US 7,125,865 B2Granted

Therapeutic compounds for treating dyslipidemic conditions

AssigneeMerck & Co., Inc.

InventorsA. Brian Jones, Alan D. Adams, Ahren I. Green, Shaei Y. Huang, Bruno Tse, Clare E. Gutteridge, Yuan Cheng

Life of this patent

Estimating the term…

Abstract

The present invention relates to novel LXR ligands of Formula I and the pharmaceutically acceptable salts, esters and tautomers thereof, which are useful in the treatment of dyslipidemic conditions, particularly depressed levels of HDL cholesterol.

Claims19

Dependent claims

A compound of formula I

or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein
R1 is selected from the group consisting of:
(a) —CF3,
(b) —CH2C(CH3)3,
(c) phenyl, unsubstituted, mono- or poly-substituted with halo,
(d) —C1-6 alkyl, and
(e) —C1-2alkyl-phenyl;
R2 is selected from the group consisting of:
(a) —C1-6 alkyl,
(b) —COOR3,
(c) —CR3R4—O—R5,
(d) —CR3R4—S—R5, and
(e) —COR3;
R3, R4 and R5 are independently selected at each occurrence from the group consisting of —H, phenyl, and C1-6 alkyl;
Y is joined together with the nitrogen and the carbonyl carbon shown in Formula I to which Y is respectively attached, to form a heterocyclic ring selected from:
(a) a 5-membered heterocyclic ring selected from the group consisting of:
(b) a 6-membered heterocyclic ring selected from the group consisting of:
provided that when R1 is —CF3, R2 is n-propyl, and Z is n-propyloxy, the 6-membered heterocyclic ring is not unsubstituted 5,6 dihydrouracil,
(d) a bicyclic heterocyclic ring selected from the group consisting of:
wherein each carbon atom in the heterocyclic ring, formed when Y is joined together with the nitrogen and the carbonyl carbon shown in Formula I, is independently unsubstituted, mono- or di-substituted with a substituent independently selected at each occurrence from R7;
R6 is independently selected at each occurrence from the group consisting of:
(a) —H,
(b) —C1-6alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —NR3R4, —OR3, —COOR3, and —CN,
(c) —C1-6alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(d) —C3-6cycloalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —OR3, —COOR3, and —CN,
(e) —C3-6cycloheteroalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —(CH2)nOR3, —OR3, —COOR3, and —CN, wherein n is an integer selected from 2, 3, 4, 5 and 6,
(f) —C2-6alkenyl,
(g) —C(O)C1-6alkyl,
(h) —COOR3,
(i) —C(O)—(CH2)p—COOR3, wherein p is an integer selected from 2, 3 and 4,
(j) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(k) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(l) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(m) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3, and
(n) thiazolyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3;
R7 is independently selected at each occurrence from the group consisting of:
(a) ═O,
(b) —C1-6alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —CN, —COOR3, —COR3, and —OH,
(c) —C1-6alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —COOR3, tetrazole and —CN,
(d) —C3-6 cycloalkyl,
(e) —C3-6 spiroalkyl,
(f) —COOR3,
(g) halo,
(h) —NR3R4,
(i) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —COOR3 and —C1-4alkyl,
(j) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(k) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3, and
(l) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3;
and
Z is selected from the group consisting of:
(a) —C1-6alkyl-,
(b) —C1-6alkyl-O—,
(c) —C3-6cycloalkyl-, and
(d) —C3-6cycloalkyl-O—;
and wherein the pharmaceutically acceptable ester of the compound of formula I is selected from the group consisting of (a) a phenyl ester, (b) a —C1-6alkyl ester and (c) a substituted C1-4alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.

52 more elements

A compound selected from the group consisting of:

(1) 1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;
(2) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;
(3) 2-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1H-isoindole-1,3(2H)-dione;
(4) 3,3-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;
(5) 3-methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;
(6) 3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;
(7) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;
(8) 5,5-dimethyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;
(9) [2,4-dioxo-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3-thiazolidin-5-yl]acetic acid;
(10) 3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(11) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(12) 1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(13) 5(R)-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(14) 5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(15) 1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(16) 5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(17) 5-methyl-5-phenyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(18) 5-methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(19) 5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione;
(20) 5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(21) 5-methyl-5-(4-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(22) 5-methyl-5-(3-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(23) 5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(24) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrimidin-2-ylimidazolidine-2,4-dione;
(25) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione;
(26) 3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoic acid;
(27) 4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]butanoic acid;
(28) 4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoic acid;
(29) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one;
(30) methyl 2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoate;
(31) 2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic acid;
(32) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(33) 5,5-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(34) 1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;
(35) 1-[trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;
(36) 1-{4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl}dihydropyrimidine-2,4(1H,3H)-dione;
(37) 5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(38) 6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(39) 5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(40) 1,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(41) 1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(42) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione;
(43) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H1,2′-bipyrimidine-2,4(3H)-dione;
(44) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione;
(45) 1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;
(46) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;
(47) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione;
(48) 1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione;
(49) 4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione;
(50) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2,5-dione;
(51) 4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one;
(52) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3,5-triazinane-2,4-dione;
(53) 3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(54) 6-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
and
(55) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one;
and pharmaceutically acceptable salts, esters and tautomers thereof, wherein the pharmaceutically acceptable ester are selected from the group consisting of (a) a phenyl ester, (b) a —C1-6alkyl ester and (c) a substituted —C1-4alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.

