • R 10 and R 11 representing, independently, a hydrogen atom, an alkyl radical or a —COR 12 group, or R 10 and R 11 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being able to be for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
  • R 12 representing a hydrogen atom or an alkyl, alkoxy or NR 13 R 14 radical
  • A represents an alkyl, cycloalkyl or cycloalkylalkyl radical
  • X represents S or NR 38 .
  • R 38 representing a hydrogen atom or an alkyl, cyanoalkyl, aralkyl, alkylcarbonyl or aralkylcarbonyl radical
  • Y represents O or S
  • R 1 represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl, alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, —(CH 2 ) g -Z 1 R 39 , —(CH 2 ) g —COR 40 , —(CH 2 ) g —NHCOR 70 , aryl, aralkyl, arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radical, the aryl group of the aryl, aralkyl, arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radicals itself being optionally substituted by one or more substituents chosen from the group constituted by the alkyl, halogen, alkoxy, nitro, cyano, cyanoalkyl, amino
  • Z 1 and Z 2 representing a bond, —O—, —NR 41 — or —S—,
  • R 39 and R 41 representing, independently each time that they occur, a hydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical
  • R 40 representing, independently each time that it occurs, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR 42 R 43 radical,
  • R 42 and R 43 representing, independently each time that they occur, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
  • R 2 represents a hydrogen atom, an alkyl aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl or —(CH 2 ) g —NHCOR 71 radical, or also one of the aralkyl or heteroarylalkyl radicals optionally substituted on the aryl or heteroaryl group by one or more of the groups chosen independently from the group composed of a halogen atom and an alkyl, alkoxy, hydroxy, cyano, nitro, amino, alkylamino or dialkylamino radical,
  • R 70 and R 71 representing independently an alkyl or alkoxy radical
  • B represents a hydrogen atom, an alkyl radical, a —(CH 2 ) g -Z 3 R 44 radical or a carbocyclic aryl radical optionally substituted 1 to 3 times by the radicals chosen from the group composed of a halogen atom, a linear or branched alkyl or alkoxy radical containing 1 to 6 carbon atoms, a hydroxy, cyano or nitro radical, an amino, alkylamino or dialkylamino radical and a carbocyclic aryl radical,
  • Z 3 representing a bond, —O—, —NR 45 — or —S—,
  • R 44 and R 45 representing, independently, a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical;
  • ⁇ represents one of the NR 46 R 47 or OR 48 radicals, in which:
  • R 46 and R 47 represent, independently, a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, (CH 2 ) g -Z 4 R 50 , —(CH 2 ) k —COR 51 , —(CH 2 ) k —COOR 51 , —(CH 2 ) k —CONHR 51 or —SO 2 R 51 radical, or also a radical chosen from the aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl, heteroaryl and in particular pyridinyl, pyridinylalkyl or pyridinylcarbonyl radicals, the aryl or heteroaryl group of said aryl, aralkyl, aryloxyalkyl, arylcarbonyl
  • Z 4 and Z 5 representing a bond, —O—, —NR 52 — or —S—,
  • R 46 and R 47 taken together form with the nitrogen atom a non aromatic heterocycle with 4 to 8 members, the elements of the chain being chosen from a group composed of —CH(R 53 )—, —NR 54 —, —O—, —S— and —CO—, said heterocycle being able to be for example an azetidine, a piperazine, a homopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, a morpholine or a thiomorpholine,
  • R 50 and R 52 representing, independently each time that they occur, a hydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,
  • R 51 representing, independently each time that they occur, a hydrogen atom, one of the cycloalkyl or cycloalkylalkyl radicals in which the cycloalkyl radical has 3 to 7 carbon atoms, a linear or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl or NR 58 R 59 radical, or also an aryl or aralkyl radical, said aryl or aralkyl radical being able to be substituted by one or more of the substituents chosen independently from a halogen atom and an alkyl or alkoxy radical,
  • R 58 and R 59 representing, independently, a hydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,
  • R 53 and R 54 representing, independently, a hydrogen atom or a —(CH 2 ) k -Z 7 R 60 or —(CH 2 ) k —COR 61 radical,
  • Z 7 representing a bond, —O—, —NR 62 — or —S—,
  • R 60 and R 62 representing, independently, a hydrogen atom or an alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl or pyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl or pyridinylcarbonyl radicals being optionally substituted by one or more substituents chosen from the group constituted by the alkyl, halogen, nitro, alkoxy, cyano, cyanoalkyl, —(CH 2 ) k -Z 8 R 63 and —(CH 2 ) k —COR 64 radicals,
  • R 61 representing a hydrogen atom, an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR 65 R 66 radical,
  • R 65 and R 66 representing, independently, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
  • Z 8 representing a bond, —O—, —NR 67 — or —S—,
  • R 63 and R 67 representing, independently, a hydrogen atom, an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
  • R 64 representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR 68 R 69 radical,
  • R 68 and R 69 representing, independently, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
  • R 48 represents a hydrogen atom or an alkyl, alkynyl or cyanoalkyl radical
  • A represents the 4-hydroxy-2,3-di-tertiobutyl-phenyl radical
  • these compounds have at least two of the activities mentioned above.
  • they inhibit both the MAO's and trap the ROS's or they will have both an antagonist activity vis-à-vis the sodium channels and a trapping activity on the ROS's.
  • the compounds of general formula (I) even combine the three activities.
  • alkyl unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms.
  • cycloalkyl when no further detail is given, is meant a monocyclic carbon system containing 3 to 7 carbon atoms.
  • alkenyl when no further detail is given, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond).
  • alkynyl when no further detail is given, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond).
  • allenyl is meant the —CH ⁇ C ⁇ CH 2 radical.
  • carbocyclic or heterocyclic aryl is meant a carbocyclic system (in particular, the phenyl radical which can be noted Ph in an abbreviated fashion) or heterocyclic system comprising at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprises it contains a heteroatom (O, N or S).
  • heterocycle is meant a mono- or polycyclic system, said system comprising at least one heteroatom chosen from O, N and S and being saturated, partially or totally unsaturated or aromatic.
  • heteroaryl is meant a heterocycle as defined previously in which at least one of the rings which comprises it is aromatic.
  • haloalkyl is meant an alkyl radical at least one of hydrogen atoms of which (and optionally all) is replaced by a halogen atom.
  • an optionally substituted radical is meant unless otherwise specified a radical comprising one or more substituents chosen independently from the group composed of a halogen atom and the alkyl and alkoxy radicals.
  • alkylthio, alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl, cycloalkylalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl, cyanoalkyl and aralkyl radicals is meant respectively the alkylthio, alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl, cycloalkylalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl, cyanoalkyl and aralkyl radicals the alkyl radical (the alkyl radicals) of which have the meaning(s) indicated previously.
  • heterocycle is meant in particular the thiophene, piperidine, piperazine, quinoline, indoline and indole radicals.
  • linear or branched alkyl having 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
  • halogen is meant the fluorine, chlorine, bromine or iodine atoms.
  • the compounds according to the invention are such that they correspond to general formula (I): in racemic, enantiomeric form or any combination of these forms, in which Het is a heterocycle with 5 members comprising 2 heteroatoms and such that general formula (I) corresponds exclusively to one of the following sub-formulae: in which A represents either a radical in which R 3 represents a hydrogen atom, the OH group or an alkoxy or alkyl radical, or a radical in which R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitro or NR 10 R 11 radical, R 10 and R 11 representing, independently, a hydrogen atom or an alkyl radical R 9 represents a hydrogen atom or an alkyl radical, and W doesn't exist, or represents a bond, or —O—, —S— or —NR 18 —, in which R 18 represents a hydrogen
  • the Q radical is preferably found in para position with respect to the heterocycle Het.
  • the compounds of general formula (I) or their salts are more especially intended to have an inhibitory activity on MAO's and/or ROS's and they will therefore be preferably such that:
  • A represents
  • R 3 represents a hydrogen atom, the OH group or an alkoxy or alkyl radical
  • R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, a halogen, the OH group or an alkyl, alkoxy or NR 10 R 11 radical
  • R 10 and R 11 representing, independently, a hydrogen atom or an alkyl radical, or R 10 and R 11 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being able to be for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine
  • R 9 represents a hydrogen atom or an alkyl radical
  • W doesn't exist, or represents a bond, or —O—, —S
  • the compounds of general formula (I) when they are intended to have an inhibitory activity on MAO's and/or ROS's, will be such that:
  • A represents
  • R 3 represents a hydrogen atom
  • R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, or an alkyl or alkoxy radical
  • R 9 represents a hydrogen atom
  • W doesn't exist, or represents a bond, or —O—, —S— or —NR 18 —, in which R 18 represents a hydrogen atom or an alkyl radical; or a radical in which Q represents —OR 22 , —SR 22 or a phenyl radical substituted by an OH radical and optionally one or more of the additional substituents chosen independently from a halogen atom and an OH, alkyl or alkoxy radical.
