[go: up one dir, main page]

EP1421077A2 - Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides - Google Patents

Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides

Info

Publication number
EP1421077A2
EP1421077A2 EP02768751A EP02768751A EP1421077A2 EP 1421077 A2 EP1421077 A2 EP 1421077A2 EP 02768751 A EP02768751 A EP 02768751A EP 02768751 A EP02768751 A EP 02768751A EP 1421077 A2 EP1421077 A2 EP 1421077A2
Authority
EP
European Patent Office
Prior art keywords
ring
group
members
alkyl
substituted
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.)
Withdrawn
Application number
EP02768751A
Other languages
German (de)
English (en)
Other versions
EP1421077A4 (fr
Inventor
Alexandros Makriyannis
Qian Liu
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.)
University of Connecticut
Original Assignee
University of Connecticut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Connecticut filed Critical University of Connecticut
Publication of EP1421077A2 publication Critical patent/EP1421077A2/fr
Publication of EP1421077A4 publication Critical patent/EP1421077A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/06—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
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/10—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 aromatic rings
    • 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
    • C07D409/10—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 aromatic rings

Definitions

  • the present invention relates generally to biologically active pyrazole analogs capable of interacting with the CB1 and/or the CB2 cannabinoid receptors.
  • One aspect of the invention is concerned with new and improved pyrazole analogs acting as antagonists for the CB1 and/or the CB2 receptors.
  • Another aspect of the invention is concerned with new and improved pyrazole analogs having selectivity for the CB1 or CB2 cannabinoid receptor.
  • Still other aspects of the invention are concerned with pharmaceutical preparations employing the inventive analogs and methods of administering therapeutically effective amounts of the inventive analogs to provide a physiological effect.
  • CB1 a central receptor found in the mammalian brain and a number of other sites in peripheral tissues
  • CB2 a peripheral receptor found principally in cells related to the immune system.
  • the CB1 receptor is believed to mediate the psychoactive properties associated with classical cannabinoids. Characterization of these receptors has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 and CP 55,940.
  • cannabinoids such as ⁇ 9 -
  • THC also affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non- receptor mediated brain function.
  • the addictive and psychotropic properties of some cannabinoids also limit their therapeutic value.
  • U.S. Patent No. 6,028,084 describes some pyrazole derivatives alleged to have binding affinity for the central cannabinoid receptor.
  • International Publication Number WO 01/29007A1 also describes some pyrazole derivatives having binding affinity for cannabinoid receptors.
  • the pharmacological effects of cannabinoi ⁇ s 1 pertain ' f ⁇ "'variety r orarea's such as the central nervous system, the cardiovascular system, the immune system and/or endocrine system.
  • CB2 cannabinoid receptors are useful as agents: acting on the central nervous system and in a variety of other roles.
  • one aspect of the invention is concerned with new and improved cannabimimetic (cannabinoid like) pyrazole analogs.
  • inventive cannabimimetic pyrazole ligands of this aspect can be represented by general formula I:
  • R1 comprises -(CH 2 ) n -Z.
  • n is an integer from 0 to about 7.
  • Z comprises H, halogen, N 3 , NCS, CN, NO 2 , NX ⁇ X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 )nOH, OCChHNXiX;,, NH-acyl, NH-aroyl, CHO, CF 3 , COOX 3) SO 3 H, SO 2 NX 1 X 2 , CONX ⁇ X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • X ⁇ ⁇ and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ X 2 .
  • n is an integer from 0 to about 6.
  • R1 comprises -(CH 2 ) n -Z.
  • n is an integer from 0 to about 7.
  • Z comprises a carbocyclic ring having ab ⁇ ut ⁇ 4 to' abbuW'Hng mefrfbe ' rs ' , " i heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotri cyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group
  • R1 comprises -(CH 2 ) n -Z.
  • n is an integer from 0 to about 7.
  • Z comprises a 5 member unsaturated ring having 0 to 2 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 2 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 3 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 3 independently selected heteroatoms; and wherein the connecting point between the -(CH 2 )n- group and the
  • Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R1 comprises -(CH 2 ) n -Z.
  • n is an integer from 0 to about 7.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring
  • X and Y each independently comprise H, halogen, N 3 , NCS,
  • CN NO 2> NXiXs, OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF 3> COOX 3 , SO3H, SO 2 NX ⁇ X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • Xi and X 2 each independently comprise H or alkyl, or
  • Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX-
  • R1 comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having from
  • a heteroaromatic ring having about 5 to about 7 members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • R2 comprises — G
  • G comprises CH or N
  • L and J each independently comprise (CH ) n , O, NH or S.
  • n is an integer from 0 to about 7.
  • R2 comprises — ⁇ j
  • G, L and J each independently comprise CH or N.
  • R2 comprises
  • X and Y each independently comprise H, halogen, N 3 , NCS, Ph, CN,
