Claims
- 1. An assay for determining the affinity of a geranylgeranyl transferase type I inhibitor test compound for geranylgeranyl transferase type I binding sites in cultured cells which comprises measuring the competition between the test compound and a radiolabeled geranylgeranyl transferase type I inhibitor for the geranylgeranyl transferase type I binding sites.
- 2. The assay of claim 1 which comprises the steps of:
a) exposing a monolayer of cells to growth media containing the radiolabeled geranylgeranyl transferase type I inhibitor in the presence or absence of the test compound; b) washing the cells; C) counting the radiation emitted by the cells; and d) comparing the radiation emitted by cells exposed to the radiolabeled GGTase-I inhibitor and the test compound to the radiation emitted by cells exposed to only the radiolabeled GGTase-I inhibitor.
- 3. The assay of claim 2 wherein the radiolabeled GGTase-I is a compound selected from:
i) a compound of the formula A: 57wherein: R1b is independently selected from:
a) hydrogen, βb) aryl, heterocycle, cycloalkyl, R10O—, —N(R10)2 or C2-C6 alkenyl, βc) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O—, or —N(R10)2; R1c is independently selected from:
a) hydrogen, βb) R10O—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, NO2, R10 C(O)—, N3, —N(R10)2 or R11OC(O)NR10—, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10O—, R10C.(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, R10C(O)—, N3, —N(R10)2 and R11OC(O)-NR10—; R3 is selected from H and CH3; NR 6R7 R2 is selected from 58or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) 59and R2 and R3 are optionally attached to the same carbon atom; R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O—, R10C(O)NR10—, CN, NO2, (R10)2N—C(NR10)—, R10C(O)—, —N(R10)2, or R11OC(O)NR10—, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O—, R10C(O)NR10—, (R10)2N—C(NR10)—, R10C(O)—, —N(R10)2, or R11C(O)NR10—; R9a is hydrogen or methyl; R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R11 is independently selected from C1-C6 alkyl and aryl; A3 is selected from: —C(O)—, —C(O)NR10— or —C(O)O—; A4 is selected from: bond and —O—; Z is substituted C5-C7 cycloalkyl, wherein the substituted C5-C7 cycloalkyl is substituted with one or more C1-4 alkyl moieties and is optionally substituted with one or two moieties selected from the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) HO, f) —S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; p is 1, 2 or 3; r is 0 to 5, and v is 0, 1, 2 or 3; and wherein at least one radionuclide or 3H-methyl is present in the molecule; ii) a compound of the formula B: 60wherein: R1b, R1c, R2, R3, R6, R7, R6a, R8, R9a, R10, R11, A3, A4, m, p, r and v are as defined above for the compound of the formula A; Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1 4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) HO, f) —S(O)mR6a, g) halogen, h) perfluoroalkyl, and i) C1-4 alkyl; C7-C10 multicyclic alkyl ring is selected from: 61and wherein at least one radionuclide or H-methyl is present in the molecule; iii) a compound of the formula C: 62wherein: R1c, R3, R6, R7, R6a , R8, R10, R11, m, p and r are as defined above for the compound of the form ula A; R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, CN, R10O—, R10NC(O)—, —N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O—, or —N(R10)2; R2 is selected from 63or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) 64and R2 and R3 are optionally attached to the same carbon atom; R9a is hydrogen, C1-C6 alkyl or chloro; A3 is selected from: —C(O)—, —C(O)NR10—, —C(O)O— and S(O)m; Z is unsubstituted or substituted phenyl, unsubstituted or substituted napthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted quinoline or unsubstituted or substituted 1,2 methylenedioxybenzene; and v is 0, 1, 2 or 3; provided that v is not 0 if A3 is —C(O)— or S(O)m; and wherein at least one radionuclide or 3H-methyl is present in the molecule; iv) a compound of the formula D: 65wherein: R1b, R2, R3, R6, R7, R6a, R8, R9a, R10, R11, A3, m, p, r and v are as defined above for the compound of the formula A; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) —OR10, f) —S(O)mR6a, g) halogen, or h) perfluoroalkyl; and wherein at least one radionuclide or 3H-methyl is present in the molecule; v) a compound of the formula E: 66wherein: R1b, R8, R11, p and r are as defined above for the compound of the formula A; R9a is hydrogen, C1-C6 alkyl or chloro; R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; A3 is —C(O)—; Z is unsubstituted or substituted phenyl, unsubstituted or substituted napthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted 2,3-dihydrobenzofuran, unsubstituted or substituted quinoline or unsubstituted or substituted isoquinoline; and wherein at least one radionuclide or 3H-methyl is present in the molecule; or a pharmaceutically acceptable salt thereof.