  • R 22 representing a hydrogen atom or an alkyl radical
  • R 19 , R 20 and R 21 represent, independently, a hydrogen, a halogen, the OH or SR 26 group, or an alkyl or alkoxy radical
  • R 26 representing a hydrogen atom or an alkyl radical, or a radical in which R 32 represents a hydrogen atom or an alkyl radical
  • the said compounds of general formula (I) (or their salts) more especially intended to have an inhibitory activity on MAO's and the ROS's, the said compounds having at least one of the following characteristics will generally be preferred:
  • the compounds of Examples 1 to 30, 210, 291, 316, 319 to 323, 329 to 336 and 346 to 349 are preferred when an inhibitory activity on MAO's and/or the ROS's is sought in the first place.
  • the compounds of Examples 1, 3, 6, 22, 24, 26 to 29, 323 and 332 are preferred when an inhibitory activity on MAO's and/or the ROS's is sought in the first place.
  • the compounds of general formula (I) or their pharmaceutically acceptable salts are more especially intended to have an modulating activity on the sodium channels and they are then preferably such that they correspond to general sub-formulae (I), and (I) 2 and that:
  • A represents
  • Q represents H, —OR 22 , SR 22 or a phenyl radical optionally substituted by one or more of the substituents chosen independently from a halogen atom, an alkyl or alkoxy radical, and a group of two substituents together representing a methylenedioxy or ethylenedioxy radical, or Q represents a —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph radical, said —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph radical being optionally substituted on its aromatic part by one or more of the substituents chosen independently from an alkyl or alkoxy radical and a halogen atom, R 22 representing a hydrogen atom or an alkyl radical, and R 19 , R 20 and R 21 represent, independently, a hydrogen, a halogen, the OH group or an alkyl, alkoxy, cyano, nitro, cycloalkyl,
  • A represents the radical in which Q represents H, —OR 22 , —SR 22 , or a phenyl radical optionally substituted by one or more of the substituents chosen independently from a halogen atom and an alkyl or alkoxy radical, or also Q represents a —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph radical, said —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph radical being optionally substituted on its aromatic part by one or more of the substituents chosen from an alkyl or alkoxy radical and a halogen atom, R 22 representing a hydrogen atom or an alkyl radical, and R 19 , R 20 and R 21 represent, independently, a hydrogen,
  • R 1 and R 2 will preferably represent hydrogen atoms.
  • the compounds of Examples 1, 3, 6, 7, 9 to 11, 13, 15 to 17, 20, 24, 26, 28 to 318, 321, 324 to 330 and 337 to 345 are preferred when a modulating activity on the sodium channels is sought in the first place.
  • Het is such that the compounds of general formula (I) correspond to one of the general sub-formulae (I), and (I), in which X represents NH or S or general sub-formula (I) 3 in which Y represents O;
  • A represents a radical in which Q represents OH, two of the R 19 , R 20 and R 21 radicals represent an alkyl radical and the third represents a hydrogen atom, or in which Q represents a phenyl radical substituted by an OH radical and one or more radicals chosen independently from alkyl radicals;
  • B represents a hydrogen atom; n represents 0 or 1; R 1 and R 2 both represent a hydrogen atom; and
  • ⁇ represents an NR 46 R 47 radical in which R 46 represents a hydrogen atom or an alkyl, alkynyl, hydroxyalkyl or cyanoalkyl radical and R 47 represents a hydrogen atom or an alkyl radical or also R 46 and R 47 form together with the nitrogen atom which carries them a non-aromatic heterocycle with 5 to 7 members, the additional members being chosen from —CH 2 — and —NH—; can be used to prepare a medicament intended both to inhibit MAO's and lipidic peroxidation and to modulate the sodium channels.
  • the compounds of general formula (I) which can be used to prepare a medicament intended both to inhibit MAO's and lipidic peroxidation and to modulate the sodium channels will be such that:
  • Het is such that the compounds of general formula (I) correspond to general sub-formula (I), in which X represents S or to general sub-formula (I) 3 in which Y represents O;
  • A represents a radical in which Q represents OH, two of the radicals R 19 , R 20 and R 21 represent an alkyl radical and the third represents a hydrogen atom; B represents a hydrogen atom; n represents 0 or 1; R 1 and R 2 both represent a hydrogen atom; and ⁇ represents an NR 46 R 47 radical in which R 46 represents a hydrogen atom or an alkyl, hydroxyalkyl or cyanoalkyl radical and R 47 represents a hydrogen atom or an alkyl radical or also R 46 and R 47 form together with the nitrogen atom which carries them an N-piperazinyl radical.
  • n will preferably represent 0 when Het is such that the compounds of general formula (I) correspond to general sub-formula (I), in which X represents S and preferably 1 when Het is such that the compounds of general formula (I) correspond to general sub-formula (I) 3 in which Y represents O.
  • Examples 1, 3, 6, 24, 26, 28 and 29 (sometimes described in the form of salts) or their pharmaceutically acceptable salts will be preferred if one wishes to prepare a medicament intended both to inhibit MAO's and lipidic peroxidation and to modulate the sodium channels.
  • the invention also offers, as medicaments, the compounds of general formula (II) in racemic, enantiomeric form or any combinations of these forms, in which Het is a heterocycle with 5 members comprising 2 heteroatoms and such that general formula (II) correspond exclusively to one of the following sub-formulae: in which A represents either a radical in which R 3 represents a hydrogen atom, the OH group or an alkoxy or alkyl radical, or a radical in which R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitro or NR 10 R 11 radical, R 10 and R 11 representing, independently, a hydrogen atom, an alkyl radical or a —COR 12 group, or R 10 and R 11 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms
  • A represents a radical in which Q represents OH and two of the R 19 , R 20 and R 21 radicals represent alkyl radicals.
  • Het represents an imidazole ring.
  • the medicaments of general formula (II) will be chosen from the compounds described (sometimes in the form of salts) in Examples 1 to 35, 52, 57, 61, 80, 82, 83, 85 to 87, 90, 94, 113, 115, 123, 127, 130, 132, 134, 138, 139, 147, 152, 154, 161, 164, 169, 171 to 173, 176 to 180, 203, 237 to 239, 243 to 247, 249, 251, 255, 258 to 262, 264 to 271, 273 to 275 and 277 to 349, or the pharmaceutically acceptable salts of these compounds.
  • the medicaments of general formula (II) will be chosen from the compounds described (sometimes in the form of salts) in Examples 1, 3, 6, 7, 11, 17, 24, 26 to 35, 57, 61, 82, 83, 85 to 87, 94, 113, 123, 130, 132, 134, 138, 139, 152, 154, 164, 169, 171 to 173, 176 to 178, 203, 237 to 239, 243 to 247, 249, 955, 258, 259, 261, 262, 264 to 271, 273 to 275, 277 to 281, 283 to 288, 293 to 313, 321, 323, 324, 332 and 338 to 340, or the pharmaceutically acceptable salts of these compounds.
  • the invention also relates, as new industrial products, to the compounds of general formula (III) in racemic, enantiomeric form or any combinations of these forms, in which Het is a heterocycle with 5 members comprising 2 heteroatoms and such that general formula (III) corresponds exclusively to one of the following sub-formulae: in which A represents either a radical in which R 3 represents a hydrogen atom, the OH group or an alkoxy or alkyl radical, or a radical in which R 4 , R 5 , R 6 , R 7 and R 8 represent, independently, a hydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitro or NR 10 R 11 radical, R 10 and R 11 representing, independently, a hydrogen atom, an alkyl radical or a —COR 12 group, or R 10 and R 11 forming together with the nitrogen atom an optionally substituted heterocycle with 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatom
  • R 15 representing a hydrogen atom or an alkyl, alkoxy or NR 16 R 17 radical
  • R 16 and R 17 representing, independently, a hydrogen atom or an alkyl radical, or R 16 and R 17 forming together with the nitrogen atom an optionally substituted heterocycle with 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, and W doesn't exist, or represents a bond, or —O—, —S— or —NR 18 —, in which R 18 represents a hydrogen atom or an alkyl radical; or a radical in which Q represents H, —OR 22 , —SR 22 , —NR 23 R 24 , a phenyl radical optionally substituted by one or more of the substituents chosen independently from a halogen atom, an OH, cyano, nitro, alkyl, alkoxy or —NR 10 R 11 radical and a group of two substitu
  • the compounds of general formula (III) will be both ROS and MAO inhibitors and have at least one of the following characteristics:
  • the compounds of general formula (III) will be modulators of the sodium channels and preferably have one of the following two characteristics:
  • the compounds of general formula (III) which are modulators of the sodium channels are such that Het represents an imidazole ring (i.e. that they correspond to one of general formulae (III) 1 or (III) 2 in which X represents an NR 38 radical in which R 38 is as defined previously).
  • the compounds of general formula (III) will be preferably chosen from the compounds described (sometimes in the form of salts) in Examples 1 to 7, 9, 10, 24, 26 to 35, 52, 57, 61, 80, 82, 83, 85 to 87, 90, 94, 113, 115, 123, 127, 130, 132, 134, 138, 139, 147, 152, 154, 161, 164, 169, 171 to 173, 176 to 180, 203, 237 to 239, 243 to 247, 249, 251, 255, 258 to 262, 264 to 271, 273 to 275, 277 to 333 and 335 to 349, or the salts of these compounds.