54 more elements

A compound selected from the group consisting of:

(1) 11-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one;
(2) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;
(3) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;
(4) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(5) 1-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(6) 5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(7) 1-Phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(8) 1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(9) 5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(10) 5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione;
(11) 5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(12) 5-(3-carboxyphenyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(13) 5-(2-Pyridyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(14) 5-Phenyl-5-(3-propionyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;
(15) 2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic acid;
(16) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;
(17) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione;
(18) 1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione;
(19) 1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;
(20) 3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione;
(21) 6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(22) 1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;
(23) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione;
(24) 3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione;
and
(25) 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one,
and pharmaceutically acceptable salts, esters and tautomers thereof, wherein the pharmaceutically acceptable ester are selected from the group consisting of (a) a phenyl ester, (b) a —C1-6alkyl ester and (c) a substituted —C1-4alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.

24 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/522,114Filed 21 Jul 2003 · us provisional application
Priority: 25 Jul 2002
Published: US 2005/0239769 A127 Oct 2005
Granted: 24 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 261/20
Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings: condensed with carbocyclic rings or ring systems
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links

Family

Application60/398,716Us provisional application · filed 25 Jul 2002
US 2005/0239769 A1Pre-grant publication · published 27 Oct 2005
US 7,125,865 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I

or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein
R1 is selected from the group consisting of:
(a) —CF3,
(b) —CH2C(CH3)3,
(c) phenyl, unsubstituted, mono- or poly-substituted with halo,
(d) —C1-6 alkyl, and
(e) —C1-2alkyl-phenyl;
R2 is selected from the group consisting of:
(a) —C1-6 alkyl,
(b) —COOR3,
(c) —CR3R4—O—R5,
(d) —CR3R4—S—R5, and
(e) —COR3;
R3, R4 and R5 are independently selected at each occurrence from the group consisting of —H, phenyl, and C1-6 alkyl;
Y is joined together with the nitrogen and the carbonyl carbon shown in Formula I to which Y is respectively attached, to form a heterocyclic ring selected from:
(a) a 5-membered heterocyclic ring selected from the group consisting of:
(b) a 6-membered heterocyclic ring selected from the group consisting of:
provided that when R1 is —CF3, R2 is n-propyl, and Z is n-propyloxy, the 6-membered heterocyclic ring is not unsubstituted 5,6 dihydrouracil,
(d) a bicyclic heterocyclic ring selected from the group consisting of:
wherein each carbon atom in the heterocyclic ring, formed when Y is joined together with the nitrogen and the carbonyl carbon shown in Formula I, is independently unsubstituted, mono- or di-substituted with a substituent independently selected at each occurrence from R7;
R6 is independently selected at each occurrence from the group consisting of:
(a) —H,
(b) —C1-6alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —NR3R4, —OR3, —COOR3, and —CN,
(c) —C1-6alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(d) —C3-6cycloalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —OR3, —COOR3, and —CN,
(e) —C3-6cycloheteroalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —(CH2)nOR3, —OR3, —COOR3, and —CN, wherein n is an integer selected from 2, 3, 4, 5 and 6,
(f) —C2-6alkenyl,
(g) —C(O)C1-6alkyl,
(h) —COOR3,
(i) —C(O)—(CH2)p—COOR3, wherein p is an integer selected from 2, 3 and 4,
(j) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(k) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(l) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(m) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3, and
(n) thiazolyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3;
R7 is independently selected at each occurrence from the group consisting of:
(a) ═O,
(b) —C1-6alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —CN, —COOR3, —COR3, and —OH,
(c) —C1-6alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —COOR3, tetrazole and —CN,
(d) —C3-6 cycloalkyl,
(e) —C3-6 spiroalkyl,
(f) —COOR3,
(g) halo,
(h) —NR3R4,
(i) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —COOR3 and —C1-4alkyl,
(j) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3,
(k) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3, and
(l) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C1-3alkyl, and —COOR3;
and
Z is selected from the group consisting of:
(a) —C1-6alkyl-,
(b) —C1-6alkyl-O—,
(c) —C3-6cycloalkyl-, and
(d) —C3-6cycloalkyl-O—;
and wherein the pharmaceutically acceptable ester of the compound of formula I is selected from the group consisting of (a) a phenyl ester, (b) a —C1-6alkyl ester and (c) a substituted C1-4alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.

52 more elements

Facts

Application

10/522,114Filed 21 Jul 2003 · us provisional application

Priority

25 Jul 2002

Published

US 2005/0239769 A127 Oct 2005

Granted

24 Oct 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 261/20
Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings: condensed with carbocyclic rings or ring systems
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links