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring naving about 5 to about 6 members).
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX 1 X 2 .
  • R2 comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having from
  • R3 comprises H, halogen, N 3 , NCS, Ph, CN, NO 2 , NX ⁇ X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) n OH, 0(CH 2 )nNX ⁇ X 2 , NH-acyl, NH-aroyl, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX ⁇ X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, or alkylsulfonyl.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members).
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX 1 X 2 .
  • n is an integer from 0 to about 6.
  • R3 comprises a carbocyclic ring having about
  • R3 comprises
  • R3 comprises -CH 2 -Z.
  • Z comprises H, halogen, N 3 , NCS, Ph, CN, NO 2 , NX ⁇ , OX 3) OAc, O-acyl, O- aroyl, O(CH 2 ) n OH, O(CH 2 ) ⁇ NX ⁇ X 2 , NH-acyl, NH-aroyl, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX ⁇ X 2 , CONX1X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, or alkylsulfonyl.
  • Xi and X 2 each independently comprise H or alkyl, or
  • Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • Xi and X2 together comprise part of an imide ring having about 5 to about 6 members).
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX 1 X 2 .
  • n is an integer from 0 to about 6.
  • R3 comprises -CH 2 OH or -CH 2 Oalkyl.
  • R3 comprises -CH 2 -Z.
  • Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring or a heterotricyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or
  • R3 comprises -CH 2 -Z.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R3 comprises -CH 2 -Q-(CH 2 )n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises H, halogen, N 3 , NCS, Ph, CN, NO 2 , NX ⁇ X 2 , OX 3 , OAc, O-acyl, O- aroyl, NH-acyl, NH-aroyl, O(CH 2 ) n OH, O(CH 2 ) n NX.,X 2 , CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, or alkylsulfonyl.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ X 2 .
  • n is an integer from 0 to about 6.
  • R3 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R3 comprises -CH 2 -Q-(CH 2 ) ⁇ -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R3 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises
  • X and Y each independently comprise H, halogen, N 3 , NCS, CN, NO 2 , NXiXz, OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF 3 , alcohol, COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino, alkylsulfinyl, alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX-
  • R4 comprises -(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises H, halogen, N 3 , NCS, CN, NO 2 , NX ⁇ , OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, O(CH 2 ) n OH, O(CH 2 )nNX ⁇ X 2 , CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX ⁇ X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino alkylsulfinyl, or alkylsulfonyl.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ .
  • n is an integer from 0 to about 6.
  • R4 comprises -(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ing ' having " arJ ⁇ ut 5 ' to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen
  • R4 comprises -(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R4 comprises -(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises
  • X and Y each independently comprise H, halogen, N 3 , NCS, CN, NO 2 , NXiXs, OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 JX 1 X 2 , CONXiX 2) alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ X 2 ,
  • R4 comprises -(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members.
  • R4 comprises -CH 2 -Q-(CH 2 )n-Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises H, halogen, N 3 , NCS, CN, NO 2> NX ⁇ X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) n OH, 0(CH 2 ) n NX 1 X 2 , NH-acyl, NH-aroyl, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX ⁇ X 2 , CONX ⁇ X 2l alkoxy, alkylmercapto, alkylamino or di-alkylamino.
  • Xi and X 2 each independently comprise H or alkyl, or
  • Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX 1 X 2 .
  • n is an integer from 0 to about 6.
  • R4 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • R4 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R4 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R4 comprises -CH 2 -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises
  • X and Y each independently comprise H, halogen, N 3 , NCS, CN, NO 2 , NXiXs, OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF 3 , alcohol, COOX 3 , SO 3 H, SO 2 NX 1 X 2) CONX ⁇ X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino, alkylsulfinyl, alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • R4 comprises -(CH 2 ) n -Q-(CH 2 ) n -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n comprises an integer from 0 to about 7.
  • Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members.
  • R4 comprises -CH 2 -Q ' -(CH 2 ] ⁇ -Z.
  • Q comprises N, O, S, CH 3 , SO 2 or OSO 2 .
  • n is an integer from 0 to about 7.
  • Z comprises
  • R4 comprises -T-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • Z comprises H, halogen, N 3 , NCS, CN, NO 2 , NX ⁇ X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) n OH, NH-acyl, NH-aroyl, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX1X2, alkoxy, alkylmercapto, alkylamino or di-alkylamino alkylsulfinyl, or alkylsulfonyl.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ X 2 .
  • n is an integer from 0 to about 6.
  • R4 comprises -T-(CH 2 ) ⁇ -Z.
  • n comprises an integer from 0 to about 7.
  • T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R4 comprises -T-(CH 2 )n-Z.
  • n comprises an integer from 0 to about 7.
  • T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by a lower-alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH 2 ) n - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom.