  • the compounds of general formula (III) will be chosen from the compounds described (sometimes in the form of salts) in Examples 1, 3, 6, 7, 24, 26 to 35, 57, 61, 82, 83, 85 to 87, 94, 113, 123, 130, 132, 134, 138, 139, 152, 154, 164, 169, 171 to 173, 176 to 178, 203, 237 to 239, 243 to 247, 249, 255, 258, 259, 261, 262, 264 to 271, 273 to 275, 277 to 281, 283 to 288, 293 to 313, 321, 323, 324, 332 and 338 to 340, or the salts of these compounds.
  • the compounds according to the present invention can contain asymmetrical carbon atoms.
  • the compounds according to the present invention have two possible enantiomeric forms, i.e. the “R” and “S” configurations.
  • the present invention includes the two enantiomeric forms and all combinations of these forms, including the racemic “RS” mixtures.
  • RS racemic
  • the invention also relates to of the pharmaceutical compositions containing, as active ingredient, a compound of general formula (II) or a pharmaceutically acceptable salt of a compound general formula (II), as well as the use of the compounds of general formula (II) for preparing a medicament intended to inhibit the monoamine oxydases, in particular monoamine oxydase B, to inhibit lipidic peroxidation, to have a modulatory activity on the sodium channels or to have two of the three or all three aforementioned activities.
  • a compound of general formula (II) or a pharmaceutically acceptable salt of a compound general formula (II) as well as the use of the compounds of general formula (II) for preparing a medicament intended to inhibit the monoamine oxydases, in particular monoamine oxydase B, to inhibit lipidic peroxidation, to have a modulatory activity on the sodium channels or to have two of the three or all three aforementioned activities.
  • the invention relates moreover, as medicaments, to the compounds of general formula (III) or their pharmaceutically acceptable salts. Similarly it relates to the pharmaceutical compositions containing, as active ingredient, a compound of general formula (III) or a pharmaceutically acceptable salt of a compound of general formula (III), as well as to the use of the compounds of general formula (III) for preparing a medicament intended to inhibit monoamine oxydases, in particular monoamine oxydase B, to inhibit lipidic peroxidation, to have a modulatory activity on the sodium channels or to have two of the three or all three of the aforementioned activities.
  • the compounds of general formula (I), (II) or (III) can be used for preparing a medicament intended to treat one of the following disorders or one of the following diseases: Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, schizophrenia, depressions, psychoses, migraine or pains and in particular neuropathic pains.
  • salt in particular the addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.
  • inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate
  • organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.
  • bases such as sodium or potassium hydroxide.
  • Salt selection for basic drugs Int. J. Pharm . (1986), 33, 201-217.
  • the pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories.
  • Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
  • compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
  • Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, similarly their mixtures, in varying proportions, in water.
  • the administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
  • the administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used.
  • the compounds of general formula (I) can be prepared by the processes described below.
  • the compounds of general formula (I) can be prepared by the 8 synthesis routes illustrated below (Diagram 1) starting from the intermediates of general formula (IV), (V), (VI), (VII), (VIII), (IX), (X) and (I) ⁇ in which A, B, Q, R 1 , R 2 , Het and n are as defined above, L is a parting group such as for example a halogen, Alk is an alkyl radical, Gp is a protective group for an amine function, for example a 2-(trimethylsilyl)ethoxymethyl (SEM) group, and Gp′ a protective group for an alcohol function, for example a group of benzyl, acetate or also silyl type such as tert-butyldimethylsilyl, and finally A represents a bond or a —(CH 2 ) x —, —CO—(CH 2 ) x —, —(CH 2 ) y —O— or —C( ⁇ NH)—
  • the protected amines of general formula (IV) are accessible by a general synthesis route described in Biorg. and Med. Chem. Lett., 1993, 3, 915 and Tetrahedron Lett., 1993. 34, 1901 and more particularly in the PCT Patent Application WO 98/58934.
  • ⁇ represents an alkyl, cycloalkylalkyl, arylalkyl, aryl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl or hydroxyalkyl radical and ⁇ ′ represents an alkyl, cycloalkylalkyl, arylalkyl or aryl radical when g or k do not represent 0, or ⁇ ′ represents an alkyl, cycloalkylalkyl, arylalkyl radical or an aryl radical preferably deactivated (i.e.
  • a reducing agent such as sodium triacetoxyborohydride or sodium borohydride
  • a lower aliphatic alcohol such as methanol
  • the compounds of general formula (V) are converted to the corresponding compounds of general formula (I) by reaction with the halogenated derivatives of general formula (XI) in a solvent such as acetonitrile, dichloromethane or acetone and in the presence of a base such as for example triethylamine or potassium carbonate at a temperature comprised between ambient temperature and the reflux temperature of the solvent.
  • a solvent such as acetonitrile, dichloromethane or acetone
  • a base such as for example triethylamine or potassium carbonate
  • the derivatives of general formula (V) are in particular accessible by a general synthesis route described in Biorg. and Med. Chem. Lett., 1993, 3, 915 and Tetrahedron Lett., 1993. 34, 1901, and more particularly in the Patent Application WO 98/58934.
  • R 46 ⁇ H the compounds of general formula (V) can be prepared, for example, according to a protocol described in the Patent Application WO 98/58934 (using the appropriate amino acid in place of N—Boc-sarcosinamide).
  • R 47 represents a cycloalkyl radical
  • the amines of general formula (I), Diagram 3a, in which A, B, R 1 , R 2 , R 46 , Het and n are as defined above and i represents an integer from 0 to 4 are prepared by condensation of the amines of general formula (V) with the cycloalkylketones of general formula (XIV) in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium borohydride in a lower aliphatic alcohol such as methanol and optionally in the presence of molecular sieves at ambient temperature.
  • a reducing agent such as sodium triacetoxyborohydride or sodium borohydride in a lower aliphatic alcohol such as methanol
  • Route 3 Het is Oxazole or Thiazole, R 1 and R 2 are both H and ⁇ is OH.
  • the alcoholic derivatives of general formula (I), Diagram 4, in which A, B, Het and n are as defined above and R 1 and R 2 are hydrogen atoms are obtained by reduction of the acids or esters of general formula (VI) (accessible by a general synthesis route described in J. Med. Chem., 1996, 39, 237-245 and the PCT Patent Application WO 99/09829).
  • This reduction can, for example, be carried out by the action of boron hydride or lithium aluminium hydride or also diisobutylaluminium hydride in an aprotic polar solvent such as tetrahydrofuran.
  • Route 4 Het is Oxazole or Thiazole and ⁇ is NR 46 R 47 .
  • the amines of general formula (I), Diagram 5, in which A, B, R 1 , R 2 , R 46 , R 47 , Het, and n are as defined above, are prepared by condensation of the primary or secondary amines of general formula R 46 —NHR 47 with the compounds of general formula (VII) (in which L preferably represents a halogen atom Hal, but can also represent a mesylate or tosylate group) according to a general synthesis route described in J. Med. Chem., 1996, 39, 237-245 and the PCT Patent Application WO 99/09829 or the U.S. Pat. No. 4,123,529.
  • This synthesis route can in particular be used when R 46 and R 47 taken together form with the nitrogen atom which carries them a non-aromatic heterocycle with 4 to 8 members.
  • the reaction typically takes place in an anhydrous solvent (for example dimethylformamide, dichloromethane, tetrahydrofuran or acetone) in the presence of a base (for example Na 2 CO 3 or K 2 CO 3 in the presence of triethylamine), and preferably while heating.
  • Route 5 Het is Imidazole and ⁇ is a Radical of Carbamate Type
  • the acids of general formula (VIII) can be cyclized in the form of derivatives of imidazoles of general formula (I), Diagram 6, by the addition of caesium carbonate followed by a condensation with an ⁇ -halogenoketone of formula A-CO—CH(B)—[Br, Cl] followed by the addition of a large excess of ammonium acetate (for example 15 or 20 equivalents per equivalent of acid of general formula (VIII)).
  • This reaction is preferably carried out in a mixture of xylenes and while heating (one can also, if appropriate, simultaneously eliminate the water formed during the reaction).
  • Route 6 Het is Imidazole, Oxazole or Thiazole and ⁇ is NR 46 R 47
  • ⁇ is an NR 46 R 47 radical in which R 47 is a radical comprising a termination of aminophenylene, alkylaminophenylene or dialkylaminophenylene type
  • the compounds of general formula (I) in which A, B, Het, n, R 1 , R 2 and R 46 are as defined above and ⁇ represents a bond or a —(CH 2 ) x —, —CO—(CH 2 ) x —, —(CH 2 ) y —O— or —C( ⁇ NH)— radical, x and y being integers from 0 to 6, can be obtained
  • Diagram 7 by reduction of the compound of general formula (IX), for example by the action of hydrogen in the presence of a catalyst of palladium on carbon type in a solvent such as for example methanol, ethanol, dichloromethane or tetrahydrofuran.
