WO2003020217A2 - Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides - Google Patents

Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides Download PDF

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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
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WO2003020217A3 (fr
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Alexandros Makriyannis
Qian Liu
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University of Connecticut
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University of Connecticut
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Priority to JP2003524531A priority Critical patent/JP2005507875A/ja
Priority to CA002457922A priority patent/CA2457922A1/fr
Priority to EP02768751A priority patent/EP1421077A4/fr
Priority to AU2002331766A priority patent/AU2002331766A1/en
Publication of WO2003020217A2 publication Critical patent/WO2003020217A2/fr
Publication of WO2003020217A3 publication Critical patent/WO2003020217A3/fr
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Priority to US10/790,498 priority patent/US7393842B2/en
Priority to US11/166,835 priority patent/US8084467B2/en
Priority to US11/244,770 priority patent/US7745440B2/en
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    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

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

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Abstract

L'invention concerne des analogues de pyrazole cannabimimétiques. L'invention concerne également de nouveaux analogues de pyrazole améliorés présentant de hautes affinités et/ou sélectivités pour le récepteur cannabinoïde GB1. L'invention concerne en outre des préparations pharmaceutiques dans lesquelles sont utilisées les analogues de l'invention, ainsi que des méthodes d'administration de quantités efficaces d'un point de vue thérapeutique des analogues de l'invention afin d'obtenir un effet physiologique.
PCT/US2002/027644 1999-10-18 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides Ceased WO2003020217A2 (fr)

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JP2003524531A JP2005507875A (ja) 2001-08-31 2002-08-29 カンナビノイド受容体に作用する新規なピラゾール類似体
CA002457922A CA2457922A1 (fr) 2001-08-31 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides
EP02768751A EP1421077A4 (fr) 2001-08-31 2002-08-29 Nouveaux analogues de pyrazole agissant sur les recepteurs cannabinoides
AU2002331766A AU2002331766A1 (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