  • R4 comprises -T-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • X and Y each independently comprise H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF 3 , COOX 3 , SO 3 H, SO 2 NX ⁇ X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di- alkylamino, alkylsulfinyl, alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • Xi and X 2 each independently comprise H or alkyl, or Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • X 1 and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX-
  • R4 comprises -T-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
  • Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members.
  • R4 comprises -Ph-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl,
  • O-aroyl O(CH 2 ) n OH, O(CH 2 ) n NX ⁇ X 2 , NH-acyl, NH-aroyl, CHO, CF 3> COOX 3> SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino.
  • X-i and X 2 each independently comprise H or alkyl, or X-i and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X 3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX 1 X 2 .
  • n is an integer from 0 to about 6.
  • R4 comprises -Ph-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises
  • X and Y each independently comprise H, halogen, N 3 , NCS, CN, NO 2 , NX Xz, OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF 3l alcohol, COOX 3 , SO 3 H, SO NX 1 X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino or di-alkylamino, alkylsulfinyl, lower-alkylsulfonyl, or methylene dioxy when Z comprises a structure having two adjacent carbon atoms.
  • Xi and X 2 each independently comprise H or alkyl, or
  • Xi and X 2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
  • Xi and X2 together comprise part of an imide ring having about 5 to about 6 members.
  • X comprises H, alkyl, hydroxyloweralkyl, or alkyl-NX ⁇ X 2 .
  • R4 comprises -Ph-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises or — N N-E
  • E comprises a C1 to about C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group.
  • R4 comprises -Ph-(CH 2 ) n -Z.
  • n comprises an integer from 0 to about 7.
  • Z comprises
  • Ai and A 2 each independently comprise a C1 to about C4 alkyl group, a phenyl group or a substituted phenyl group.
  • R5 comprises H, alkyl or substituted alkyl.
  • compositions of the invention may be alternately formulated to comprise, consist of, or consist essentially of, any appropriate components herein disclosed.
  • compositions of the invention may additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any components, materials, ingredients, adjuvants or species used in the prior art compositions or that are otherw ise not necessary to the achievement of the function and/or objectives of the present invention.
  • acyl refers to the general formula -C(O)alkyl.
  • acyloxy refers to the general formula -O-acyl.
  • alcohol refers to the general formula alkyl-OH and includes primary, secondary and tertiary variations.
  • alkyl or “lower alkyl” refers to a linear, branched or cyclic alkyl group having from 1 to about 16 carbon atoms including, for example, methyl, ethyl, propyl, butyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclooctyl, vinyl and allyl.
  • the alkyl group can be saturated or unsaturated.
  • the alkyl group can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • a cyclic alkyl group includes monocyclic, bicyclic, tricyclic, tetracyciic ana polycyclic rings, for example norDornyl, adamantyl and related terpenes.
  • alkoxy refers to the general formula -O-alkyl.
  • alkylmercapto refers to the general formula -S-alkyl.
  • alkylamino refers to the general formula -(NH)-alkyl.
  • di-alkylamino refers to the general formula -N-(alkyl) 2 . Unless otherwise specifically limited di-alkylamino includes cyclic amine compounds such as piperidine and morpholine.
  • an aromatic ring is an unsaturated ring structure having about 5 to about 7 ring members and including only carbon as ring atoms.
  • the aromatic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • aryl refers to an aromatic ring system that includes only carbon as ring atoms, for example phenyl, biphenyl or napthyl.
  • the aryl group can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • aroyl refers to the general formula
  • a bicyclic ring structure comprises 2 fused rings that include only carbon as ring atoms.
  • the bicyclic ring structure can be saturated or unsaturated.
  • the bicyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • the individual rings may or may not be of the same type.
  • Examples of bicyclic ring structures include naphthalene and bicyclooctane.
  • a carbocyclic ring is a non-aromatic ring structure, saturated or unsaturated, having about 3 to about 8 ring members that includes only carbon as ring atoms, for example, benzene or cyclohexane.
  • the carbocyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • a heteroaromatic ring is an unsaturated ring structure having about 5 to about 8 ring members independently selected from carbon atoms and one or more heteroatoms, including oxygen, nitrogen and/or sulfur, for example, pyridine, furan, quinoline, and their derivatives.
  • the heteroaromatic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • a heterobicyclic ring structure comprises 2 fused rings having ring members independently selected from carbon and one or more heteroatoms, including oxygen, nitrogen and/or sulfur.
  • the heterobicyclic ring structure is typically unsaturated.
  • the heterobicyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • the individual rings may or may not be of the same type. Examples of heterobicyclic ring structures include isobenzofuran and indole.