  • Reduction of the nitro function can also be carried out, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl 2 ( J. Heterocyclic Chem . (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) or in the presence of SnCl 2 /Zn ( Synthesis . (1996), 9, 1076-1078), using NaBH 4 —BiCl 3 ( Synth. Com .
  • an appropriate solvent such as ethyl acetate with a little ethanol
  • SnCl 2 J. Heterocyclic Chem . (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842
  • SnCl 2 /Zn Synthesis . (1996), 9, 1076-1078
  • R 47 is a radical of aminophenylene, alkylaminophenylene or dialkylaminophenylene type (Alk and Alk′ are identical or different alkyl radicals)
  • the compound of general formula (IX) is reduced in order to produce the aniline derivative of general formula (I) and optionally mono- or di-alkylated according to standard reactions known to a person skilled in the art.
  • the mono-alkylation is carried out by reducing amination with an aldehyde or by a nucleophilic substitution by reaction with an equivalent of halogenoalkyl Alk-Hal.
  • a second alkylation can then be carried out if appropriate using a halogenoalkyl Alk′-Hal.
  • the deprotection can be carried out, for example, by adding tetra-tert-butylammonium fluoride in a solvent such as tetrahydrofuran.
  • a solvent such as for example methanol, ethanol, dichloromethane or tetrahydrofuran.
  • the deprotection can be carried out, for example, using sodium or potassium carbonate in an alcoholic solvent such as methanol.
  • a solvent such as dichloromethane, acetonitrile, anhydrous tetrahydrofuran or anhydrous ether
  • a base such as potassium or sodium carbonate, sodium hydride or triethylamine.
  • the acid of general formula (V.iii), in which Gp represents a protective group for an amine function, for example a protective group of carbamate type, is treated, Diagram 3.2, with Cs 2 CO 3 in a solvent such as methanol or ethanol.
  • the ⁇ -halogeno-ketone of general formula (V.ii) in an inert solvent such as dimethylformamide is added to the caesium salt recovered.
  • the intermediate ketoester is cyclized by heating to reflux in xylene (mixture of isomers) in the presence of a large excess of ammonium acetate (15 or 20 equivalents for example) in order to produce the imidazole derivative of general formula (V.iv) (the water formed being optionally eliminated during the reaction).
  • the protected amine function is then deprotected under standard conditions in a strong acid medium (for example: trifluoroacetic acid or HCl in an organic solvent when it is a protective group of carbamate type), releasing the amine of general formula (V).
  • a strong acid medium for example: trifluoroacetic acid or HCl in an organic solvent when it is a protective group of carbamate type
  • the indoline or tetrahydroquinoline (T represents —CH 2 — or —(CH 2 ) 2 —) is protected using chloroacetyl chloride in order to produce the compound of general formula (XVII) which is subjected to a Friedel-Crafts reaction (substituted chloroacetyl chloride of general formula (XVIII), in which B has the meaning, indicated previously, in a solvent such as carbon disulphide and in the presence of aluminium chloride) in order to produce the compound of general formula (XIX).
  • a Friedel-Crafts reaction substituted chloroacetyl chloride of general formula (XVIII), in which B has the meaning, indicated previously, in a solvent such as carbon disulphide and in the presence of aluminium chloride
  • the compound of general formula (XIX) is hydrolyzed in the presence of acid, for example an acetic acid/HCl mixture, in order to produce the compounds of general formula (V.ii) in the form of a mixture of meta and para isomers.
  • acid for example an acetic acid/HCl mixture
  • isomers can be separated by fractioned crystallization from a solvent such as glacial acetic acid.
  • a person skilled in the art will know how to adapt the syntheses described previously to the case where A represents an indolinyl or tetrahydroquinolyl radical in which R 33 does not represent H.
  • R 33 represents an alkyl or aralkyl radical, the protection and deprotection stages will be unnecessary.
  • the carbazole of general formula (XXIII) is protected using acetic anhydride in order to produce the compound of general formula (XXIV), which is subjected to a Friedel-Crafts reaction (substituted chloroacetyl chloride of general formula (XVIII) as defined previously in a solvent such as carbon disulphide and in the presence of aluminium chloride) in order to produce the compound of general formula (XXV).
  • a Friedel-Crafts reaction substituted chloroacetyl chloride of general formula (XVIII) as defined previously in a solvent such as carbon disulphide and in the presence of aluminium chloride
  • the acyl group protecting the amine function is hydrolyzed in the presence of acid, for example an AcOH/HCl mixture, in order to produce the compound of general formula (V.ii).
  • A represents a carbazolyl radical in which R 9 represents alkyl or a —COR 15 group (case not shown in Diagram 3.8)
  • the initial acylation stage is unnecessary and the last two stages of Diagram 3.8 allow the compounds of general formula (V.ii) to be obtained.
  • the intermediates of general formula (V.ii) in which A represents a phenothiazinyl radical can be prepared according to a protocol which is slightly modified with respect to that described for the phenothiazinyl radical in Arzneistoffmaschine (1962), 12, 48, which is summarized in Diagram 3.9 hereafter (see also the examples).
  • the phenothiazine of general formula (XXVI) is protected using chloroacetyl chloride in order to produce the compound of general formula (XXVII), which is then subjected to a Friedel-Crafts reaction (compound of general formula (XVIII) in a solvent such as carbon disulphide in the presence of aluminium chloride) in order to produce the compound of general formula (XXVIII).
  • the intermediates of general formula (V.i)a and (V.ii)a in which A represents a phenylaminophenyl radical can be prepared according to a protocol which is slightly modified with respect to that described for the phenylaminophenyl radical in Chem Ber . (1986), 119, 3165-3197. This protocol is summarized in Diagram 3.10 hereafter.
  • the compounds of general formula (V.i) are prepared from the compounds of general formula (XXXII) by a substitution reaction with a Grignard reagent, MeMgCl ( J. Het. Chem . (1990), 27, 1709-1712) or with MeLi ( J. Med. Chem . (1992), 35, 13).
  • a Grignard reagent MeMgCl ( J. Het. Chem . (1990), 27, 1709-1712) or with MeLi ( J. Med. Chem . (1992), 35, 13).
  • the bromoacetophenones of general formula (V.ii) are now accessible from the acetophenone of general formula (V.i) under previously described conditions.
  • the compound of general formula (V.ii) in which R 32 represents a hydrogen atom or an alkyl radical can be prepared according to a process in only 3 stages (cf. Diagram 3.12—see also the examples).
  • the bromination in the last stage of the compound of general formula (V.i) in order to produce the compound of general formula (V.ii) will preferably be carried out according to J. Am. Chem. Soc. (1999), 121, 24.
  • 2,6-diisopropylphenol is acetylated according to methods known to a person skilled in the art, for example by reacting it with acetic acid in the presence of trifluoroacetic acid anhydride or with acetyl chloride in the presence of a base such as for example K 2 CO 3 .
  • the acetylated homologue of 2,6-diisopropylphenol is then subjected to a Fries rearrangement in the presence of aluminium chloride in a solvent such as nitrobenzene in order to produce the compound of formula (V.i).
  • the compound of formula (V.i) is acetylated in order to produce the compound of formula (V.i)b.
  • the acids of general formula (XXXVI) are subjected to coupling with N,O-dimethylhydroxylamine ( Syn. Commun . (1995), 25, (8), 1255 ; Tetrahedron Lett . (1999), 40, (3), 411-414) in a solvent such as dimethylformamide or dichloromethane, in the presence of a base such as triethylamine with dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and hydroxybenzotriazol, in order to produce the intermediates of general formula (XXXVII).
  • a base such as triethylamine with dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and hydroxybenzotriazol
  • solvents such as ether or anhydrous tetrahydrofuran.
  • the protected amino acids of general formula (XXXVIII) are obtained by protection of the corresponding amino acids by a group of carbamate type according to methods known to a person skilled in the art.
  • the acids of general formula (XXXVIII) are then subjected to coupling with N,O-dimethylhydroxylamine ( Syn. Commun . (1995), 25, (8), 1255; Tetrahedron Lett .
  • the bromo or chloroacetophenones of general formula (V.vii) are now accessible from the acetophenone of general formula (XLI) under the conditions previously described.
  • the thiocarboxamides of general formula (V.v) can be obtained in three stages starting from the compounds of general formula (V.vi) as indicated in the Diagram 3.18 below.
  • the amine function of the amino acid of general formula (V.vi) is firstly protected under standard conditions with tBu-O—CO—Cl or (tBu-O—CO) 2 O (or other protective groups known to a person skilled in the art), then the intermediate obtained is converted to its corresponding amide by methods described in the literature (cf. for example, J. Chem. Soc., Perkin Trans. 1, (1998), 20, 3479-3484 or the PCT Patent Application WO 99/09829).
