WO2003020217A2 - Novel pyrazole analogs acting on cannabinoid receptors - Google Patents
Novel pyrazole analogs acting on cannabinoid receptors Download PDFInfo
- Publication number
- WO2003020217A2 WO2003020217A2 PCT/US2002/027644 US0227644W WO03020217A2 WO 2003020217 A2 WO2003020217 A2 WO 2003020217A2 US 0227644 W US0227644 W US 0227644W WO 03020217 A2 WO03020217 A2 WO 03020217A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ring
- group
- members
- alkyl
- substituted
- Prior art date
Links
- 0 CC(CC(C1)CC2)C1*2=C(C)C Chemical compound CC(CC(C1)CC2)C1*2=C(C)C 0.000 description 7
- SBYHFKPVCBCYGV-UHFFFAOYSA-N C(C1)C2CCN1CC2 Chemical compound C(C1)C2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- IHDQGSRGEWKRNW-UHFFFAOYSA-N CCC(C1)C(CC2)C2/C1=[O]/CC Chemical compound CCC(C1)C(CC2)C2/C1=[O]/CC IHDQGSRGEWKRNW-UHFFFAOYSA-N 0.000 description 1
- FAOHMIJKABVWSZ-UHFFFAOYSA-N CCOC1CC(CCC2)N(C)C2C1 Chemical compound CCOC1CC(CCC2)N(C)C2C1 FAOHMIJKABVWSZ-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
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 ***e 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 ***e 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
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003524531A JP2005507875A (en) | 2001-08-31 | 2002-08-29 | Novel pyrazole analogues acting on cannabinoid receptors |
AU2002331766A AU2002331766A1 (en) | 2001-08-31 | 2002-08-29 | Novel pyrazole analogs acting on cannabinoid receptors |
CA002457922A CA2457922A1 (en) | 2001-08-31 | 2002-08-29 | Novel pyrazole analogs acting on cannabinoid receptors |
EP02768751A EP1421077A4 (en) | 2001-08-31 | 2002-08-29 | Novel pyrazole analogs acting on cannabinoid receptors |
US10/790,498 US7393842B2 (en) | 2001-08-31 | 2004-03-01 | Pyrazole analogs acting on cannabinoid receptors |
US11/166,835 US8084467B2 (en) | 1999-10-18 | 2005-06-24 | Pyrazole derivatives as cannabinoid receptor antagonists |
US11/244,770 US7745440B2 (en) | 1999-10-18 | 2005-10-06 | Pyrazole analogs acting on cannabinoid receptors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31651501P | 2001-08-31 | 2001-08-31 | |
US60/316,515 | 2001-08-31 |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/041239 Continuation WO2001029007A1 (en) | 1999-10-18 | 2000-10-18 | Pyrazole derivatives as cannabinoid receptor antagonists |
US10110865 Continuation | 2000-10-18 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/790,498 Continuation-In-Part US7393842B2 (en) | 1999-10-18 | 2004-03-01 | Pyrazole analogs acting on cannabinoid receptors |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003020217A2 true WO2003020217A2 (en) | 2003-03-13 |
WO2003020217A3 WO2003020217A3 (en) | 2003-08-21 |
Family
ID=23229374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/027644 WO2003020217A2 (en) | 1999-10-18 | 2002-08-29 | Novel pyrazole analogs acting on cannabinoid receptors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1421077A4 (en) |
JP (1) | JP2005507875A (en) |
AU (1) | AU2002331766A1 (en) |
CA (1) | CA2457922A1 (en) |
WO (1) | WO2003020217A2 (en) |
Cited By (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004099157A1 (en) * | 2003-05-07 | 2004-11-18 | Pfizer Products Inc. | Cannabinoid receptor ligands and uses thereof |
WO2004085385A3 (en) * | 2003-03-20 | 2004-11-25 | Schering Corp | Cannabinoid receptor ligands |
WO2005007628A1 (en) | 2003-07-11 | 2005-01-27 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
WO2005012256A1 (en) | 2003-07-22 | 2005-02-10 | Astex Therapeutics Limited | 3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
WO2005016877A3 (en) * | 2003-08-07 | 2005-04-28 | Merck & Co Inc | Pyrazole carboxamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