  • a heterocyclic ring is a saturated ring structure having about 3 to about 8 ring members independently selected from carbon atoms and one or more heteroatoms, including oxygen, nitrogen and/or sulfur; for example, piperidine, morpholine, piperazine, pyrrolidine, thiomorpholine, and their derivatives.
  • the heterocyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • a heterotricyclic ring structure comprises
  • heterotricyclic ring structure is typically unsaturated.
  • the heterotricyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • the individual rings may or may not be of the same type.
  • heterotricyclic ring structures include carbazole, phenanthroline and phenazine.
  • a heteropolycyclic ring structure comprises more than 3 fused rings having ring members independently selected from carbon and one or more heteroatoms, including oxygen, nitrogen and/or sulfur.
  • the heteropolycyclic ring structure is typically unsaturated.
  • the heteropolycyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • the individual rings may or may not be of the same type.
  • Examples of heteropolycyclic ring structures include azaadamantine, tropane and homotroapane.
  • phenacyl refers to the general formula -phenyl-acyl.
  • a polycyclic ring structure comprises more than 3 fused rings and includes carbon as ring atoms.
  • the polycyclic ring structure can be saturated or unsaturated.
  • the polycyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • the individual rings may or may not be of the same type.
  • Examples of polycyclic ring structures include adamantine, bicyclooctane, norbornane and bicyclononanes.
  • a spirocycle refers to a ring system wherein a single atom is the only common member of two rings.
  • a spirocycle can comprise a saturated carbocyclic ring comprising about 3 to about 8 ring members, a heterocyclic ring comprising about 3 to about 8 ring atoms wherein up to about 3 ring atoms may be N, S, or O or a combination thereof.
  • a tricyclic ring structure comprises 3 fused rings and includes carbon as ring atoms.
  • the tricyclic ring structure can be saturated or unsaturated.
  • the tricyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position, and may be substituted or unsubstituted.
  • the individual rings may or may not be of the same type. Examples of tricyclic ring structures include fluorene and anthracene.
  • Substituent groups for the above moieties useful in the invention are those groups that do not significantly diminish the biological activity of the inventive compound.
  • Substituent groups that do not significantly diminish the biological activity of the inventive compound include, for example, H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, NHCOalkyl, CHO, CF 3 , COOX3, SO3H, PO3H 2 , SO 2 NX 1 X 2 , CONX ⁇ s, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, sulfonamide, thioalkoxy or methylene dioxy when the substituted structure has two adjacent carbon atoms, wherein Xi and X 2 each independently comprise H or alkyl, or X ⁇ and X 2 together comprise"
  • an aspect of the invention is use of at least one of the inventive compounds to interact with cannabinoid receptors.
  • Some of the novel pyrazole derivatives show selectivity for the CB1 cannabinoid receptor.
  • These inventive CB1 selective analogs are able to interact with the CB1 receptor without affecting the peripheral (CB2) receptor to the same degree. Therefore, still another aspect of the invention is use of at least one of the inventive compounds to preferentially interact with the CB1 receptor.
  • known cannabimimetic pyrazole ligands generally have long in vivo half-lives and are more lipophilic than desired for optimal in vivo activity.
  • novel pyrazole analogs described herein are less lipophilic than known cannabimimetic pyrazole ligands and have shorter in vivo half-lives then known pyrazole analogs, providing the compounds of this embodiment with a favorable therapeutic profile. Therefore, yet another aspect of the invention is a cannabimimetic pyrazole analog that is less lipophilic than known cannabimimetic pyrazole analogs.
  • CB1 cannabinoid receptor antagonists that prevent binding of endogenous agonists to the cannabinoid receptors and thereby block the biological actions of such endogenous agonists. Therefore, a further aspect of the invention is use of at least one of the inventive compounds to prevent binding of a cannabinoid agonist to the CB1 cannabinoid receptor.
  • inventive pyrazole analogs described herein, and physiologically acceptable salts thereof have pharmacological properties when administered in therapeutically effective amounts for providing a physiological effect useful to treat marijuana abuse, obesity, schizophrenia, epilepsy, stress, memory disorders, migraine, vomiting, thymic disorders, dyskinesia, kinetic disorder, anxiety disorders, psychotic disorders, cognitive disorders, appetite disorders, mood d sordelrs deli i ⁇ tis " disorders, neuropathies, Parkinson's disease, Alzheimers disease, depression, psychosomatic-induced disease, as well as for alcohol, opioid, nicotine and cocaine addiction, etc. Additionally, these analogs can be used in cancer chemotherapy.
  • another aspect of the invention is the administration of a therapeutically effective amount of an inventive compound, or a physiologically acceptable salt thereof, to an individual or animal to provide a physiological effect.
  • Figure 1 is a graph of a dose vs. response curve for inventive compound 5.
  • a "therapeutically effective amount" of a compound is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a physiological response.