  • the carboxamide is converted to the thiocarboxamide of general formula (V.v), for example by reaction with Lawesson reagent in a solvent such as dioxane or tetrahydrofuran at a temperature preferably comprised between ambient temperature and the reflux temperature of the mixture, or also using (P 2 S 5 ) 2 under standard conditions for a person skilled in the art.
  • a solvent such as dioxane or tetrahydrofuran
  • the carboxamides of general formula (VII.ii) are treated under standard conditions in order to produce the thiocarboxamide of general formula (VII.iii), for example by Lawesson reagent or also using (P 2 S 5 ) 2 under standard conditions for a person skilled in the art.
  • the acid of general formula (VII.i) is activated by the action of 1,1′-carbonyldiimidazole then treated with methylamine in an aprotic polar solvent such as for example tetrahydrofuran.
  • the carboxamide intermediate obtained is converted to the thiocarboxamide of general formula (VI.i) under standard conditions, for example using Lawesson reagent or also using (P 2 S 5 ) 2 under standard conditions for a person skilled in the art.
  • the thiocarboxamide of general formula (VII.iii) or (VI.i) is then reacted with the compound of general formula (VI.ii), for example while heating at reflux in a solvent such as benzene, dioxane or dimethylformamide.
  • the ester of general formula (VI.iii) obtained can then be saponified by the action of a base such as for example potash in alcoholic medium or LiOH in tetrahydrofuran in order to produce the acid of general formula (VI).
  • the acids of general formula (VI) derived from oxazoles can be prepared according to a procedure represented in Diagram 4.2 below.
  • the carboxamides of general formula (VII.ii) are reacted with the compound of general formula (VI.ii) while heating, for example at reflux, in the absence or in the presence of a solvent such as dimethylformamide.
  • the ester of general formula (VI.iv) obtained can then be saponified by the action of a base such as for example potash in alcoholic medium or LiOH in tetrahydrofuran in order to produce the acid of general formula (VI).
  • the acids of general formula (VI) derived from isoxazolines can be prepared as follows: the commercial aldehydes of general formula (VI.v) are reacted with hydroxylamine hydrochloride.
  • the oxime of general formula (VI.vi) thus obtained is activated in the form of oxime chloride, of general formula (VI.vii), by reaction with N-chlorosuccinimide in DMF before reacting with the esters of general formula (VI.viii) (in which Alk represents an alkyl radical) in order to produce the isoxazoline derivatives according to an experimental protocol described in the literature ( Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084).
  • Saponification of the isoxazolines of general formula (VI.ix) is then carried out in a standard fashion (for example by the action of KOH in an alcoholic solvent or LiOH in a solvent such as tetrahydrofuran) in order to produce the acid derivative of general formula (VI).
  • the non-commercial unsaturated esters of general formula (VI.x) can be prepared according to the methods described in the literature ( J. Med. Chem., 1987, 30, 193; J. Org. Chem., 1980, 45, 5017).
  • the thiazoles of general formula (VII) intended for the preparation of compounds of general formula (I) 3 can be prepared according to the method summarized in Diagram 5.2.
  • the carboxamide of general formula (VII.ii) is converted to the corresponding thiocarboxamide of general formula (VII.iii) in the presence of Lawesson reagent in a solvent such as dioxane or benzene at a temperature preferably comprised between ambient temperature and that of reflux of the mixture.
  • the thiocarboxamide of general formula (VII.iii) is then treated with the ⁇ -halogenoketoester of general formula (VII.iv) in which Alk represents an alkyl radical (for example methyl, ethyl or tert-butyl), in order to produce the ester of general formula (VII.v), which is reduced to the corresponding alcohol of general formula (VII.vi), for example by the action of lithium aluminium hydride or diisobutylaluminium hydride in a solvent such as tetrahydrofuran.
  • Alk represents an alkyl radical (for example methyl, ethyl or tert-butyl)
  • the thiazoles of general formula (VII) intended for the preparation of compounds of general formula (I), can be prepared according to the method summarized in Diagram 5.3.
  • the cyano derivative of general formula (VII.vii) in which Gp′ is a protective group for an alcohol function (for example a benzyl or —CO- ⁇ group in which ⁇ represents alkyl, for example methyl or tert-butyl) is converted to the corresponding thiocarboxamide of general formula (VII.viii) by the action of H 2 S in a solvent such as ethanol in the presence of triethanolamine at a temperature preferably comprised between ambient temperature and that of reflux of the mixture.
  • the thiocarboxamide of general formula (VII.viii) is then treated with the ⁇ -halogenoketone of general formula (VII.ix) in order to produce the compound of general formula (VII.x), which is deprotected in order to produce the corresponding alcohol of general formula (VII.xi) according to methods known to a person skilled in the art (for example when Gp′ is a protective group of acetate type, this is removed in situ by the action of an aqueous solution of sodium carbonate).
  • the oxazoles of general formula (VII) intended for the preparation of compounds of general formula (I) 3 can be prepared according to the method summarized in Diagram 5.4.
  • the carboxamide of general formula (VII.ii) is treated with the ⁇ -halogenoketoester of general formula (VII.iv) in which Alk represents an alkyl radical (for example methyl, ethyl or tert-butyl), in order to produce the ester/acid of general formula (VII.xii).
  • R 1 and R 2 both represent H
  • the protected amino acids of general formula (VIII) are either commercial, or obtained by protection of commercial amino acids by a group of carbamate type according to the methods known to a person skilled in the art.
  • the expected product is obtained after chromatography on a silica column (eluent: 20% ethyl acetate in heptane) in the form of an oil which crystallizes very slowly in a refrigerator with a yield of 28%. Melting point: 126.5-127.3° C.
  • Example 8 0.8 ml of paraformaldehyde and 0.10 g of 20% palladium on carbon is added to a solution of 0.5 g (1.1 mmol) of Example 8 in 20 ml of ethanol. The medium is placed under hydrogen for 4 hours. The catalyst is filtered out and the solvent evaporated to dryness. The expected product is obtained after chromatography on a silica column (eluent: 3% ethanol in dichloromethane). The expected compound is obtained in the form of a brown oil with a yield of 54%.
  • the compound is produced according to an experimental protocol described in the Patent Application WO 98/58934 (see preparation of intermediates 26.1 and 26.2), using Z-Gly-NH 2 in place of the N—Boc sarcosinamide.
  • the expected compound is obtained in the form of a pale yellow oil with a yield of 99%.
  • Example 13 The experimental protocol used is identical to that described for Example 13, the compound of Example 14 being used as starting product in place of the compound of Example 12. A yellow gum is obtained with a yield of 83%.
  • Example 23 The compound of Example 23 can be obtained according to the procedures described in the PCT Patent Application WO 99/09829.
  • the compound of Example 23 is converted to brominated derivative, intermediate 3, according to the procedure indicated in Diagram 1(c) of the PCT Application WO 99/09829. Then the brominated derivative (0.5 g; 1.31 mmol) is added to a solution of N-methylpropargylamine 0.34 ml (3.94 mmol) and potassium carbonate (1.11 g) in dimethylformamide (20 ml). After overnight stirring at 80° C., the reaction mixture is concentrated under vacuum and the residue is diluted with dichloromethane and 50 ml of a saturated solution of NaCl. After stirring and decantation, the organic phase is separated and dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 50% ethyl acetate in heptane). After evaporation, the pure fractions produce a yellow oil with a yield of 24%.
  • a stream of HCl gas is passed bubblewise into a solution at 0° C. of intermediate 29.1 (0.450 g; 9.27 mmol) in ethyl acetate (30 ml). The mixture is left to return to ambient temperature overnight.
  • a stream of argon is passed through the reaction mass, then the powder obtained is filtered and washed with ethyl acetate then with ether in order to produce a white solid with a yield of 70%. Melting point: >200° C.
  • this compound can be obtained according to a similar method, but using 2-chloro-1-(10H-phenothiazin-2-yl)ethanone instead of 2-bromo-1-(10H-phenothiazin-2-yl)ethanone:
  • a solution containing ⁇ -alanine (8.9 g; 0.1 mol) and 100 ml of a 1N solution of sodium hydroxide is cooled down to 10° C.
  • n-butyl chloroformate (13.66 g; 0.1 mol) and 50 ml of a 2N solution of sodium hydroxide are added simultaneously.
  • approximately 10 ml of a solution of concentrated hydrochloric acid (approximately 11 N) is added in order to adjust the pH to 4-5.
  • the oil obtained is extracted with ethyl acetate (2 ⁇ 50 ml), washed with water then dried over magnesium sulphate.
  • the product crystallizes from isopentane in the form of a white powder (yield of 68%). Melting point: 50.5° C.
  • a mixture of N-(butoxycarbonyl)- ⁇ -alanine (prepared in Stage 31.1; 5.67 g; 0.03 mol) and caesium carbonate (4.89 g; 0.015 mol) in 100 ml of ethanol is stirred at 23° C. for 1 hour.
  • the ethanol is eliminated by evaporation under reduced pressure in a rotary evaporator.
  • the mixture obtained is dissolved in 100 ml of dimethylformamide then 4-phenyl-bromoacetophenone (8.26 g; 0.03 mol) is added. After stirring for 16 hours, the solvent is evaporated off under reduced pressure.