WO2005044822A1 (en) * | 2003-11-07 | 2005-05-19 | Pfizer Products Inc. | Bicyclic pyrazolyl and imidazolyl compounds and uses thereof |
US6900236B1 (en) | 1999-10-18 | 2005-05-31 | University Of Connecticut | Cannabimimetic indole derivatives |
WO2005080343A2 (en) * | 2004-02-20 | 2005-09-01 | Astrazeneca Ab | 3-substituted 1,5-diphenylpyrazole derivatives useful as cb1 modulators |
US6939977B2 (en) | 1998-05-04 | 2005-09-06 | The University Of Connecticut | Analgesic and immunomodulatory cannabinoids |
JP2005255685A (en) * | 2004-03-01 | 2005-09-22 | Univ Of Connecticut | New pyrazole analog acting on cannabinoid receptor |
US6972295B2 (en) | 2002-03-12 | 2005-12-06 | Merck & Co., Inc. | Substituted amides |
EP1602656A1 (en) | 2004-05-24 | 2005-12-07 | NEUROSCIENZE PHARMANESS S.C. a R.L. | Pyrazole derivatives having affinity for cb1 and/or cb2 receptors |
EP1623741A2 (en) | 2004-07-22 | 2006-02-08 | Cadila Healthcare Ltd. | Cannabinoid receptor ligands for hair growth modulation |
WO2006032851A1 (en) | 2004-09-20 | 2006-03-30 | Biolipox Ab | Pyrazole compounds useful in the treatment of inflammation |
WO2006035310A2 (en) * | 2004-09-27 | 2006-04-06 | Pfizer Products Inc. | Process for preparing bicyclic pyrazolyl compounds |
WO2006050842A1 (en) | 2004-11-09 | 2006-05-18 | F. Hoffmann-La Roche Ag | Dibenzosuberone derivatives |
WO2006067443A1 (en) * | 2004-12-23 | 2006-06-29 | Astrazeneca Ab | Therapeutic agents |
WO2006077424A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
WO2006077428A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
US7129239B2 (en) | 2002-10-28 | 2006-10-31 | Pfizer Inc. | Purine compounds and uses thereof |
US7141669B2 (en) | 2003-04-23 | 2006-11-28 | Pfizer Inc. | Cannabiniod receptor ligands and uses thereof |
US7144890B2 (en) | 2004-01-28 | 2006-12-05 | Hoffman-La Roche Inc. | Spiro-pentacyclic compounds |
US7145012B2 (en) | 2003-04-23 | 2006-12-05 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
FR2887550A1 (en) * | 2005-06-24 | 2006-12-29 | Sanofi Aventis Sa | New 1-benzylpyrazole-3-acetamide compounds are cannabinoids receptor antagonists useful to treat/prevent immune disorders, pain, gastrointestinal disturbances, cardiovascular/kidney disorders and in cancer chemotherapy |
WO2007003961A2 (en) * | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
WO2007003960A1 (en) * | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
US7176210B2 (en) | 2003-02-10 | 2007-02-13 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
WO2007046550A1 (en) | 2005-10-21 | 2007-04-26 | Mitsubishi Tanabe Pharma Corporation | Pyrazole compounds having cannabinoid receptor (cb1) antagonizing activity |
US7232823B2 (en) | 2003-06-09 | 2007-06-19 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
US7247628B2 (en) | 2002-12-12 | 2007-07-24 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
US7268133B2 (en) | 2003-04-23 | 2007-09-11 | Pfizer, Inc. Patent Department | Cannabinoid receptor ligands and uses thereof |
WO2007148061A1 (en) * | 2006-06-20 | 2007-12-27 | Astrazeneca Ab | Therapeutic agents |
WO2007148062A1 (en) * | 2006-06-20 | 2007-12-27 | Astrazeneca Ab | Therapeutic agents |
JP2008019205A (en) * | 2006-07-12 | 2008-01-31 | Sanofi-Aventis | N-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl]sulfonamide derivative, method for preparing the same and its application in treatment |
US7326706B2 (en) | 2003-08-15 | 2008-02-05 | Bristol-Myers Squibb Company | Pyrazine modulators of cannabinoid receptors |
US7329658B2 (en) | 2003-02-06 | 2008-02-12 | Pfizer Inc | Cannabinoid receptor ligands and uses thereof |
WO2008075012A1 (en) | 2006-12-18 | 2008-06-26 | 7Tm Pharma A/S | Cb1 receptor modulators |