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Cited By (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004099157A1 (fr) * 2003-05-07 2004-11-18 Pfizer Products Inc. Ligands de recepteurs cannabinoides et leurs applications
WO2004085385A3 (fr) * 2003-03-20 2004-11-25 Schering Corp Ligands de recepteurs de cannabinoides
WO2005007111A2 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
WO2005012256A1 (fr) 2003-07-22 2005-02-10 Astex Therapeutics Limited Composes 1h-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (cdk) et modulateurs de la glycogene synthase kinase-3 (gsk-3)
WO2005016877A3 (fr) * 2003-08-07 2005-04-28 Merck & Co Inc Carboxamides de pyrazole utilises comme inhibiteurs de la dehydrogenase-1 11-beta-hydroxysteroide
WO2005044822A1 (fr) * 2003-11-07 2005-05-19 Pfizer Products Inc. Composes bicycliques pyrazolyliques et imidazolyliques et leurs utilisations
US6900236B1 (en) 1999-10-18 2005-05-31 University Of Connecticut Cannabimimetic indole derivatives
US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
JP2005255685A (ja) * 2004-03-01 2005-09-22 Univ Of Connecticut カンナビノイド受容体に作用する新規なピラゾール類似体
US6972295B2 (en) 2002-03-12 2005-12-06 Merck & Co., Inc. Substituted amides
EP1602656A1 (fr) 2004-05-24 2005-12-07 NEUROSCIENZE PHARMANESS S.C. a R.L. Derivees du pyrazole presentant une affinite vis-a-vis des recepteurs cb1 et/ou cb2
WO2005080343A3 (fr) * 2004-02-20 2006-01-12 Astrazeneca Ab Agents therapeutiques
US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
EP1623741A2 (fr) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. LIGANDS DU RECEPTEUR CANNABINOIDE pour moduler LA POUSSE DES CHEVEUX
WO2006032851A1 (fr) 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006050842A1 (fr) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Derives dibenzosuberone
WO2006035310A3 (fr) * 2004-09-27 2006-06-01 Pfizer Prod Inc Procede permettant de preparer des composes de pyrazolyle bicycliques
US7057076B2 (en) 2001-07-13 2006-06-06 University Of Connecticut Bicyclic and tricyclic cannabinoids
WO2006067443A1 (fr) * 2004-12-23 2006-06-29 Astrazeneca Ab Agents thérapeutiques
WO2006077428A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
WO2006077424A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
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 (fr) * 2005-06-24 2006-12-29 Sanofi Aventis Sa Derives de 1-benzylpyrazole-3-acetamide, leur preparation et leur application en therapeutique
WO2007003960A1 (fr) * 2005-06-30 2007-01-11 Prosidion Limited Agonistes du gpcr
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
WO2007003961A3 (fr) * 2005-06-30 2007-03-01 Prosidion Ltd Agonistes de gpcr
WO2007046550A1 (fr) 2005-10-21 2007-04-26 Mitsubishi Tanabe Pharma Corporation Composes pyrazole presentant une activite antagoniste du recepteur cannabinoide (cb1)
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 (fr) * 2006-06-20 2007-12-27 Astrazeneca Ab Agents thérapeutiques
WO2007148062A1 (fr) * 2006-06-20 2007-12-27 Astrazeneca Ab Agents thérapeutiques
JP2008019205A (ja) * 2006-07-12 2008-01-31 Sanofi-Aventis Ｎ−［（１，５−ジフェニル−１ｈ−ピラゾール−３−イル）メチル］スルホンアミド誘導体、その調製法および治療におけるその応用
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 (fr) 2006-12-18 2008-06-26 7Tm Pharma A/S Modulateurs de récepteur cb1
WO2008081208A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081207A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081206A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081204A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes du gpcr de pipéridine
WO2008081205A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr de type pipéridine
JP2008526887A (ja) * 2005-01-10 2008-07-24 ユニバーシティ オブ コネチカット カンナビノイド受容体に作用する新規なヘテロピロール類似体
WO2009050523A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé à la protéine g de type azéditinyle
WO2009050522A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé a une protéine g de type azétidinyle
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2009037244A3 (fr) * 2007-09-20 2009-08-20 Solvay Pharm Bv 5-aryl-4,5-dihydro-(1h)-pyrazoles en tant qu'agonistes des récepteurs cannabinoïdes cb1
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
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 (fr) 2005-06-30 2011-04-13 Prosidion Limited Agonistes de GPCR
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2343302A1 (fr) 2004-07-12 2011-07-13 Cadila Healthcare Limited Derives tricycliques de pyrazole comme modulateurs des recepteurs cannabinoides
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
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 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
WO2013048989A3 (fr) * 2011-09-30 2013-05-23 National Health Research Institutes Composés de pyrazole
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014023367A1 (fr) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Hétérocycles à 5 chaînons contenant de l'azote substitués par carboxamide ou sulfonamide en tant que modulateurs pour le récepteur nucléaire orphelin ror gamma
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
US8916555B2 (en) 2012-03-16 2014-12-23 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
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 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
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
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7589220B2 (en) 1998-06-09 2009-09-15 University Of Connecticut Inhibitors of the anandamide transporter
US7161016B1 (en) 1998-11-24 2007-01-09 University Of Connecticut Cannabimimetic lipid amides as useful medications
US7276613B1 (en) 1998-11-24 2007-10-02 University Of Connecticut Retro-anandamides, high affinity and stability cannabinoid receptor ligands
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
US7119108B1 (en) 1999-10-18 2006-10-10 University Of Connecticut Pyrazole derivatives as cannabinoid receptor antagonists
EP1361876A4 (fr) 2001-01-26 2004-03-31 Univ Connecticut Nouveaux ligands cannabimimetiques
DE60237431D1 (de) 2001-01-29 2010-10-07 Univ Connecticut Rezeptor-selektive cannabimimetische aminoalkylindole

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3041343A (en) * 1959-10-14 1962-06-26 Sandoz Ltd 4-(thienyl-2'')-and 4-(pyridyl-3'')-5-aminopyrazoles
FR2692575B1 (fr) * 1992-06-23 1995-06-30 Sanofi Elf Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2742148B1 (fr) * 1995-12-08 1999-10-22 Sanofi Sa Nouveaux derives du pyrazole-3-carboxamide, procede pour leur preparation et compositions pharmaceutiques les contenant
US5939429A (en) * 1997-09-30 1999-08-17 Virginia Commonwealth University Cardiovascular uses of cannabinoid compounds
WO2001058869A2 (fr) * 2000-02-11 2001-08-16 Bristol-Myers Squibb Company Modulateurs de recepteurs aux cannabinoides, leurs procedes de preparation et utilisations de modulateurs de recepteurs aux cannabinoides pour le traitement de maladies respiratoires et non respiratoires

Cited By (131)