  • the mixture obtained is taken up in ethyl acetate then the caesium bromide is filtered.
  • the ethyl acetate of the filtrate is evaporated and the reaction oil is taken up in a mixture of xylene (100 ml) and ammonium acetate (46.2 g; 0.6 mol).
  • the reaction medium is heated at reflux for approximately one hour and 30 minutes then, after cooling down, a mixture of ice-cooled water and ethyl acetate is poured into the reaction medium.
  • the organic phase is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate then evaporated under vacuum.
  • the solid obtained is filtered then washed with ether in order to produce a light beige-coloured powder (yield of 50%). Melting point: 136.7° C.
  • tert-butyl 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate (4.8 g; 0.013 mol) is stirred in 120 ml of a solution of ethyl acetate saturated in hydrochloric acid for 2 hours 30 minutes at a temperature of 55° C.
  • the solid obtained is filtered and washed with ether.
  • a light beige-coloured powder is obtained with a yield of 89%.
  • a mixture containing valeric acid (0.24 ml; 0.002 mol), dicyclohexylcarbodiimide (2.2 ml; 1M solution in methylene chloride) and 1-hydroxybenzotriazole hydrate (336 mg; 0.0022 mol) in 15 ml of dimethylformamide (DMF) is stirred at 23° C. for thirty minutes.
  • the 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine prepared previously is added then the mixture is stirred for 48 hours at 23° C.
  • the dicyclohexylurea formed is filtered then the DMF is evaporated off under reduced pressure.
  • This compound is obtained according to an operating method similar to the preparation of the compound of Stage 31.2 of Example 31 using Boc-aminocyclohexylglycine (9.4 g; 0.036 mol) in place of the N-(butoxycarbonyl)- ⁇ -alanine and parafluorobromoacetophenone (7.9 g; 0.036 mol) in place of the 4-phenyl-bromoacetophenone.
  • Boc-aminocyclohexylglycine (9.4 g; 0.036 mol) in place of the N-(butoxycarbonyl)- ⁇ -alanine and parafluorobromoacetophenone (7.9 g; 0.036 mol) in place of the 4-phenyl-bromoacetophenone.
  • a white-coloured powder is obtained with a yield of 53%.
  • This compound is prepared according to an operating method similar to that of Stage 32.2 of Example 32 using tert-butyl(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methylcarbamate (7.5 g; 0.02 mol) as starting compound.
  • a white-coloured powder is obtained with a yield of 92%.
  • This compound is obtained according to an operating method similar to that of Stage 31.2 of Example 31, using 2-[(tert-butoxycarbonyl)amino]octanoic acid (8.1 g; 0.0314 mol) in place of the N-(butoxycarbonyl)- ⁇ -alanine and 2-bromo-1-cyclohexylethanone (6.4 g; 0.0314 mol) in place of the 4-phenyl-bromoacetophenone.
  • An oil is obtained which is sufficiently pure to be used in the following reaction (yield of 88%).
  • This compound is obtained according to an operating method similar to that of Stage 32.2 of Example 32 using as starting compound tert-butyl 1-(4-cyclohexyl-1H-imidazol-2-yl)heptylcarbamate (prepared in Stage 6.3; 10 g; 0.0275 mol).
  • a yellow solid is obtained in the form of a paste (yield of 37%).
  • This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine 1-(4-cyclohexyl-1H-imidazol-2-yl)-1-heptanamine (obtained in Stage 6.4; 2.5 g; 0.074 mol) and as ketone, cyclohexanone (1 ml; 0.0097 mol).
  • a silica column eluent: ethyl acetate—heptane/7-3 with CH 2 Cl 2 -MeOH/95-05
  • a white-coloured powder is obtained with a yield of 12%. Melting point: 172-174° C.
  • a solution of diisopropylamine (13.2 ml; 0.094 mol) in 130 ml of tetrahydrofuran (THF) is cooled down to ⁇ 40° C.
  • n-butyllithium 37 ml of a 2.5 M solution in hexane; 0.094 mol
  • the temperature is allowed to rise to 0° C.
  • Boc-glycine (5 g; 0.028 mol) in solution in 30 ml of THF is introduced into the mixture.
  • the reaction medium is left for ten minutes at this temperature then 1-bromo-4-methylpentane (7.9 ml; 0.056 mol) in solution in 20 ml of THF is added rapidly.
  • This compound is obtained according to an operating method similar to that of Stage 31.2 of Example 31 using 2-[(tert-butoxycarbonyl)amino]-6-methylheptanoic acid (3.5 g; 0.0135 mol) in place of the N-(butoxycarbonyl)- ⁇ -alanine and 3-bromophenacyl bromide (3.75 g; 0.0135 mol) in place of the 4-phenyl-bromoacetophenone.
  • a white powder is obtained with a yield of 63%. Melting point: 134-136° C.
  • This compound is obtained according to an operating method similar to that of Stage 32.2 of Example 32 using as starting compound tert-butyl 1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methylhexylcarbamate (obtained in Stage 37.2; 3.5 g; 0.008 mol).
  • a white-coloured powder is obtained with a yield of 97%. Melting point: 200-202° C.
  • This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine, 1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine (obtained in Stage 7.3; 0.8 g; 0.0019 mol) and as ketone, cyclohexanone (0.32 ml; 0.0023 mol).
  • a white-coloured powder is obtained with a yield of 38%. Melting point: 236-238° C.
  • This compound is obtained according to an operating method similar to that of Stage 31.2 of Example 31 using 2-[(tert-butoxycarbonyl)amino]octanoic acid (6.2 g; 0.024 mol) in place of the N-(butoxycarbonyl)- ⁇ -alanine and 2-bromo-4-fluoroacetophenone (5.2 g; 0.024 mol) in place of the 4-phenyl-bromoacetophenone.
  • a white powder is obtained (yield: 58%) which is sufficiently pure to be used as it is for the following stage.
  • This compound is obtained according to an operating method similar to that of Stage 32.2 of Example 32 using as starting compound tert-butyl 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]heptylcarbamate (5.2 g; 0.014 mol). After purification on a silica column (eluent: CH 2 Cl 2 -MeOH—NH 4 OH/89-10-1), a grey-coloured powder is obtained (yield of 72%). Melting point: 148-150° C.
  • This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine, 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-heptanamine (0.5 g; 0.0014 mol) and as ketone, cyclohexanone (0.17 ml; 0.0014 mol).
  • a white-coloured powder is obtained with a yield of 15%.
  • Triethylamine (0.83 ml; 0.006 mol) is added at 23° C. to a solution containing (1R)-1-(1-benzyl-4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethanamine (0.7 g; 0.002 mol; prepared under experimental conditions similar to those previously and using suitable starting reagents and reaction products) in 15 ml of acetonitrile. The mixture is stirred for one hour at 23° C. then benzyl chloride (0.23 ml; 0.002 mol) is added. Stirring is maintained for 16 hours.
  • the reaction mixture is concentrated using a rotary evaporator and the oil obtained is taken up in ethyl acetate and water.
  • the aqueous phase is extracted with ethyl acetate and washed with water then with a saturated solution of sodium chloride.
  • the solvents are evaporated off under vacuum.
  • a silica column eluent: AE-heptane/7-3
  • a deep beige-coloured solid is obtained in the form of a paste (yield of 5% c). Free base. Melting point: 60-62° C.