WO2008081206A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081207A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081205A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081208A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081204A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
JP2008526887A (en) * | 2005-01-10 | 2008-07-24 | ユニバーシティ オブ コネチカット | Novel heteropyrrole analogs that act on cannabinoid receptors |
WO2009037244A2 (en) * | 2007-09-20 | 2009-03-26 | Solvay Pharmaceuticals B.V. | 5-aryl-4,5-dihydro-(1h)-pyrazoles as cannabinoid cb1 receptor agonists |
WO2009050523A1 (en) | 2007-10-18 | 2009-04-23 | Prosidion Limited | Azetidinyl g-protein coupled receptor agonists |
WO2009050522A1 (en) | 2007-10-18 | 2009-04-23 | Prosidion Limited | Azetidinyl g-protein coupled receptor agonists |
EP2088154A1 (en) | 2004-03-09 | 2009-08-12 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
WO2010047982A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2010051206A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
EP2305352A1 (en) | 2004-04-02 | 2011-04-06 | Merck Sharp & Dohme Corp. | 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders |
US7923465B2 (en) | 2005-06-02 | 2011-04-12 | Glenmark Pharmaceuticals S.A. | Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
EP2308840A1 (en) | 2005-06-30 | 2011-04-13 | Prosidion Limited | GPCR agonists |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
EP2343302A1 (en) | 2004-07-12 | 2011-07-13 | Cadila Healthcare Limited | Tricyclic pyrazole derivatives as cannabinoid receptor modulators |
WO2011106273A1 (en) | 2010-02-25 | 2011-09-01 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
US8013163B2 (en) | 2005-01-21 | 2011-09-06 | Astex Therapeutics Limited | 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors |
WO2012116145A1 (en) | 2011-02-25 | 2012-08-30 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
WO2013048989A3 (en) * | 2011-09-30 | 2013-05-23 | National Health Research Institutes | Pyrazole compounds |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
WO2014022528A1 (en) | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
WO2014023367A1 (en) | 2012-08-09 | 2014-02-13 | Phenex Pharmaceuticals Ag | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma |
WO2014130608A1 (en) | 2013-02-22 | 2014-08-28 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
US8916555B2 (en) | 2012-03-16 | 2014-12-23 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
WO2015051725A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US9540351B2 (en) | 2013-09-18 | 2017-01-10 | Axikin Pharmaceuticals, Inc. | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
US9546163B2 (en) | 2014-12-23 | 2017-01-17 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
WO2018106518A1 (en) | 2016-12-06 | 2018-06-14 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
US11535618B2 (en) | 2018-10-05 | 2022-12-27 | Forma Therapeutics, Inc. | Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors |
Citations (1)
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 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2692575B1 (en) * | 1992-06-23 | 1995-06-30 | Sanofi Elf | NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2742148B1 (en) * | 1995-12-08 | 1999-10-22 | Sanofi Sa | NOVEL PYRAZOLE-3-CARBOXAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US5939429A (en) * | 1997-09-30 | 1999-08-17 | Virginia Commonwealth University | Cardiovascular uses of cannabinoid compounds |
AU2001234958A1 (en) * | 2000-02-11 | 2001-08-20 | Bristol-Myers Squibb Company | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases |
-
2002
- 2002-08-29 JP JP2003524531A patent/JP2005507875A/en active Pending
- 2002-08-29 CA CA002457922A patent/CA2457922A1/en not_active Abandoned
- 2002-08-29 AU AU2002331766A patent/AU2002331766A1/en not_active Abandoned
