Therapeutic compounds for treating dyslipidemic conditions
View Patent ↗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.
1. A compound of formula I
or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein
R 1 is selected from the group consisting of:
(a) —CF 3 ,
(b) —CH 2 C(CH 3 ) 3 ,
(c) phenyl, unsubstituted, mono- or poly-substituted with halo,
(d) —C 1-6 alkyl, and
(e) —C 1-2 alkyl-phenyl;
R 2 is selected from the group consisting of:
(a) —C 1-6 alkyl,
(b) —COOR 3 ,
(c) —CR 3 R 4 —O—R 5 ,
(d) —CR 3 R 4 —S—R 5 , and
(e) —COR 3 ;
R 3 , R 4 and R 5 are independently selected at each occurrence from the group consisting of —H, phenyl, and C 1-6 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 R 1 is —CF 3 , R 2 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 R 7 ;
R 6 is independently selected at each occurrence from the group consisting of:
(a) —H,
(b) —C 1-6 alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —NR 3 R 4 , —OR 3 , —COOR 3 , and —CN,
(c) —C 1-6 alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(d) —C 3-6 cycloalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —OR 3 , —COOR 3 , and —CN,
(e) —C 3-6 cycloheteroalkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —(CH 2 ) n OR 3 , —OR 3 , —COOR 3 , and —CN, wherein n is an integer selected from 2, 3, 4, 5 and 6,
(f) —C 2-6 alkenyl,
(g) —C(O)C 1-6 alkyl,
(h) —COOR 3 ,
(i) —C(O)—(CH 2 ) p —COOR 3 , 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, —C 1-3 alkyl, and —COOR 3 ,
(k) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(l) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(m) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 , and
(n) thiazolyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ;
R 7 is independently selected at each occurrence from the group consisting of:
(a) ═O,
(b) —C 1-6 alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —CN, —COOR 3 , —COR 3 , and —OH,
(c) —C 1-6 alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —COOR 3 , tetrazole and —CN,
(d) —C 3-6 cycloalkyl,
(e) —C 3-6 spiroalkyl,
(f) —COOR 3 ,
(g) halo,
(h) —NR 3 R 4 ,
(i) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —COOR 3 and —C 1-4 alkyl,
(j) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(k) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 , and
(l) pyrazinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ; and
Z is selected from the group consisting of:
(a) —C 1-6 alkyl-,
(b) —C 1-6 alkyl-O—,
(c) —C 3-6 cycloalkyl-, and
(d) —C 3-6 cycloalkyl-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 —C 1-6 alkyl ester and (c) a substituted C 1-4 alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.
2. The compound of claim 1 wherein Z is —C 2-4 alkyl-O—.
3. The compound of claim 2 wherein
R 1 is selected from the group consisting of:
(a) —CF 3 ,
(b) —CH 2 C(CH 3 ) 3 , and
(c) phenyl, unsubstituted, mono- or poly-substituted with halo; and
R 2 is selected from the group consisting of:
(a) —C 1-6 alkyl, and
(b) —COR 3 .
4. The compound of claim 3 wherein R 2 is n-propyl.
5. The compound of claim 4 wherein 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:
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 R 7 .
6. The compound of claim 5 wherein R 6 is independently selected at each occurrence from the group consisting of:
(a) —H,
(b) —C 1-6 alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —NR 3 R 4 , —OR 3 , —COOR 3 , and —CN,
(c) —C 1-6 alkyl-phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(d) —C(O)—(CH 2 ) p —COOR 3 , wherein p is an integer selected from 2, 3 and 4,
(e) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 ,
(f) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 , and
(g) pyrimidinyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 .
7. The compound of claim 6 wherein R 7 is independently selected from the group consisting of:
(a) ═O,
(b) —CH 2 -phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —CN, —COOR 3 , —COR 3 , and —OH,
(c) —C 1-6 alkyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —OH, —COOR 3 , tetrazole and —CN,
(d) halo,
(e) —NH 2 ,
(f) phenyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —COOR 3 and —C 1-4 alkyl, and
(g) pyridyl, unsubstituted, mono- or poly-substituted with a substituent selected from the group consisting of halo, —C 1-3 alkyl, and —COOR 3 .
8. The compound of claim 2 wherein R 1 is selected from the group consisting of:
(a) —CF 3 , and
(b) phenyl, unsubstituted, mono- or poly-substituted with halo.
9. The compound of claim 8 wherein 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:
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 R 7 .
10. The compound of claim 2 wherein R 1 is —CF 3 .
11. The compound of claim 10 wherein 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:
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 R 7 .
12. The compound of claim 1 wherein Z is —C 3-6 cycloalkyl-O—.
13. The compound of claim 1 wherein Z is —C 4-6 alkyl-.
14. 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 —C 1-6 alkyl ester and (c) a substituted —C 1-4 alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.
15. A method for treating dyslipidemia comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.
16. The method of claim 15 wherein the dyslipidemia comprises depressed plasma HDL cholesterol level.
17. A method for treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.
18. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier.
19. 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 —C 1-6 alkyl ester and (c) a substituted —C 1-4 alkyl ester wherein the substituent is selected from the group consisting of phenyl-, dimethylamino- and acetylamino-.