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US6939977B2 (en) 1998-05-04 2005-09-06 The University Of Connecticut Analgesic and immunomodulatory cannabinoids
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US6995187B1 (en) 1999-10-18 2006-02-07 University Of Connecticut Peripheral cannabinoid receptor (CB2) selective ligands
US7057076B2 (en) 2001-07-13 2006-06-06 University Of Connecticut Bicyclic and tricyclic cannabinoids
US6972295B2 (en) 2002-03-12 2005-12-06 Merck & Co., Inc. Substituted amides
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
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
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US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
JP2007211017A (ja) * 2003-03-20 2007-08-23 Schering Plough Corp カンナビノイドレセプターリガンド
WO2004085385A3 (fr) * 2003-03-20 2004-11-25 Schering Corp Ligands de recepteurs de cannabinoides
JP2006520795A (ja) * 2003-03-20 2006-09-14 シェーリング　コーポレイション カンナビノイドレセプターリガンド
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7354929B2 (en) 2003-04-23 2008-04-08 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
WO2004099157A1 (fr) * 2003-05-07 2004-11-18 Pfizer Products Inc. Ligands de recepteurs cannabinoides et leurs applications
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
WO2005007111A2 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
US7884113B2 (en) 2003-07-11 2011-02-08 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
WO2005007628A1 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
US8119808B2 (en) 2003-07-11 2012-02-21 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
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
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
EP2256106A1 (fr) 2003-07-22 2010-12-01 Astex Therapeutics Limited Composes 1H-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (CDK) et modulateurs de la glycogene synthase kinase-3 (GSK-3)
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
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
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
WO2005012256A1 (fr) 2003-07-22 2005-02-10 Astex Therapeutics Limited Composes 1h-pyrazole 3,4-disubstitues et leur utilisation en tant que kinases dependant des cyclines (cdk) et modulateurs de la glycogene synthase kinase-3 (gsk-3)
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
US7659408B2 (en) 2003-08-07 2010-02-09 Merck Sharp & Dhome Corp. Pyrazole carboxamides as inhibitors of 11-β-hydroxysteroid dehydrogenase-1
AU2004265299B2 (en) * 2003-08-07 2008-05-01 Merck & Co., Inc. Pyrazole carboxamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
WO2005016877A3 (fr) * 2003-08-07 2005-04-28 Merck & Co Inc Carboxamides de pyrazole utilises comme inhibiteurs de la dehydrogenase-1 11-beta-hydroxysteroide
US7326706B2 (en) 2003-08-15 2008-02-05 Bristol-Myers Squibb Company Pyrazine modulators of cannabinoid receptors
EA009742B1 (ru) * 2003-11-07 2008-04-28 Пфайзер Продактс Инк. Соединения бициклических пиразолила и имидазолила и их применение
US7151097B2 (en) 2003-11-07 2006-12-19 Pfizer Inc. Bicyclic pyrazolyl and imidazolyl compounds and uses thereof
WO2005044822A1 (fr) * 2003-11-07 2005-05-19 Pfizer Products Inc. Composes bicycliques pyrazolyliques et imidazolyliques et leurs utilisations
NL1027434C2 (nl) * 2003-11-07 2007-11-27 Pfizer Prod Inc Bicyclische pyrazolyl- en imidazolylverbindingen, en toepassingen daarvan.
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
RU2375349C2 (ru) * 2004-02-20 2009-12-10 Астразенека Аб Производные 3-замещенного 1,5-дифенилпиразола, полезные в качестве св1 модуляторов
AU2005214130B2 (en) * 2004-02-20 2008-03-06 Astrazeneca Ab 3-substituted 1,5-diphenylpyrazole derivatives useful as CB1 modulators
WO2005080343A3 (fr) * 2004-02-20 2006-01-12 Astrazeneca Ab Agents therapeutiques
JP2005255685A (ja) * 2004-03-01 2005-09-22 Univ Of Connecticut カンナビノイド受容体に作用する新規なピラゾール類似体
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
EP1602656A1 (fr) 2004-05-24 2005-12-07 NEUROSCIENZE PHARMANESS S.C. a R.L. Derivees du pyrazole presentant une affinite vis-a-vis des recepteurs cb1 et/ou cb2
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
JP2005350458A (ja) * 2004-05-24 2005-12-22 Neuroscienze Pharmaness Scarl 医薬化合物
EP2343302A1 (fr) 2004-07-12 2011-07-13 Cadila Healthcare Limited Derives tricycliques de pyrazole comme modulateurs des recepteurs cannabinoides
EP1623741A2 (fr) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. LIGANDS DU RECEPTEUR CANNABINOIDE pour moduler LA POUSSE DES CHEVEUX
WO2006032851A1 (fr) 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006035310A3 (fr) * 2004-09-27 2006-06-01 Pfizer Prod Inc Procede permettant de preparer des composes de pyrazolyle bicycliques