- 2002-08-29 WO PCT/US2002/027644 patent/WO2003020217A2/en active Application Filing
- 2002-08-29 EP EP02768751A patent/EP1421077A4/en not_active Withdrawn
Patent Citations (1)
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 |
Non-Patent Citations (1)
Title |
---|
See also references of EP1421077A2 * |
Cited By (130)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6939977B2 (en) | 1998-05-04 | 2005-09-06 | The University Of Connecticut | Analgesic and immunomodulatory cannabinoids |
US6900236B1 (en) | 1999-10-18 | 2005-05-31 | University Of Connecticut | Cannabimimetic indole derivatives |
US6972295B2 (en) | 2002-03-12 | 2005-12-06 | Merck & Co., Inc. | Substituted amides |
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 |
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 |
WO2004085385A3 (en) * | 2003-03-20 | 2004-11-25 | Schering Corp | Cannabinoid receptor ligands |
JP2006520795A (en) * | 2003-03-20 | 2006-09-14 | シェーリング コーポレイション | Cannabinoid receptor ligand |
US7642272B2 (en) | 2003-03-20 | 2010-01-05 | Schering Corporation | Cannabinoid receptor ligands |
JP2007211017A (en) * | 2003-03-20 | 2007-08-23 | Schering Plough Corp | Cannabinoid receptor ligand |
US7141669B2 (en) | 2003-04-23 | 2006-11-28 | Pfizer Inc. | Cannabiniod receptor ligands and uses thereof |
US7145012B2 (en) | 2003-04-23 | 2006-12-05 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
US7268133B2 (en) | 2003-04-23 | 2007-09-11 | Pfizer, Inc. Patent Department | Cannabinoid receptor ligands and uses thereof |
US7354929B2 (en) | 2003-04-23 | 2008-04-08 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
WO2004099157A1 (en) * | 2003-05-07 | 2004-11-18 | Pfizer Products Inc. | Cannabinoid receptor ligands and uses thereof |
US7232823B2 (en) | 2003-06-09 | 2007-06-19 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
US7884113B2 (en) | 2003-07-11 | 2011-02-08 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
US7276608B2 (en) | 2003-07-11 | 2007-10-02 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
WO2005007111A2 (en) | 2003-07-11 | 2005-01-27 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
WO2005007628A1 (en) | 2003-07-11 | 2005-01-27 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
US8119808B2 (en) | 2003-07-11 | 2012-02-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
US7745638B2 (en) | 2003-07-22 | 2010-06-29 | Astex Therapeutics Limited | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
US7385059B2 (en) | 2003-07-22 | 2008-06-10 | Astex Therapeutics Limited | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
US8080666B2 (en) | 2003-07-22 | 2011-12-20 | Astex Therapeutics, Ltd. | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
EP2256106A1 (en) | 2003-07-22 | 2010-12-01 | Astex Therapeutics Limited | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) modulators |
US7825140B2 (en) | 2003-07-22 | 2010-11-02 | Astex Therapeutics, Ltd. | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
US9051278B2 (en) | 2003-07-22 | 2015-06-09 | Astex Therapeutics, Ltd. | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
WO2005012256A1 (en) | 2003-07-22 | 2005-02-10 | Astex Therapeutics Limited | 3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
US8779147B2 (en) | 2003-07-22 | 2014-07-15 | Astex Therapeutics, Ltd. | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators |
AU2004265299B2 (en) * | 2003-08-07 | 2008-05-01 | Merck & Co., Inc. | Pyrazole carboxamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
US7659408B2 (en) | 2003-08-07 | 2010-02-09 | Merck Sharp & Dhome Corp. | Pyrazole carboxamides as inhibitors of 11-β-hydroxysteroid dehydrogenase-1 |
WO2005016877A3 (en) * | 2003-08-07 | 2005-04-28 | 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 |