  • N-benzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine (1 g; 0.0024 mol; prepared under experimental conditions similar to those previously and using suitable starting reagents and reaction products) is diluted in 15 ml of dimethylformamide. Potassium carbonate (1 g; 0.0073 mol) is added at 23° C. then hexane bromide (0.34 ml; 0.0024 mol) is added fairly slowly. The reaction mixture is brought to about 70° C. for 3 hours before being poured into ice-cooled water. The mixture is extracted with ethyl acetate and the organic phase is washed with water.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Psychology (AREA)
  • Communicable Diseases (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Biochemistry (AREA)
  • AIDS & HIV (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Addiction (AREA)
  • Transplantation (AREA)
US11/256,901 1999-10-11 2005-10-24 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments Abandoned US20070021390A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/256,901 US20070021390A1 (en) 1999-10-11 2005-10-24 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US11/708,531 US20070179153A1 (en) 1999-10-11 2007-02-20 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
FR99/12643 1999-10-11
FR9912643A FR2799461B1 (fr) 1999-10-11 1999-10-11 Derives d'heterocycles a 5 chainons, leur preparation et leur application a titre de medicaments
FR0010151A FR2812546B1 (fr) 2000-08-01 2000-08-01 Derives d'heterocycles a 5 chainons, leur preparation et leur application a titre de medicaments
FR00/10151 2000-08-01
FR00/11169 2000-09-01
FR0011169 2000-09-01
PCT/FR2000/002805 WO2001026656A2 (fr) 1999-10-11 2000-10-10 Derives d'heterocycles a 5 chainons et leur application comme inhibiteurs de monoamine oxydase
US8999302A 2002-04-04 2002-04-04
US11/256,901 US20070021390A1 (en) 1999-10-11 2005-10-24 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/FR2000/002805 Division WO2001026656A2 (fr) 1999-10-11 2000-10-10 Derives d'heterocycles a 5 chainons et leur application comme inhibiteurs de monoamine oxydase
US8999302A Division 1999-10-11 2002-04-04

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/708,531 Division US20070179153A1 (en) 1999-10-11 2007-02-20 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Publications (1)

Publication Number Publication Date
US20070021390A1 true US20070021390A1 (en) 2007-01-25

Family

ID=27248695

Family Applications (4)

Application Number Title Priority Date Filing Date
US11/256,901 Abandoned US20070021390A1 (en) 1999-10-11 2005-10-24 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US11/708,531 Abandoned US20070179153A1 (en) 1999-10-11 2007-02-20 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US12/001,439 Expired - Fee Related US7956075B2 (en) 1999-10-11 2007-12-11 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US13/053,092 Expired - Fee Related US8288560B2 (en) 1999-10-11 2011-03-21 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11/708,531 Abandoned US20070179153A1 (en) 1999-10-11 2007-02-20 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US12/001,439 Expired - Fee Related US7956075B2 (en) 1999-10-11 2007-12-11 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US13/053,092 Expired - Fee Related US8288560B2 (en) 1999-10-11 2011-03-21 Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Country Status (27)

Country Link
US (4) US20070021390A1 (da)
EP (3) EP1223933B1 (da)
JP (1) JP4972263B2 (da)
KR (2) KR20070068491A (da)
CN (1) CN100488506C (da)
AR (1) AR029006A1 (da)
AT (2) ATE522213T1 (da)
AU (1) AU783129B2 (da)
BR (1) BR0014649A (da)
CA (1) CA2388505C (da)
CY (1) CY1106237T1 (da)
CZ (1) CZ304331B6 (da)
DE (1) DE60030574T2 (da)
DK (2) DK1223933T3 (da)
ES (2) ES2544856T3 (da)
HK (1) HK1049957B (da)
HU (1) HU228254B1 (da)
IL (3) IL148896A0 (da)
MX (1) MXPA02003665A (da)
MY (1) MY145388A (da)
NO (1) NO331874B1 (da)
NZ (2) NZ518304A (da)
PL (1) PL215580B1 (da)
PT (2) PT1589007E (da)
RU (1) RU2271355C2 (da)
TW (2) TWI283577B (da)
WO (1) WO2001026656A2 (da)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070185174A1 (en) * 2001-07-26 2007-08-09 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Use of thiazole derivatives for preparing a medicament intended to protect the mitochondria
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2823208B1 (fr) * 2001-04-10 2004-03-19 Sod Conseils Rech Applic Derives d'heterocycles a 5 chainons, leur preparation et leur application a titre de medicaments
US7291641B2 (en) * 1999-10-11 2007-11-06 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
TWI283577B (en) * 1999-10-11 2007-07-11 Sod Conseils Rech Applic Pharmaceutical composition of imidazole derivatives acting as modulators of sodium channels and the use thereof
FR2818978B1 (fr) * 2000-12-28 2003-02-28 Sod Conseils Rech Applic Modulateurs de canaux sodiques derives de 2-piperidylimidazoles
TWI248438B (en) * 2001-04-10 2006-02-01 Sod Conseils Rech Applic Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
FR2825926A1 (fr) 2001-06-14 2002-12-20 Sod Conseils Rech Applic Derives d'imidazoles modulant les canaux sodiques
WO2003026632A2 (en) * 2001-09-26 2003-04-03 Theravance, Inc. Substituted phenol compounds useful for anesthesia and sedation
EP1443930A1 (en) 2001-10-25 2004-08-11 AstraZeneca AB Isoxazoline derivatives useful as antimicrobials
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
FR2835254B1 (fr) * 2002-01-25 2006-04-07 Sod Conseils Rech Applic Derives de thiazoles dans le traitement de maladies neurologiques
FR2842808B1 (fr) * 2002-07-25 2004-09-10 Sod Conseils Rech Applic Nouveaux derives d'arylimidazoles, leur preparation et leurs applications therapeutiques
WO2004014881A2 (en) 2002-08-09 2004-02-19 Astra Zeneca Ab '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5
MXPA05001592A (es) * 2002-08-09 2005-05-05 Astrazeneca Ab Oxadiazoles como moduladores de receptor-5 de glutamato metabotropico.
CA2495179A1 (en) 2002-08-09 2004-02-19 Astrazeneca Ab Compounds having an activity at metabotropic glutamate receptors
US20040186151A1 (en) * 2003-02-12 2004-09-23 Mjalli Adnan M.M. Substituted azole derivatives as therapeutic agents
WO2004089918A1 (ja) * 2003-04-09 2004-10-21 Japan Tobacco Inc. 複素芳香５員環化合物及びその医薬用途
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
US7446127B2 (en) 2003-08-27 2008-11-04 Sk Holdings Co, Ltd. Chroman carboxylic acid derivatives for the treatment of diabetes and lipid disorders
EP1533295A1 (en) * 2003-11-24 2005-05-25 Newron Pharmaceuticals S.p.A. Cyclopentyl Derivatives
EP2520290B1 (en) * 2003-12-23 2014-12-10 Abraxis BioScience, LLC Propofol analogs, process for their preparation, and methods of use
US7453002B2 (en) 2004-06-15 2008-11-18 Bristol-Myers Squibb Company Five-membered heterocycles useful as serine protease inhibitors
MXPA06014909A (es) 2004-06-18 2007-02-28 Chiron Corp Derivados de n-(1-(1-bencil -4-fenil-1h -imidazol -2-il)-2, 2-dimetilpropil) benzamida y compuestos relacionados como inhibidores de proteina de huso de cinesina (ksp) para el tratamiento del cancer.
JP5197014B2 (ja) * 2004-12-10 2013-05-15 イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・エルレ・エルレ ヒストンデアセチラーゼ（ｈｄａｃ）阻害剤としての複素環誘導体
EP1841426B1 (en) * 2005-01-19 2011-04-27 Merck Sharp & Dohme Corp. Tertiary carbinamines having substituted heterocycles, which are active as inhibitors of beta-secretase, for the treatment of alzheimer's disease
FR2888116A1 (fr) * 2005-07-08 2007-01-12 Sod Conseils Rech Applic Derives de thiazoles pour traiter les dyskinesies
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
ATE554085T1 (de) 2006-11-30 2012-05-15 Probiodrug Ag Neue inhibitoren von glutaminylcyclase
CN101622247A (zh) 2007-01-05 2010-01-06 诺瓦提斯公司 作为驱动蛋白纺锤体蛋白抑制剂的咪唑衍生物
TW200848417A (en) * 2007-02-22 2008-12-16 Organon Nv Indole derivatives
EP2117540A1 (en) 2007-03-01 2009-11-18 Probiodrug AG New use of glutaminyl cyclase inhibitors
JP5138708B2 (ja) * 2007-03-05 2013-02-06 エフ．ホフマン−ラ ロシュ アーゲー オレキシンアンタゴニストとしてのアミノアミド
JP5667440B2 (ja) 2007-04-18 2015-02-12 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体
EP2105163B1 (de) * 2008-03-28 2011-06-08 MagForce Nanotechnologies AG Magnetwechselfeld-Applikationsvorrichtung zur Aufheizung von magnetischen oder magnetisierbaren Substanzen in biologischem Gewebe