  • inventive compounds described herein, and physiologically acceptable salts thereof have pharmacological properties when administered in therapeutically effective amounts for providing a physiological response useful to treat marijuana abuse, obesity, schizophrenia, epilepsy, stress, memory disorders, migraine, vomiting, thymic disorders, dyskinesia, kinetic disorder, anxiety disorders, psychotic disorders, cognitive disorders, appetite disorders, mood disorders, delirious disorders, neuropathies, Parkinson's disease, Alzheimers disease, depression, psychosomatic-induced disease, as well as for alcohol, opioid, nicotine and cocaine addiction, etc.
  • a "therapeutically effective amount" of an inventive compound is believed to range from about 10 g/day to about 1 ,000 mg/day.
  • an "individual” refers to a human.
  • AW “animal refefs ⁇ cvfor example, veterinary animals, such as dogs, cats, horses and the like, and farm animals, such as cows, pigs and the like.
  • the compound of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasal or topical).
  • parenteral routes e.g., intramuscular, intravenous, subcutaneous, nasal or topical.
  • the form in which the compounds are administered will be determined by the route of administration.
  • Such forms include, but are not limited to, capsular and tablet formulations (for oral and rectal administration), liquid formulations (for oral, intravenous, intramuscular, subcutaneous, ocular, intranasal, inhalation-based and transdermal administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration).
  • the formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives.
  • Suitable physiologically acceptable vehicles include, for example, saline, sterile water, Ringer's solution and isotonic sodium chloride solutions.
  • the specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.
  • Table 1 illustrates some prepared CB1 selective pyrazole analogs (compounds 1- 29).
  • CB1 selective pyrazole analogs comprised compounds 1-6.
  • binding affinity is represented by the Kj value which is the inhibition constant correlated with the concentration of an analog required to occupy the 50% of the total number (Bmax) of the receptors. The lower the Ki value the higher the binding affinity.
  • an analog is said to have "binding selectivity" if it has higher binding affinity for one receptor compared to the other receptor; e.g. a cannabinoid analog which has a Kj of 0.1 nM for CB1 and 10 nM for CB2, is 100 times more selective for the CB1 receptor.
  • TME Tris-HCl buffer, 5 mM MgCI 2 and 1 mM EDTA
  • the treated membranes were subsequently used in the binding assay described below. Approximately 30 ⁇ g of membranes were incubated in silanized 96-well microtiter plate with TME containing 0.1% essentially fatty acid-free bovine serum albumin (BSA), 0.8 nM [ 3 H] CP-55,940, and various concentrations of test materials in a final volume of 200 ⁇ L. The assays were incubated for 1 hour at 30 °C and then immediately filtered using Packard Filtermate 196 harvester and Whatman GF/C filterplates and washed with wash buffer (TME) containing 0.5% BSA.
  • BSA essentially fatty acid-free bovine serum albumin
  • Radioactivity was detected using MicroScint 20 scintillation cocktail added directly to the dried filterplates, and the filterplates were counted using a Packard Instruments Top-Count. Nonspecific binding was assessed 1 l ⁇ 'ing 100 nM CSP- 55,940. Data collected from three independent experiments performed with duplicate determinations was normalized between 100% and 0% specific binding for [ 3 H] CP-55,940, determined using buffer and 100 nM CP-55,940. The normalized data was analyzed using a 4-parameter nonlinear logistic equation to yield IC 5 o values.
  • the CB1 cannabinoid receptor binding affinities (Ki) for the synthesized analogs range between 1.51 and 85.1.
  • the CB2 cannabinoid receptor binding affinities (Ki) for the synthesized analogs range between 5.81 and 2312.
  • the CB1 cannabinoid receptor selectivity for some of the synthesized analogs range from about 2 to about 452.
  • the CB2 cannabinoid receptor selectivity for some of the synthesized analogs range from about 1 to about 4.
  • Modification of the direct aromatic substitution at pyrazole position 1 can be obtained by varying the respective starting hydrazine (i.e. '2 I 4 'L dichlorophenylhydrazine hydrochloride).
  • the starting hydrazine i.e. '2 I 4 'L dichlorophenylhydrazine hydrochloride.
  • the starting hydrazine will having the general formula:
  • Modification at pyrazole position 3 can be obtained by varying the respective starting material (i.e. 1-aminopiperidine).
  • the starting material i.e. 1-aminopiperidine
  • the starting material will have the general formula:
  • Lithium salt of ethyl 2,4-dioxo-3-methyl-4-(4-bromophenyl)butanoate To a magnetically stirred solution of lithium bis(trimethylsilyl)amide (40 mL, 1.0 M solution in hexane, 40 mmol) in diethyl ether (120 mL) was added a solution of 4'- bromopropiophenone (8.52 g, 40 mmol) in diethyl ether (50 mL) at -78 °C. After the mixture was stirred at the same temperature for an additional 45 min, diethyl oxalate (6.4 mL, 47 mmol) was added to the mixture. The reaction mixture was allowed to warm to room temperature (RT) and stirred for 16 h. The precipitate was filtered, washed with diethyl ether, and dried under vacuum to afford the lithium salt.
  • RT room temperature
  • Some of the 5-substituted analogs can be prepared from Int. B via a Suzuki coupling reaction.
  • the Suzuki coupling reaction allows synthesis of novel compounds in which the 5-phenyl ring is substituted with an aromatic ring or a heteroaromatic ring.
  • the coupling of a saturated heterocyclic ring (for example, morpholine) on the 5-phenyl ring can be obtained by Pd-catalyzed amination reaction (J. Org. Chem. 2000, 65, 1144-1157).
  • Compound 5 was obtained from Int. E using a Suzuki coupling reaction as described above.
  • Method D Modification at Pyrazole Position 1