WO2006050842A1 (fr) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Derives dibenzosuberone
US7220743B2 (en) 2004-11-09 2007-05-22 Hoffmann-La Roche Inc. Heterocyclic CB1 receptor antagonists
WO2006067443A1 (fr) * 2004-12-23 2006-06-29 Astrazeneca Ab Agents thérapeutiques
JP2008526887A (ja) * 2005-01-10 2008-07-24 ユニバーシティ オブ コネチカット カンナビノイド受容体に作用する新規なヘテロピロール類似体
WO2006077424A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
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
WO2006077428A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
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
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
FR2887550A1 (fr) * 2005-06-24 2006-12-29 Sanofi Aventis Sa Derives de 1-benzylpyrazole-3-acetamide, leur preparation et leur application en therapeutique
WO2007003961A3 (fr) * 2005-06-30 2007-03-01 Prosidion Ltd Agonistes de gpcr
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
EP2308840A1 (fr) 2005-06-30 2011-04-13 Prosidion Limited Agonistes de GPCR
WO2007003960A1 (fr) * 2005-06-30 2007-01-11 Prosidion Limited Agonistes du gpcr
WO2007046550A1 (fr) 2005-10-21 2007-04-26 Mitsubishi Tanabe Pharma Corporation Composes pyrazole presentant une activite antagoniste du recepteur cannabinoide (cb1)
WO2007148062A1 (fr) * 2006-06-20 2007-12-27 Astrazeneca Ab Agents thérapeutiques
WO2007148061A1 (fr) * 2006-06-20 2007-12-27 Astrazeneca Ab Agents thérapeutiques
JP2008019205A (ja) * 2006-07-12 2008-01-31 Sanofi-Aventis Ｎ−［（１，５−ジフェニル−１ｈ−ピラゾール−３−イル）メチル］スルホンアミド誘導体、その調製法および治療におけるその応用
WO2008075012A1 (fr) 2006-12-18 2008-06-26 7Tm Pharma A/S Modulateurs de récepteur cb1
WO2008081204A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes du gpcr de pipéridine
WO2008081206A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081208A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081205A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr de type pipéridine
WO2008081207A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
EP2377863A1 (fr) 2007-01-04 2011-10-19 Prosidion Limited Agonistes du GPCR de piperidine
EP2377864A1 (fr) 2007-01-04 2011-10-19 Prosidion Limited Agonistes de GPCR piperidiniques
EP2383270A1 (fr) 2007-01-04 2011-11-02 Prosidion Limited Agonistes de GPCR de type piperidine
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
WO2009037244A3 (fr) * 2007-09-20 2009-08-20 Solvay Pharm Bv 5-aryl-4,5-dihydro-(1h)-pyrazoles en tant qu'agonistes des récepteurs cannabinoïdes cb1
US7928134B2 (en) 2007-09-20 2011-04-19 Solvay Pharmaceuticals B.V. 5-aryl-4,5-dihydro-(1H)-pyrazolines as cannabinoid CB1 receptor agonists
WO2009050522A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé a une protéine g de type azétidinyle
WO2009050523A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé à la protéine g de type azéditinyle
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
AU2012316331B2 (en) * 2011-09-30 2016-02-25 National Health Research Institutes Pyrazole compounds
EP2632919A4 (fr) * 2011-09-30 2014-04-16 Nat Health Research Institutes Composés de pyrazole
WO2013048989A3 (fr) * 2011-09-30 2013-05-23 National Health Research Institutes Composés de pyrazole
KR20130094341A (ko) * 2011-09-30 2013-08-23 내셔날 헬스 리서치 인스티튜트 피라졸 화합물
KR101586714B1 (ko) * 2011-09-30 2016-01-19 내셔날 헬스 리서치 인스티튜트 피라졸 화합물
US8962845B2 (en) 2011-09-30 2015-02-24 National Health Research Institutes Pyrazole compounds
TWI472514B (zh) * 2011-09-30 2015-02-11 Nat Health Research Institutes 吡唑類化合物
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
US8916555B2 (en) 2012-03-16 2014-12-23 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9382237B2 (en) 2012-03-16 2016-07-05 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9365556B2 (en) 2012-03-16 2016-06-14 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9346792B2 (en) 2012-03-16 2016-05-24 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014023367A1 (fr) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Hétérocycles à 5 chaînons contenant de l'azote substitués par carboxamide ou sulfonamide en tant que modulateurs pour le récepteur nucléaire orphelin 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 (fr) 2012-08-09 2017-01-18 Phenex Pharmaceuticals AG Azote substitue de carboxamide ou sulfonamide contenant des heterocycles a 5 chainons en tant que modulateurs de recepteur nucleaire orphelin gamma ror
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
US9540351B2 (en) 2013-09-18 2017-01-10 Axikin Pharmaceuticals, Inc. Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
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 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
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

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