US20110190356A1 (en) * 2008-08-19 2011-08-04 Knopp Neurosciences Inc. Compositions and Methods of Using (R)- Pramipexole
GB0822486D0 (en) * 2008-12-10 2009-01-14 Univ Liverpool Compounds for use in the treatment of pain
KR101220182B1 (ko) * 2009-02-25 2013-01-11 에스케이바이오팜 주식회사 치환된 아졸 유도체 화합물, 이를 포함하는 약제학적 조성물 및 이를 이용한 파킨슨씨 병 치료방법
SG178953A1 (en) 2009-09-11 2012-04-27 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
AU2011226074B2 (en) 2010-03-10 2015-01-22 Vivoryon Therapeutics N.V. Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
US8541596B2 (en) 2010-04-21 2013-09-24 Probiodrug Ag Inhibitors
ES2570167T3 (es) 2011-03-16 2016-05-17 Probiodrug Ag Derivados de benzimidazol como inhibidores de glutaminil ciclasa
RU2506082C2 (ru) * 2011-05-24 2014-02-10 Государственное учебно-научное учреждение Химический факультет Московского государственного университета им. М.В. Ломоносова Антигипотоническое средство
PE20141682A1 (es) * 2011-10-26 2014-11-14 Pfizer Ltd Derivados de (4-fenilimidazol-2-il) etilamina utiles como moduladores de canal de sodio
WO2013096816A1 (en) 2011-12-22 2013-06-27 Biogen Idec Ma Inc. Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
WO2013131018A1 (en) * 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Biaryl inhibitors of the sodium channel
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
LT3019167T (lt) 2013-07-12 2021-03-25 Knopp Biosciences Llc Eozinofilų ir (arba) bazofilų padidintų kiekių gydymas
AU2014306597B2 (en) 2013-08-13 2018-05-17 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
EP3038467B1 (en) 2013-08-13 2020-07-29 Knopp Biosciences LLC Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa
US20230265242A1 (en) * 2020-07-15 2023-08-24 Board Of Trustees Of Michigan State University Compositions and related methods for closed-loop recycling of polyesters

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR4231E (fr) 1905-08-25 Francisque Voland Disposition nouvelle de métier à tisser, en vue de l'obtention d'un tissu biaisé
US1743083A (en) * 1928-02-03 1930-01-07 Winthrop Chem Co Catechol thiazoles and process of making the same
FR2132632A1 (en) * 1971-04-07 1972-11-24 Berlin Chemie Veb Prepn of 2-aminomethyl imidazole derivs - hypotensives mao inhibitors anticonvulsant s, antiphlogistics, choleretics and ant
US4123529A (en) 1976-04-23 1978-10-31 Lilly Industries Limited Phenylpiperazine derivatives
DE2702714A1 (de) 1977-01-24 1978-07-27 Lek Tovarna Farmacevtskih Verfahren zur herstellung von phenothiazin-derivaten
US4348404A (en) * 1980-07-21 1982-09-07 E. I. Du Pont De Nemours And Company Antiinflammatory 4,5-diaryl-α-polyfluoroalkyl-1H-imidazole-2-methanamines
US4372964A (en) * 1980-10-30 1983-02-08 E. I. Du Pont De Nemours And Company Antiinflammatory 4,5-diaryl-1H-imidazole-2-methanols
JPS62132871A (ja) * 1985-12-03 1987-06-16 Yamanouchi Pharmaceut Co Ltd 新規チアゾ−ル誘導体
JP3003148B2 (ja) * 1989-01-05 2000-01-24 藤沢薬品工業株式会社 チアゾール化合物、その製造法およびそれを含有する医薬組成物
EP0388909A3 (en) * 1989-03-22 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same
DE3941438A1 (de) * 1989-12-15 1991-06-20 Hoechst Ag Neue 2-substituierte 4-(3-alkyl-5-tert.-butyl-4-hydroxy-phenyl)-thiazole, verfahren zu ihrer herstellung, die sie enthaltenden arzneimittel und ihre verwendung
GB9204958D0 (en) * 1992-03-06 1992-04-22 Fujisawa Pharmaceutical Co Thiazole derivatives
WO1996000730A1 (en) * 1994-06-29 1996-01-11 Smithkline Beecham Corporation Vitronectin receptor antagonists
US5620999A (en) * 1994-07-28 1997-04-15 Weier; Richard M. Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation
JP2941950B2 (ja) * 1994-11-23 1999-08-30 ニューロゲン コーポレイション 或る種の４−アミノメチル−２−置換イミダゾール誘導体および２−アミノメチル−４−置換イミダゾール誘導体；新規な種類のドーパミン リセプタ亜型特異性リガンド
FR2727969B1 (fr) * 1994-12-09 1997-01-17 Roussel Uclaf Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
US6156748A (en) * 1996-10-07 2000-12-05 Eli Lilly And Company Compounds useful as neuro-protective agents
JP2001505585A (ja) 1996-12-16 2001-04-24 藤沢薬品工業株式会社 新規アミド化合物およびそれらの一酸化窒素シンターゼ阻害剤としての用途
US6335445B1 (en) * 1997-03-24 2002-01-01 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
FR2764889B1 (fr) * 1997-06-20 2000-09-01 Sod Conseils Rech Applic Nouveaux derives du 2-(iminomethyl)amino-phenyle, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant
JP2001513532A (ja) * 1997-08-28 2001-09-04 イーライ・リリー・アンド・カンパニー 痛みを処置するための方法
TR200001750T2 (tr) * 1997-10-06 2001-01-22 Eli Lilly And Company Nöro-koruyucu maddeler olarak yararlı yeni bileşikler.
CA2335339A1 (en) * 1998-06-12 1999-12-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R .beta.-carboline compounds
DK1086086T3 (da) 1998-06-12 2005-01-24 Sod Conseils Rech Applic Imidazolylderivater og anvendelse deraf som somatostatinreceptorligander
CZ20012358A3 (cs) * 1998-12-31 2002-01-16 Societe De Conseils De Recherches Et D´Application Prenyltransferázové inhibitory
CN1353605A (zh) * 1999-03-26 2002-06-12 欧洲凯尔特股份有限公司 芳基取代的吡唑、咪唑、噁唑、噻唑和吡咯及其应用
TWI283577B (en) * 1999-10-11 2007-07-11 Sod Conseils Rech Applic Pharmaceutical composition of imidazole derivatives acting as modulators of sodium channels and the use thereof
ES2275619T3 (es) * 2000-12-20 2007-06-16 Astrazeneca Ab Quetiapina para el tratamiento de discinesia en pacientes no psicoticos.
TWI248438B (en) 2001-04-10 2006-02-01 Sod Conseils Rech Applic Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070185174A1 (en) * 2001-07-26 2007-08-09 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Use of thiazole derivatives for preparing a medicament intended to protect the mitochondria
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof

Also Published As

Publication number Publication date
NZ518304A (en) 2004-07-30
MY145388A (en) 2012-01-31
HUP0203841A2 (en) 2003-05-28
WO2001026656A2 (fr) 2001-04-19
US20080146627A1 (en) 2008-06-19
HK1049957B (zh) 2009-08-28
US20070179153A1 (en) 2007-08-02
HUP0203841A3 (en) 2003-07-28
DK1223933T3 (da) 2007-01-15
EP1228760A2 (fr) 2002-08-07
US7956075B2 (en) 2011-06-07
PL355147A1 (en) 2004-04-05
CN1391474A (zh) 2003-01-15
IL185118A0 (en) 2007-12-03
EP1223933B1 (fr) 2006-09-06
EP1228760A3 (fr) 2004-01-28
NO331874B1 (no) 2012-04-23
KR100731698B1 (ko) 2007-06-25
IL148896A0 (en) 2002-09-12
DK1589007T3 (da) 2015-08-10
HU228254B1 (en) 2013-02-28
ES2544856T3 (es) 2015-09-04
KR20070068491A (ko) 2007-06-29
JP4972263B2 (ja) 2012-07-11
EP1589007A2 (fr) 2005-10-26
CA2388505C (fr) 2013-03-12
PT1589007E (pt) 2015-10-12
DE60030574D1 (de) 2006-10-19
AR029006A1 (es) 2003-06-04
EP1228760B1 (fr) 2011-08-31
US20110172434A1 (en) 2011-07-14
US8288560B2 (en) 2012-10-16
AU7796500A (en) 2001-04-23
TW200509916A (en) 2005-03-16
IL148896A (en) 2009-02-11
CZ20021292A3 (cs) 2002-10-16
AU783129B2 (en) 2005-09-29
NO20021689L (no) 2002-05-30
DE60030574T2 (de) 2007-09-20
PT1223933E (pt) 2006-12-29
TWI283577B (en) 2007-07-11
RU2002112227A (ru) 2004-01-27
KR20020060195A (ko) 2002-07-16
EP1589007B1 (fr) 2015-06-03
CA2388505A1 (fr) 2001-04-19
WO2001026656A3 (fr) 2002-04-18
HK1049957A1 (en) 2003-06-06
CY1106237T1 (el) 2011-06-08
JP2003511416A (ja) 2003-03-25
RU2271355C2 (ru) 2006-03-10
ATE338547T1 (de) 2006-09-15
ES2270873T3 (es) 2007-04-16
ATE522213T1 (de) 2011-09-15
CZ304331B6 (cs) 2014-03-05
EP1223933A2 (fr) 2002-07-24
CN100488506C (zh) 2009-05-20
EP1589007A3 (fr) 2009-04-29
MXPA02003665A (es) 2003-10-14
NZ533429A (en) 2004-09-24
TWI292316B (en) 2008-01-11
BR0014649A (pt) 2002-06-18
NO20021689D0 (no) 2002-04-10
PL215580B1 (pl) 2013-12-31

Similar Documents

Publication Publication Date Title
US20070021390A1 (en) Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US7291641B2 (en) Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
US20040132788A1 (en) Derivatives of heterocycles with 5 members, their preparation and their use as medicaments
RU2288224C2 (ru) Производные 5-членных гетероциклов, их получение и применение в качестве лекарственных средств
ES2370274T3 (es) Derivados de heterociclos de 5 miembros, su preparación y su aplicación como medicamentos.
KR100822085B1 (ko) 5-원 헤테로사이클 유도체, 이의 제조 방법 및의약으로서의 이의 용도
RU2380362C2 (ru) Производные пятичленных гетероциклов, способ их получения и их применение в качестве лекарственных средств
FR2812546A1 (fr) Derives d'heterocycles a 5 chainons, leur preparation et leur application a titre de medicaments

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION