NOVEL PYRAZOLE-BASED HMG CoA REDUCTASE INHIBITORS
First Claim
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1. A compound of the formula (I):
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or a pharmaceutically acceptable salt thereof, wherein;
R1 is hydrogen, halogen, C1-C7alkyl, C3-C8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R1 is optionally substituted;
R2 is R2bR2aNCO(CH2)n—
or R2b-J-C(O)NR2a(CH2)n—
;
J is a direct bond, O, or N;
R2a and R2b are each independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R2a and R2b is optionally substituted;
or R2a and R2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C1-C10 alkyl, C1-C10 haloalkyl, C3-C8 cycloalkyl, halogen, R7O—
, R7OOC(CH2)n—
, R7R8NCO(CH2)n—
, R7O2S(CH2)n—
, R8R7NSO2—
or NC—
;
R7 and R8 are each independently hydrogen, C1-C12 alkyl, aryl or aralkyl;
where alkyl, aryl or aralkyl of R7 and R8 is optionally substituted;
n is 0, 1 or 2;
R3 is hydrogen, C1-6 alkyl, C3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R3 is optionally substituted; and
--- is a bond or is absent.
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Abstract
Novel compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents are described. More specifically, potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG CoA reductase”) are described. Methods of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer'"'"'s Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis are also described.
7 Citations
20 Claims
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1. A compound of the formula (I):
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or a pharmaceutically acceptable salt thereof, wherein; R1 is hydrogen, halogen, C1-C7alkyl, C3-C8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R1 is optionally substituted; R2 is R2bR2aNCO(CH2)n—
or R2b-J-C(O)NR2a(CH2)n—
;J is a direct bond, O, or N; R2a and R2b are each independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R2a and R2b is optionally substituted;or R2a and R2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C1-C10 alkyl, C1-C10 haloalkyl, C3-C8 cycloalkyl, halogen, R7O—
, R7OOC(CH2)n—
, R7R8NCO(CH2)n—
, R7O2S(CH2)n—
, R8R7NSO2—
or NC—
;R7 and R8 are each independently hydrogen, C1-C12 alkyl, aryl or aralkyl;
where alkyl, aryl or aralkyl of R7 and R8 is optionally substituted;n is 0, 1 or 2; R3 is hydrogen, C1-6 alkyl, C3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R3 is optionally substituted; and--- is a bond or is absent. - View Dependent Claims (2, 3, 4, 5, 6, 7, 11, 12, 14, 15, 16, 17, 18)
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3. A compound according to claim 1 having the structural formula (II):
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or a pharmaceutically acceptable salt thereof, wherein; R2a and R2b are each independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R2a and R2b is optionally substituted;or R2a and R2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C1-C10 alkyl, C3-C8 cycloalkyl, halogen, R7O—
, R7OOC(CH2)n—
, R7R8NCO(CH2)n—
, R7O2S(CH2)n—
, R8R7NSO2—
or NC—
;R7 and R8 are each independently hydrogen, C1-C12 alkyl, aryl or aralkyl;
where alkyl, aryl or aralkyl of R7 and R8 is optionally substituted;n is 0, 1, or 2; and --- is a bond or is absent.
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4. A compound according to claim 3, wherein R2a is:
Where R4 and R5 are each independently hydrogen or lower alkyl; q is 0, 1 or 2; each R6 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or cyano; and p is 0, 1, 2, 3, 4, or 5.
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5. A compound according to claim 4 having the following (3R,5R) stereospecific formula (IIa):
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6. A compound according to claim 1 having the structure of formula (III):
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or a pharmaceutically acceptable salt thereof.
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7. A compound according to claim 6 having the following (3R,5R) stereospecific formula (IIIa):
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11. A compound according to claim 1 selected from the group consisting of:
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(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-(R)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid; 7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid; 7-{5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid; 7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid; 7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α
-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α
-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; 3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-heptanoic acid; 7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid; 7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid; 7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid; 3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α
-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid; (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid; 7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; 7-[5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; 7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; 7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; 7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; and (3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
ora pharmaceutically acceptable salt thereof.