- 4. The assay of claim 2 wherein the radiolabeled GGTase-I inhibitor is selected from a radiolabeled derivative of a compound selected from the group of compounds comprising:
1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3,5,5-tetramethyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazin-3-one-{4-[2-(1,3,3-trimethylcyclohexane)-1-ethyl]}1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(3,3-dimethylcyclohexyloxycarbonyl)-(cis)-2,6-dimethylpiperazine 1-(4-cyanobenzyl)-5-[1-(3,3-dimethylcylohexylacetyl)piperazin-4-ylmethyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2-hydroxy-2-cyclohexylacetamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-[(1R,2S,5R)-2-isopropyl-5-methyl]cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,6-dimethyl)cyclohexylmethyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2-tert-butyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3-methyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] 4-(2,2-dicyclohexyl)acetyl piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2,2-dimethyl-3-isobutenylcyclopropane)carboxamide 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl]piperazine-4-cyclohexyloxycarbonyl R/S 1-(4-Cyanobenzyl)-5-[1-(2-hydroxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-(4-Cyanobenzyl)-5-[1-(2-acetyloxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-1-adamantyl)carboxamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(N-1-adamantyl)carbonyl piperazine 1-(4-Cyanobenzyl)-5-[1-(2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid (2-norbomane)methyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine4-carboxylic acid (2-norbornane)methyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(2-bicyclo-[2.2.2]-octylcarbonyl)piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-cis/trans-(2,6,6-trimethylbicyclo[3.1.1 ]heptanecarbonyl)-piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-phenyl-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[cyclohexylphenylacetyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(3-methoxyphenyl)-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(3-phenoxyphenyl)-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyano-3-fluorobenzyl) imidazol-5-ylmethyl]-4-[1-(3-hydroxyphenyl)-1-cyclohexylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(2,6-dimethoxy)benzyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(DL-2-hydroxy-2-(o-methoxyphenyl)) acetarnide 1-[1-(4′-methylbenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(4-nitro)phenyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-3-isopropenyl-1,1-dimethylbenzyl)carboxamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-2-chlorobenzyl)carboxamide 1-[(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-2,4-dimethylbenzyloxycarbonyl 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2-methylbenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-[(3′-methylbenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2′-methoxybenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(4′-pyridinemethyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2′,5′-dimethylbenzyloxycarbonyl) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,2-dimethyl)propyl ester 1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(N-(1,1,3,3-tetramethyl)-butyl) carboxamide]piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2,5,5-tetramethyl)hexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2-dimethyl)pent-3-yl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)butyric ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2-hydroxy-4,4-dimethyl)valeramide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,2-dimethyl)propyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid-(2-t-butoxy)ethyl ester 1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(N-(1,1,3,3-tetramethyl)-butyl) carboxamide]piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2,5,5-tetramethyl)hexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2-dimethyl)pent-3-yl ester 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-methoxyquinolin-4-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-diethylamino-3-ethoxypyrid-5-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-ethylamino-4-isoquinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-bromo-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[5-(pent-1-ynyl)-1-naphthoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[5-(prop-1-ynyl)-1-naphthoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-propyl-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(4-bromo-3-methylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[3-methyl-4-(prop-1-ynyl)benzoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-methyl-4-pentylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-cyclopropyleth-ynyl-5-methoxybenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-methoxy-2-pent-1-ynylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-chloro-2-cyclohexylethynylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-chloro-2-cyclohexylethylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(4-indoloyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3,5-dimethylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(8-quinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-ethoxy-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-quinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-methoxy-4-methylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(6-diethylamino-pyrid-2-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(1-isoquinolinoyl)piperazine or a pharmaceutically acceptable salt or optical isomer thereof.