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Psychology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Rheumatology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des analogues de pyrazole cannabimimétiques. L'invention concerne également de nouveaux analogues de pyrazole améliorés présentant de hautes affinités et/ou sélectivités pour le récepteur cannabinoïde GB1. L'invention concerne en outre des préparations pharmaceutiques dans lesquelles sont utilisées les analogues de l'invention, ainsi que des méthodes d'administration de quantités efficaces d'un point de vue thérapeutique des analogues de l'invention afin d'obtenir un effet physiologique.
EP02768751A 2001-08-31 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides Withdrawn EP1421077A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US31651501P 2001-08-31 2001-08-31
US316515P 2001-08-31
PCT/US2002/027644 WO2003020217A2 (fr) 2001-08-31 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides

Publications (2)

Publication Number Publication Date
EP1421077A2 true EP1421077A2 (fr) 2004-05-26
EP1421077A4 EP1421077A4 (fr) 2004-11-17

Family

ID=23229374

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02768751A Withdrawn EP1421077A4 (fr) 2001-08-31 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides

Country Status (5)

Country Link
EP (1) EP1421077A4 (fr)
JP (1) JP2005507875A (fr)
AU (1) AU2002331766A1 (fr)
CA (1) CA2457922A1 (fr)
WO (1) WO2003020217A2 (fr)