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12. A compound of claim 11, wherein said pharmaceutically acceptable salt is a sodium salt.
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14. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, solvent or vehicle.
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15. A method of treating a subject suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer'"'"'s Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis comprising administering a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.
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16. A combination comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active agent.
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17. The combination of claim 16, wherein said second pharmaceutically active agent is a CETP inhibitor, a PPAR-activator, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, HDL-cholesterol raising agent, triglyceride lowering agent, a cholesterol synthesis inhibitor, a cholesterol modulating agent, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, bile acid sequestrant, an anti-hypertensive agent, or an acetylcholine esterase inhibitor.
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18. The combination of claim 16 further comprising a pharmaceutically acceptable carrier, diluent, solvent or vehicle.
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8. A compound of formula (IV):
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or a pharmaceutically acceptable salt thereof, wherein; R1 is hydrogen, halogen, C1-C7alkyl, C3-C8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R1 is optionally substituted; R2 is R2bR2aN(CH2)n—
or R2b-J-C(O)NR2a(CH2)n—
;J is a direct bond, O, or N; R2a and R2b are each independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R2a and R2b is optionally substituted;or R2a and R2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C1-C10 alkyl, C3-C8 cycloalkyl, halogen, R7O—
, R7OOC(CH2)n—
, R7R8NCO(CH2)n—
, R7O2S(CH2)n—
, R8R7NSO2—
or NC—
;R7 and R8 are each independently hydrogen, C1-C12 alkyl, aryl or aralkyl;
where alkyl, aryl or aralkyl of R7 and R8 is optionally substituted;n is 0, 1 or 2; R3 is hydrogen, C1-6 alkyl, C3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R3 is optionally substituted; and--- is a bond or is absent. - View Dependent Claims (9, 13)
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13. A compound according to claim 8 selected from the group consisting of:
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1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid (3-fluoro-benzyl)-methyl-amide; 1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid benzyl-methyl-amide; and 1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methyl-benzylamide;
ora pharmaceutically acceptable salt thereof.
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10. A compound of formula (V):
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or a pharmaceutically acceptable salt thereof, wherein; R1 is hydrogen, halogen, C1-C7alkyl, C3-C8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R1 is optionally substituted; R2 is R2bR2aNCO(CH2)n—
or R2b-J-C(O)NR2a(CH2)n—
;J is a direct bond, O, or N; R2a and R2b are each independently hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R2a and R2b is optionally substituted;or R2a and R2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C1-C10 alkyl, C3-C8 cycloalkyl, halogen, R7O—
, R7OOC(CH2)n—
, R7R8NCO(CH2)n—
, R7O2S(CH2)n—
, R8R7NSO2—
or NC—
;R7 and R8 are each independently hydrogen, C1-C12 alkyl, aryl or aralkyl;
where alkyl, aryl or aralkyl of R7 and R8 is optionally substituted;n is 0, 1 or 2; R3 is hydrogen, C1-6 alkyl, C3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R3 is optionally substituted; and--- is a bond or is absent.
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19. (canceled)
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20. (canceled)
Specification
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Current AssigneeWarner-Lambert Company LLC (Pfizer Inc.)
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Original AssigneePfizer Inc.
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InventorsBowles, Daniel Merritt, Pfefferkorn, Jeffrey A., Choi, Chulho, Hutchings, Richard H., Park, William K.C.
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Application NumberUS12/247,434Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/236.500CPC Class CodesA61P 13/08 of the prostateA61P 19/10 for osteoporosisA61P 25/28 for treating neurodegenerat...A61P 3/06 AntihyperlipidemicsA61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...C07D 231/12 with only hydrogen atoms, h...C07D 231/14 with hetero atoms or with c...C07D 401/06 linked by a carbon chain co...C07D 401/12 linked by a chain containin...C07D 405/06 linked by a carbon chain co...