- 5. The assay of claim 2 wherein the radiolabeled GGTase-I inhibitor is selected from a radiolabeled derivative of a compound selected from the group of compounds comprising:
(R,S) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2R,6R-dimethyl)cyclohexylmethyl ester 67(R,S) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2R,6S-dimethyl)cyclohexylmethyl ester 681-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3,5,5-tetramethyl)cyclohexyl ester 691-(4′-Cyanobenzyl) irnidazol-5-ylmethyl piperazine-4-(2,2-dimethyl-3-isobutenylcyclopropane)carboxamide 70(±)-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)cyclohexyl ester 711-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(2,6-dimethoxy)benzyl ester 721-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 731-[1-(4′-methylbenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 741-[1-(4′-cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(2-ethoxybenzyloxycarbonyl] piperazine 751-[1-(4′-Cyanobenzyl)imidazol-5-ylmethyl]-piperazine-4-(N-2-(ethoxybenzyl)carbamide) 761-[1-1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-{1-[(2-ethoxypyridin-3-yl)methyloxycarbonyl] piperazine 774-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[3-methyl-4-(prop-1-ynyl)benzoyl]piperazine 784-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(6-diethylamino-pyrid-2-oyl)piperazine 794-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(1-naphthoyl)piperazine 80or a pharmaceutically acceptable salt or optical isomer thereof.
- 6. The assay of claim 2 wherein the radiolabeled GGTase-I inhibitor is:
- 7. A compound selected from:
i) a compound of the formula A: 82wherein: R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O—, —N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O—, or —N(R10)2; R1c is independently selected from: a) hydrogen, b) R10O—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, NO2, R10C(O)—, N3, —N(R10)2 or R11OC(O)NR10—, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10O—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, R10C(O)—, N3, —N(R10)2 and R11OC(O)—NR10—; R3 is selected from H and CH3; R2 is selected from 83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) 84and R2 and R3 are optionally attached to the same carbon atom; R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O—, R10C(O)NR10—, CN, NO2, (R10)2N—C(NR10)—, R10C(O)—, —N(R10)2, or R10C(O)NR10—, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O—, R10C(O)NR10—, (R10)2N—C(NR10)—, R10C(O)—, —N(R10)2, or R10C(O)NR10—; R9a is hydrogen or methyl; R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R11 is independently selected from C1-C6 alkyl and aryl; A3 is selected from: —C(O)—, —C(O)NR10— or —C(O)O—; A4 is selected from: bond and —O—; Z is substituted C5-C7 cycloalkyl, wherein the substituted C5-C7 cycloalkyl is substituted with one or more C1-4 alkyl moieties and is optionally substituted with one or two moieties selected from the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) HO, f) —S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; p is 1,2 or 3; r is 0 to 5, and v is 0, 1, 2 or 3; and wherein at least one radionuclide or 3H-methyl is present in the molecule; ii) a compound of the formula B: 85wherein: R1b, R1c, R2, R3, R6, R7, R6a, R8, R9a, R10 , R11, A3, A4, m, p, r and v are as defined above for the compound of the formula A; Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) HO, f) —S(O)mR6a, g) halogen, h) perfluoroalkyl, and i) C1-4alkyl; C7-C10 multicyclic alkyl ring is selected from: 86and wherein at least one radionuclide or 3H-methyl is present in the molecule; iii) a compound of the formula C: 87wherein: R1c, R3, R6, R7, R6a, R8, R10, R11, m, p and r are as defined above for the compound of the formula A; R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, CN, R10O—, R10NC(O)—, —N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O—, or —N(R10)2; R2 is selected from 88or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one ormoreof: 1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) 89and R2 and R3 are optionally attached to the same carbon atom; R9a is hydrogen, C1-C6 alkyl or chloro; A3 is selected from: —C(O)—, —C(O)NR10—, —C(O)O— and S(O)m; Z is unsubstituted or substituted phenyl, unsubstituted or substituted napthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted