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US 2009/0156640 A1Published application
Nociceptin analogs
AssigneeEuro-Celtique S.A.
InventorsQun SUN, R. Richard Goehring, Donald Kyle, Zhengming Chen, Sam Victory, John Whitehead
Life of this patent
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Abstract
A compound of the formula (I), (II), (III) or (IV) wherein Z, A, B, C, R, R1, R2, Q, and n are as described herein.
Claims30
A compound of the formula (I):
- wherein D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
- n is an integer from 0 to 3;
- A, B and Q are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, —NHSO2, hydroxyC1-10alkyl-, aminocarbonyl, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C1-5 bridge;
- Z is selected from the group consisting of a bond, straight or branched C1-6 alkylene, —NH—, —CH2O—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, —O— and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
- R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10 alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, —COOV1, —C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2—, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
- wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
- and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, —COOV1, —C1-4COOV1, cyanoC1-10alkyl-, —C1-5(═O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano;
- and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl C1-10 alkoxy, and cyano;
- W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, amino, C1-4alkylamino-, diC1-4allylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
- V1 is H, C1-6 alkyl, C3-6 cycloalkyl, benzyl or phenyl;
- R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group;
- or a pharmaceutically acceptable salt thereof or a solvate thereof.
9 more elements
A compound of the formula (IA):
- wherein n is an integer from 0 to 3;
- Z is selected from the group consisting of a bond, —CH2—, —NH—, —CH2O—, —CH2CH2—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;
- R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
- wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
- wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
- wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
- R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
- or a pharmaceutically acceptable salt thereof.
5 more elements
A compound selected from the group consisting of:
- 3-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(naphth-1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(p-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(p-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-[4,4-Bis-(4-fluorophenyl)butyl]-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(cyclooctylmethyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(5-methylhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(norbornan-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-{1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undeca-9-yl)-4-piperidinyl}-2H-benzoxazol-2-one;
- 3-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
- 3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-one;
- and pharmaceutically acceptable salts thereof.
17 more elements
A compound of the formula (IA):
- wherein R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
- n is an integer from 0 to 3;
- ZR1 is the following
- wherein Y1 is R3—(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6—(C3-C12)cyclo-alkyl, R7—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR8R9;
- Y2 is hydrogen or Y1;
- Y3 is hydrogen or (C1-C6)alkyl;
- or Y1, Y2 and Y3, together with the carbon to which they are attached, form one of the following
- structures:
- wherein r is 0 to 3;
- w and u are each 0-3, provided that the sum of w and u is 1-3;
- c and d are independently 1 or 2;
- s is 1 to 5;
- and ring E is a fused. R4-phenyl or R5-heteroaryl ring;
- R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6) alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 and —(C1-C6)alkyl-NR8R9;
- R11 is 1 to 3 substituents independently selected from the group consisting of R10, —CF3, —OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
- R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl (C1-C6) alkyl;
- R3 is 1 to 3 substituents independently selected from the group consisting of H, R4— aryl, R6—(C3-C12) cycloalkyl, R5-heteroaryl, R7—(C3-C7)heterocycloalkyl, —NR8R9, —OR12 and —S(O)0-2R12;
- R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, —NR8R9, —OR12 and —SR12;
- R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6) alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —SO2R8, —SOR8, —SR8, —NO2, —CONR8R9, —NR9COR8, —COR8, —COCF3, —OCOR8, —OCO2R8, —COOR8, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl-NHSO2—(C1-C6)alkyl, —(C1-C6)alkyl-NHCONH—(C1-C6)-alkyl and
- wherein f is 0 to 6;
- or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
- R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —NO2, —CONR8R9, —NR9COR8, —COR8, —OCOR8, —OCO2R8 and —COOR8;
- R7 is H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 or —(C1-C6)alkyl-NR8R9;
- R12 is H, (C1-C6)alkyl, R4-aryl, —(C1-C6) alkyl-OR8, —(C1-C6)alkyl-NR8R9, —(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
- R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6) alkoxy and halo;
- R14 is independently selected from the group consisting of H, (C1-C6)alkyl and R13—C6H4—CH2—;
- or a pharmaceutically acceptable salt thereof.
24 more elements
30-124. (canceled)
Dependencies are inferred from the claim text.