EA009742B1 (en) * | 2003-11-07 | 2008-04-28 | Пфайзер Продактс Инк. | Bicyclic pyrazolyl and imidazolyl compounds and uses thereof |
WO2005044822A1 (en) * | 2003-11-07 | 2005-05-19 | Pfizer Products Inc. | Bicyclic pyrazolyl and imidazolyl compounds and uses thereof |
NL1027434C2 (en) * | 2003-11-07 | 2007-11-27 | Pfizer Prod Inc | Bicyclic pyrazolyl and imidazolyl compounds, and uses thereof. |
US7151097B2 (en) | 2003-11-07 | 2006-12-19 | Pfizer Inc. | Bicyclic pyrazolyl and imidazolyl compounds and uses thereof |
US7144890B2 (en) | 2004-01-28 | 2006-12-05 | Hoffman-La Roche Inc. | Spiro-pentacyclic compounds |
AU2005214130B2 (en) * | 2004-02-20 | 2008-03-06 | Astrazeneca Ab | 3-substituted 1,5-diphenylpyrazole derivatives useful as CB1 modulators |
WO2005080343A2 (en) * | 2004-02-20 | 2005-09-01 | Astrazeneca Ab | 3-substituted 1,5-diphenylpyrazole derivatives useful as cb1 modulators |
WO2005080343A3 (en) * | 2004-02-20 | 2006-01-12 | Astrazeneca Ab | 3-substituted 1,5-diphenylpyrazole derivatives useful as cb1 modulators |
JP2005255685A (en) * | 2004-03-01 | 2005-09-22 | Univ Of Connecticut | New pyrazole analog acting on cannabinoid receptor |
EP2088154A1 (en) | 2004-03-09 | 2009-08-12 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
EP2305352A1 (en) | 2004-04-02 | 2011-04-06 | Merck Sharp & Dohme Corp. | 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders |
US7659407B2 (en) | 2004-05-24 | 2010-02-09 | Neuroscienze Pharmaness S.C.a.R.I. | Pharmaceutical compounds |
US8227620B2 (en) | 2004-05-24 | 2012-07-24 | Neuroscienze Pharmaness S.C. A.R.L. | Pharmaceutical compounds |
EP1602656A1 (en) | 2004-05-24 | 2005-12-07 | NEUROSCIENZE PHARMANESS S.C. a R.L. | Pyrazole derivatives having affinity for cb1 and/or cb2 receptors |
JP2005350458A (en) * | 2004-05-24 | 2005-12-22 | Neuroscienze Pharmaness Scarl | Medicinal compound |
EP2343302A1 (en) | 2004-07-12 | 2011-07-13 | Cadila Healthcare Limited | Tricyclic pyrazole derivatives as cannabinoid receptor modulators |
EP1623741A2 (en) | 2004-07-22 | 2006-02-08 | Cadila Healthcare Ltd. | Cannabinoid receptor ligands for hair growth modulation |
WO2006032851A1 (en) | 2004-09-20 | 2006-03-30 | Biolipox Ab | Pyrazole compounds useful in the treatment of inflammation |
WO2006035310A2 (en) * | 2004-09-27 | 2006-04-06 | Pfizer Products Inc. | Process for preparing bicyclic pyrazolyl compounds |
WO2006035310A3 (en) * | 2004-09-27 | 2006-06-01 | Pfizer Prod Inc | Process for preparing bicyclic pyrazolyl compounds |
US7220743B2 (en) | 2004-11-09 | 2007-05-22 | Hoffmann-La Roche Inc. | Heterocyclic CB1 receptor antagonists |
WO2006050842A1 (en) | 2004-11-09 | 2006-05-18 | F. Hoffmann-La Roche Ag | Dibenzosuberone derivatives |
WO2006067443A1 (en) * | 2004-12-23 | 2006-06-29 | Astrazeneca Ab | Therapeutic agents |
JP2008526887A (en) * | 2005-01-10 | 2008-07-24 | ユニバーシティ オブ コネチカット | Novel heteropyrrole analogs that act on cannabinoid receptors |
US8013163B2 (en) | 2005-01-21 | 2011-09-06 | Astex Therapeutics Limited | 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors |
WO2006077424A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8293767B2 (en) | 2005-01-21 | 2012-10-23 | Astex Therapeutics Limited | 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors |
WO2006077428A1 (en) | 2005-01-21 | 2006-07-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
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 (en) * | 2005-06-24 | 2006-12-29 | Sanofi Aventis Sa | New 1-benzylpyrazole-3-acetamide compounds are cannabinoids receptor antagonists useful to treat/prevent immune disorders, pain, gastrointestinal disturbances, cardiovascular/kidney disorders and in cancer chemotherapy |
WO2007003960A1 (en) * | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