quinoline or unsubstituted or substituted 1,2 methylenedioxybenzene; and v is 0, 1, 2 or 3; provided that v is not 0 if A3 is —C(O)— or S(O)m; and wherein at least one radionuclide or 3H-methyl is present in the molecule; iv) a compound of the formula D: 90wherein: R1b, R2, R3, R6, R7, R6a, R8 R9a, R10, R11, A3, m, p, r and v are as defined above for the compound of the formula A; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) —NR6C(O)R7, e) —OR10, f) —S(O)mR6a, g) halogen, or h) perfluoroalkyl; and wherein at least one radionuclide or 3H-methyl is present in the molecule; v) a compound of the formula E: 91wherein: R1b, R8, R11, p and r are as defined above for the compound of the formula A; R9a is hydrogen, C1-C6 alkyl or chloro; R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; A3 is —C(O)—; Z is unsubstituted or substituted phenyl, unsubstituted or substituted napthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted 2,3-dihydrobenzofuran, unsubstituted or substituted quinoline or unsubstituted or substituted isoquinoline; and wherein at least one radionuclide or 3H-methyl is present in the molecule; or a pharmaceutically acceptable salt thereof.
- 8. A radiolabeled derivative of a compound selected from the group of compounds comprising:
1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3,5,5-tetramethyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazin-3-one-{4-[2-(1,3,3-trimethylcyclohexane)-1-ethyl]}
1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(3,3-dimethylcyclohexyloxycarbonyl)-(cis)-2,6-dimethylpiperazine 1-(4-cyanobenzyl)-5-[1-(3,3-dimethylcylohexylacetyl)piperazin-4-ylmethyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2-hydroxy-2-cyclohexylacetamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-[(1R,2S,5R)-2-isopropyl-5-methyl]cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,6-dimethyl)cyclohexylmethyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2-tertbutyl)cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3-methyl )cyclohexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] 4-(2,2-dicyclohexyl)acetyl piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2,2-dimethyl-3-isobutenylcyclopropane)carboxamide 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethylpiperazine-4-cyclohexyloxycarbonyl R/S 1-(4-Cyanobenzyl)-5-[1-(2-hydroxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-(4-Cyanobenzyl)-5-[1-(2-acetyloxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-1-adamantyl)carboxamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(N-1-adamantyl)carbonyl piperazine 1-(4-Cyanobenzyl)-5-[1-(2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid (2-norbomane)methyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2-norbomane)methyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(2-bicyclo-[2.2.2]-octylcarbonyl)piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-cis/trans-(2,6,6-trimethylbicyclo[3.1.1]heptanecarbonyl)-piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-phenyl-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[cyclohexylphenylacetyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(3-methoxyphenyl)-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(3-phenoxyphenyl)-1-cyclopentylcarbonyl] piperazine 1-[1-(4′-Cyano-3-fluorobenzyl) imidazol-5-ylmethyl]-4-[1-(3-hydroxyphenyl)-1-cyclohexylcarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(2,6-dimethoxy)benzyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(DL-2-hydroxy-2-(o-methoxyphenyl)) acetamide 1-[1-(4′-methylbenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(4-nitro)phenyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-3-isopropenyl-1,1-dimethylbenzyl)carboxamide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-(N-2-chlorobenzyl)carboxamide 1-[(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-2,4-dimethylbenzyloxycarbonyl 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2-methylbenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-[(3′-methylbenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2′-methoxybenzyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(4′-pyridinemethyloxycarbonyl) 1-[1-(4-cyanophenyl)methylimidazol-5-ylmethyl] piperazine-4-(2′,5′-dimethylbenzyloxycarbonyl) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,2-dimethyl)propyl ester 