Families Citing this family (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010009965A1 (en) 1998-05-04 2001-07-26 Alexandros Makriyannis Novel analgesic and immunomodulatory cannabinoids
US7589220B2 (en) 1998-06-09 2009-09-15 University Of Connecticut Inhibitors of the anandamide transporter
US7276613B1 (en) 1998-11-24 2007-10-02 University Of Connecticut Retro-anandamides, high affinity and stability cannabinoid receptor ligands
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
DE60033834T2 (de) 1999-10-18 2007-11-15 The University Of Connecticut, Farmington Für periphäre cannabinoid-rezeptoren selektive liganden
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
US7393842B2 (en) * 2001-08-31 2008-07-01 University Of Connecticut Pyrazole analogs acting on cannabinoid receptors
US7119108B1 (en) 1999-10-18 2006-10-10 University Of Connecticut Pyrazole derivatives as cannabinoid receptor antagonists
WO2002058636A2 (fr) 2001-01-26 2002-08-01 University Of Connecticut Nouveaux ligands cannabimimetiques
EP1363632B1 (fr) 2001-01-29 2010-08-25 The University of Connecticut Aminoalkylindoles cannabimimetiques selectifs d'un recepteur
EP1414775B1 (fr) 2001-07-13 2012-12-19 The University of Connecticut Cannabinoide bicyclique
NZ534757A (en) 2002-03-12 2006-07-28 Merck & Co Inc Substituted amides
JP2006511460A (ja) 2002-08-23 2006-04-06 ユニバーシティ オブ コネチカット 治療適応を持つケトカンナビノイド
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
AR043633A1 (es) * 2003-03-20 2005-08-03 Schering Corp Ligandos de receptores de canabinoides
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
WO2004099157A1 (fr) * 2003-05-07 2004-11-18 Pfizer Products Inc. Ligands de recepteurs cannabinoides et leurs applications
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
EP1644335A4 (fr) 2003-07-11 2008-06-04 Bristol Myers Squibb Co Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
CA2532965C (fr) 2003-07-22 2013-05-14 Astex Therapeutics Limited Composes 1h-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (cdk) et modulateurs de la glycogene synthase kinase-3 (gsk-3)
AU2004265299B2 (en) * 2003-08-07 2008-05-01 Merck & Co., Inc. Pyrazole carboxamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
US7326706B2 (en) 2003-08-15 2008-02-05 Bristol-Myers Squibb Company Pyrazine modulators of cannabinoid receptors
US7151097B2 (en) * 2003-11-07 2006-12-19 Pfizer Inc. Bicyclic pyrazolyl and imidazolyl compounds and uses thereof
JP4436369B2 (ja) 2004-01-28 2010-03-24 エフ．ホフマン−ラ ロシュ アーゲー スピロ−ベンゾジオキソール類およびそれらのｃｂ１アンタゴニストとしての使用
BRPI0507786A (pt) * 2004-02-20 2007-07-17 Astrazeneca Ab composto e sais farmaceuticamente aceitáveis do mesmo, formulação farmacêutica, uso de um composto, método de tratar uma doença, e, processo para a preparação de compostos
EP1734963A4 (fr) 2004-04-02 2008-06-18 Merck & Co Inc Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
ITMI20041032A1 (it) 2004-05-24 2004-08-24 Neuroscienze S C A R L Compositi farmaceutici
CA2586011C (fr) 2004-07-12 2011-07-19 Cadila Healthcare Limited Derives tricycliques de la pyrazole en tant que modulateurs de recepteurs cannabinoides
US20060025448A1 (en) 2004-07-22 2006-02-02 Cadila Healthcare Limited Hair growth stimulators
WO2006032851A1 (fr) 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006035310A2 (fr) * 2004-09-27 2006-04-06 Pfizer Products Inc. Procede permettant de preparer des composes de pyrazolyle bicycliques
ES2351348T3 (es) 2004-11-09 2011-02-03 F. Hoffmann-La Roche Ag Derivados de la dibenzosuberona.
WO2006067443A1 (fr) * 2004-12-23 2006-06-29 Astrazeneca Ab Agents thérapeutiques
CA2594488C (fr) * 2005-01-10 2015-04-28 University Of Connecticut Nouveaux analogues d'heteropyrroles agissant sur les recepteurs cannabinoides
AR054425A1 (es) 2005-01-21 2007-06-27 Astex Therapeutics Ltd Sales de adicion de piperidin 4-il- amida de acido 4-(2,6-dicloro-benzoilamino) 1h-pirazol-3-carboxilico.
KR101345002B1 (ko) 2005-01-21 2013-12-31 아스텍스 테라퓨틱스 리미티드 제약 화합물
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
KR101346886B1 (ko) 2005-01-21 2014-01-02 아스텍스 테라퓨틱스 리미티드 제약 화합물
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
FR2887550A1 (fr) * 2005-06-24 2006-12-29 Sanofi Aventis Sa Derives de 1-benzylpyrazole-3-acetamide, leur preparation et leur application en therapeutique
JP5114395B2 (ja) * 2005-06-30 2013-01-09 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
JP2008545009A (ja) 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
WO2007046550A1 (fr) 2005-10-21 2007-04-26 Mitsubishi Tanabe Pharma Corporation Composes pyrazole presentant une activite antagoniste du recepteur cannabinoide (cb1)
US20100234439A1 (en) * 2006-06-20 2010-09-16 Leifeng Cheng Therapeutic agents
EP2035389A1 (fr) * 2006-06-20 2009-03-18 AstraZeneca AB Agents thérapeutiques
JP2008019205A (ja) * 2006-07-12 2008-01-31 Sanofi-Aventis Ｎ−［（１，５−ジフェニル−１ｈ−ピラゾール−３−イル）メチル］スルホンアミド誘導体、その調製法および治療におけるその応用
CN103145620A (zh) 2006-12-18 2013-06-12 7Tm制药联合股份有限公司 Cb1受体调节剂
PE20081659A1 (es) 2007-01-04 2008-10-24 Prosidion Ltd Agonistas de gpcr
CL2008000017A1 (es) 2007-01-04 2008-08-01 Prosidion Ltd Compuestos derivados de heterociclos de nitrogeno y oxigeno, agonistas de gpcr; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de la obesidad, diabetes, sindrome metabolico, hiperlipidemia, toleranci
GB0700122D0 (en) 2007-01-04 2007-02-14 Prosidion Ltd GPCR agonists
EA016507B1 (ru) 2007-01-04 2012-05-30 Прозидион Лимитед Пиперидиновые агонисты gpcr
ATE523507T1 (de) 2007-01-04 2011-09-15 Prosidion Ltd Piperidin-gpcr-agonisten
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
JP5546451B2 (ja) 2007-06-04 2014-07-09 シナジー ファーマシューティカルズ インコーポレイテッド 胃腸の障害、炎症、癌および他の障害の処置に有用なグアニル酸シクラーゼのアゴニスト
US20100120694A1 (en) 2008-06-04 2010-05-13 Synergy Pharmaceuticals, Inc. Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders
KR20100072037A (ko) 2007-09-20 2010-06-29 애보트 헬스케어 프로덕츠 비.브이. 칸나비노이드 ｃｂ₁수용체 효능제로서의 5-아릴-4,5-디하이드로-(1ｈ)-피라졸
GB0720390D0 (en) 2007-10-18 2007-11-28 Prosidion Ltd G-Protein coupled receptor agonists
GB0720389D0 (en) 2007-10-18 2008-11-12 Prosidion Ltd G-Protein Coupled Receptor Agonists
EP3241839B1 (fr) 2008-07-16 2019-09-04 Bausch Health Ireland Limited Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2348857B1 (fr) 2008-10-22 2016-02-24 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
AU2009309037A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
MY159058A (en) 2011-02-25 2016-12-15 Merck Sharp & Dohme Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agent
BR112013013490B1 (pt) * 2011-09-30 2019-10-22 National Health Research Institutes compostos e composição farmacêutica
SG11201405761WA (en) 2012-03-16 2014-10-30 Axikin Pharmaceuticals Inc 3,5-diaminopyrazole kinase inhibitors
EP2880028B1 (fr) 2012-08-02 2020-09-30 Merck Sharp & Dohme Corp. Composés tricycliques anti-diabétiques
JO3215B1 (ar) 2012-08-09 2018-03-08 Phenex Pharmaceuticals Ag حلقات غير متجانسة بها 5 ذرات تحتوي على النيتروجين بها استبدال بكربوكساميد أو سلفوناميد كمعدلات لمستقبل نووي غير محمي RORy
JP2016516004A (ja) 2013-02-22 2016-06-02 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 抗糖尿病二環式化合物
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
AU2014235209B2 (en) 2013-03-15 2018-06-14 Bausch Health Ireland Limited Guanylate cyclase receptor agonists combined with other drugs
HK1220696A1 (zh) 2013-03-15 2017-05-12 Bausch Health Ireland Limited 鸟苷酸环化酶激动剂及其用途
EP4424697A3 (fr) 2013-06-05 2024-12-25 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
WO2015051496A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
HUE049801T2 (hu) 2014-12-23 2020-10-28 Sma Therapeutics Inc 3,5-diaminopirazol kináz inhibitorok
US11072602B2 (en) 2016-12-06 2021-07-27 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
ES2950757T3 (es) 2017-10-06 2023-10-13 Forma Therapeutics Inc Inhibición de la peptidasa específica de la ubiquitina 30
BR112020021921A2 (pt) 2018-05-17 2021-01-26 Forma Therapeutics, Inc. compostos bicíclicos fundidos úteis como inibidores de peptidase 30 específica de ubiquitina
LT3860989T (lt) 2018-10-05 2023-06-12 Forma Therapeutics, Inc. Sulieti pirolinai, kurie veikia kaip ubikvitinui specifinės proteazės 30 (ups30) inhibitoriai