EP2308840A1 (en) | 2005-06-30 | 2011-04-13 | Prosidion Limited | GPCR agonists |
WO2007003961A2 (en) * | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
JP2008545008A (en) * | 2005-06-30 | 2008-12-11 | プロシディオン・リミテッド | GPCR agonist |
WO2007003961A3 (en) * | 2005-06-30 | 2007-03-01 | Prosidion Ltd | Gpcr agonists |
WO2007046550A1 (en) | 2005-10-21 | 2007-04-26 | Mitsubishi Tanabe Pharma Corporation | Pyrazole compounds having cannabinoid receptor (cb1) antagonizing activity |
WO2007148061A1 (en) * | 2006-06-20 | 2007-12-27 | Astrazeneca Ab | Therapeutic agents |
WO2007148062A1 (en) * | 2006-06-20 | 2007-12-27 | Astrazeneca Ab | Therapeutic agents |
JP2008019205A (en) * | 2006-07-12 | 2008-01-31 | Sanofi-Aventis | N-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl]sulfonamide derivative, method for preparing the same and its application in treatment |
WO2008075012A1 (en) | 2006-12-18 | 2008-06-26 | 7Tm Pharma A/S | Cb1 receptor modulators |
WO2008081208A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
EP2383270A1 (en) | 2007-01-04 | 2011-11-02 | Prosidion Limited | Piperidine GPCR agonists |
WO2008081205A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081207A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081204A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
WO2008081206A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
EP2377864A1 (en) | 2007-01-04 | 2011-10-19 | Prosidion Limited | Piperidine GPCR agonists |
EP2377863A1 (en) | 2007-01-04 | 2011-10-19 | Prosidion Limited | Piperidine GPCR agonists |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2009037244A2 (en) * | 2007-09-20 | 2009-03-26 | Solvay Pharmaceuticals B.V. | 5-aryl-4,5-dihydro-(1h)-pyrazoles as cannabinoid cb1 receptor agonists |
WO2009037244A3 (en) * | 2007-09-20 | 2009-08-20 | Solvay Pharm Bv | 5-aryl-4,5-dihydro-(1h)-pyrazoles as cannabinoid cb1 receptor agonists |
US7928134B2 (en) | 2007-09-20 | 2011-04-19 | Solvay Pharmaceuticals B.V. | 5-aryl-4,5-dihydro-(1H)-pyrazolines as cannabinoid CB1 receptor agonists |
WO2009050523A1 (en) | 2007-10-18 | 2009-04-23 | Prosidion Limited | Azetidinyl g-protein coupled receptor agonists |
WO2009050522A1 (en) | 2007-10-18 | 2009-04-23 | Prosidion Limited | Azetidinyl g-protein coupled receptor agonists |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
WO2010047982A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2010051206A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
WO2011106273A1 (en) | 2010-02-25 | 2011-09-01 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2012116145A1 (en) | 2011-02-25 | 2012-08-30 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
EP3243385A1 (en) | 2011-02-25 | 2017-11-15 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
EP2632919A4 (en) * | 2011-09-30 | 2014-04-16 | Nat Health Research Institutes | Pyrazole compounds |
EP2632919A2 (en) * | 2011-09-30 | 2013-09-04 | National Health Research Institutes | Pyrazole compounds |
WO2013048989A3 (en) * | 2011-09-30 | 2013-05-23 | National Health Research Institutes | Pyrazole compounds |
KR20130094341A (en) * | 2011-09-30 | 2013-08-23 | 내셔날 헬스 리서치 인스티튜트 | Pyrazole compounds |
AU2012316331B2 (en) * | 2011-09-30 | 2016-02-25 | National Health Research Institutes | Pyrazole compounds |
KR101586714B1 (en) * | 2011-09-30 | 2016-01-19 | 내셔날 헬스 리서치 인스티튜트 | Pyrazole Compounds |
US8962845B2 (en) | 2011-09-30 | 2015-02-24 | National Health Research Institutes | Pyrazole compounds |
TWI472514B (en) * | 2011-09-30 | 2015-02-11 | Nat Health Research Institutes | Pyrazole compounds |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