1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(N-(1,1,3,3-tetramethyl)-butyl) carboxamide]piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2,5,5-tetramethyl)hexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2 -dimethyl)pent-3-yl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)butyric ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-(2-hydroxy-4,4-dimethyl)valeramide 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2,2-dimethyl)propyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid-(2-t-butoxy)ethyl ester 1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(N-(1,1,3 ,3-tetramethyl)-butyl) carboxamide]piperazine 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2,5,5-tetramethyl)hexyl ester 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2,2-dimethyl)pent-3-yl ester 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl] 1-(2-methoxyquinolin-4-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-diethylamino-3-ethoxypyrid-5-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-ethylamino-4-isoquinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-bromo-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[5-(pent-1-ynyl)-1-naphthoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[5-(prop-1-ynyl)-1-naphthoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-propyl-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(4-bromo-3-methylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[3-methyl-4-(prop-1-ynyl)benzoyl]piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-methyl-4-pentylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-cyclopropyleth-ynyl-5-methoxybenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-methoxy-2-pent-1-ynylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-chloro-2-cyclohexylethynylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(5-chloro-2-cyclohexylethylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(4-indoloyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3 ,5-dimethylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(8-quinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-ethoxy-1-naphthoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2-quinolinoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(3-methoxy-4-methylbenzoyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(6-diethylamino-pyrid-2-oyl)piperazine 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(1-isoquinolinoyl)piperazine or a pharmaceutically acceptable salt thereof.
- 9. A radiolabeled derivative of a compound selected from the group of compounds comprising:
(R,S) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2 R,6R-dimethyl)cyclohexylmethyl ester 92(R,S) 1-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(2R,6S-dimethyl)cyclohexylmethyl ester 931-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3,5,5-tetramethyl)cyclohexyl ester 941-(4-Cyanobenzyl)imidazol-5-ylmethyl piperazine-4-(2,2-dimethyl-3-isobutenylcyclopropane)carboxamide 95(±)(1-[1-(4′-Cyanobenzyl) irnidazol-5-ylmethyl]piperazine-4-carboxylic acid-(3,3-dimethyl)cyclohexyl ester 961-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl] piperazine-4-carboxylic acid-(2,6-dimethoxy)benzyl ester 971-[1-(4′-Cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 981-[1-(4′-methylbenzyl) imidazol-5-ylmethyl]-4-[1-(2,6-dimethylbenzyloxycarbonyl] piperazine 991-[1-(4′-cyanobenzyl) imidazol-5-ylmethyl]-4-[1-(2-ethoxybenzyloxycarbonyl] piperazine 1001-[1-(4′-Cyanobenzyl)imidazol-5-ylmethyl]-piperazine-4-(N-2-(ethoxybenzyl)carbamide) 1011-[-1-1-(4′-Cyanobenzyl) irnidazol-5-ylmethyl]-4-{1-[(2-ethoxypyridin-3-yl)methyloxycarbonyl] piperazine 1024-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-[3-methyl-4-(prop-1-ynyl)benzoyl]piperazine 1034-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(6-diethylamino-pyrid-2-oyl)piperazine 1044-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(1-naphthoyl)piperazine 105or a pharmaceutically acceptable salt or optical isomer thereof.
- 10. A compound which is:
RELATED APPLICATION
[0001] The present patent application claims the benefit of co-pending provisional application Ser. No. 60/230,270, filed Sep. 6, 2000.
Provisional Applications (1)
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Number |
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60230270 |
Sep 2000 |
US |