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3041343A (en) * 1959-10-14 1962-06-26 Sandoz Ltd 4-(thienyl-2'')-and 4-(pyridyl-3'')-5-aminopyrazoles
FR2692575B1 (fr) * 1992-06-23 1995-06-30 Sanofi Elf Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2742148B1 (fr) * 1995-12-08 1999-10-22 Sanofi Sa Nouveaux derives du pyrazole-3-carboxamide, procede pour leur preparation et compositions pharmaceutiques les contenant
US5939429A (en) * 1997-09-30 1999-08-17 Virginia Commonwealth University Cardiovascular uses of cannabinoid compounds
US6653304B2 (en) * 2000-02-11 2003-11-25 Bristol-Myers Squibb Co. Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases

Also Published As

Publication number Publication date
WO2003020217A3 (fr) 2003-08-21
JP2005507875A (ja) 2005-03-24
WO2003020217A2 (fr) 2003-03-13
EP1421077A4 (fr) 2004-11-17
CA2457922A1 (fr) 2003-03-13
AU2002331766A1 (en) 2003-03-18

Similar Documents

Publication Publication Date Title
EP1421077A2 (fr) Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides
EP1571147A2 (fr) Analogues de pyrazole agissant sur les récepteurs cannabinoides
US7745440B2 (en) Pyrazole analogs acting on cannabinoid receptors
US7666867B2 (en) Heteroindanes: a new class of potent cannabimimetic ligands
US8410097B2 (en) Heteropyrrole analogs acting on cannabinoid receptors
US8084467B2 (en) Pyrazole derivatives as cannabinoid receptor antagonists
CA2753061C (fr) Nouveaux analogues heteropyrroles agissant sur les recepteurs cannabinoides
DE69719191T2 (de) Tetrahydroisoquinoline derivate als modulatoren von dopamine d3 rezeptoren
CA2218552C (fr) Composes de benzimidazole et leur utilisation en tant que modulateurs du complexe de recepteurs gabaa
KR20130143141A (ko) 피라졸리딘-3-온 유도체
US20120046280A1 (en) Novel heteropyrrole analogs acting on cannabinoid receptors
AU2004201292A1 (en) Novel pyrazole analogs acting on cannabinoid receptors
TWI472514B (zh) 吡唑類化合物
JP3258531B2 (ja) ベンズイミダゾール誘導体
JP2007169270A (ja) 医薬組成物
AU2002353895A1 (en) Heteroindanes: a new class of potent cannabimimetic ligands
HK1187610A (en) Pyrazole compounds
HK1187610B (en) Pyrazole compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040205

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61P 29/00 B

Ipc: 7A 61K 31/415 B

Ipc: 7C 07D 401/10 B

Ipc: 7C 07D 231/14 B

Ipc: 7C 07D 401/12 A

A4 Supplementary search report drawn up and despatched

Effective date: 20040930

17Q First examination report despatched

Effective date: 20070530

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090324