US9346792B2 (en) | 2012-03-16 | 2016-05-24 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9365556B2 (en) | 2012-03-16 | 2016-06-14 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9382237B2 (en) | 2012-03-16 | 2016-07-05 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US8916555B2 (en) | 2012-03-16 | 2014-12-23 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
WO2014022528A1 (en) | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
WO2014023367A1 (en) | 2012-08-09 | 2014-02-13 | Phenex Pharmaceuticals Ag | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma |
US9458104B2 (en) | 2012-08-09 | 2016-10-04 | Phenex Pharmaceuticals Ag | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor RORγ |
EP3118189A1 (en) | 2012-08-09 | 2017-01-18 | Phenex Pharmaceuticals AG | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma |
WO2014130608A1 (en) | 2013-02-22 | 2014-08-28 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
US9540351B2 (en) | 2013-09-18 | 2017-01-10 | Axikin Pharmaceuticals, Inc. | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
WO2015051725A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
US9730914B2 (en) | 2014-12-23 | 2017-08-15 | Axikin Pharmaceuticals | 3,5-diaminopyrazole kinase inhibitors |
US9546163B2 (en) | 2014-12-23 | 2017-01-17 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
WO2018106518A1 (en) | 2016-12-06 | 2018-06-14 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
US11535618B2 (en) | 2018-10-05 | 2022-12-27 | Forma Therapeutics, Inc. | Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors |
US11814386B2 (en) | 2018-10-05 | 2023-11-14 | Forma Therapeutics, Inc. | Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP1421077A4 (en) | 2004-11-17 |
AU2002331766A1 (en) | 2003-03-18 |
JP2005507875A (en) | 2005-03-24 |
WO2003020217A3 (en) | 2003-08-21 |
CA2457922A1 (en) | 2003-03-13 |
EP1421077A2 (en) | 2004-05-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2003020217A2 (en) | Novel pyrazole analogs acting on cannabinoid receptors | |
EP1571147A2 (en) | Pyrazole analogs acting on cannabinoid receptors | |
US7745440B2 (en) | Pyrazole analogs acting on cannabinoid receptors | |
US8084467B2 (en) | Pyrazole derivatives as cannabinoid receptor antagonists | |
US7666867B2 (en) | Heteroindanes: a new class of potent cannabimimetic ligands | |
US8410097B2 (en) | Heteropyrrole analogs acting on cannabinoid receptors | |
CA2753061C (en) | Novel hetero pyrrole analogs acting on cannabinoid receptors | |
US8729101B2 (en) | 1H-imidazole derivative having CB1, agonistic, CB1 partial agonistic or CB1 antagnistic activity | |
JP4177435B2 (en) | Remedy | |
CA2218552C (en) | Benzimidazole compounds and their use as modulators of the gabaa receptor complex | |
WO2012036278A1 (en) | Glycine transporter inhibitor | |
KR20130143141A (en) | Pyrazolidin-3-one derivatives | |
US20120046280A1 (en) | Novel heteropyrrole analogs acting on cannabinoid receptors | |
JP4943826B2 (en) | Pharmaceutical composition | |
TWI472514B (en) | Pyrazole compounds | |
JP3258531B2 (en) | Benzimidazole derivatives | |
AU2004201292A1 (en) | Novel pyrazole analogs acting on cannabinoid receptors | |
AU2002353895A1 (en) | Heteroindanes: a new class of potent cannabimimetic ligands |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW Kind code of ref document: A2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR CA CH CN CR CU CZ DE DK DM EE ES GB GD GE GH GM HR HU ID IL IN IS KE KG KP KR KZ LC LK LR LS LT LU MA MD MG MK MN MW MX NO NZ PT RO RU SD SE SG SI SK SL TJ TM TT TZ UA UG US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002768751 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2457922 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003524531 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10790498 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 2002768751 Country of ref document: EP |