Cholesteryl ester transfer protein inhibitors
View Patent ↗Compounds of Formula (I), including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. In the compounds of Formula (I), A 1 is a cyclic group, and B is a cyclic group which is attached to the heterocyclic ring directly or through a methylene group.
1. A compound of formula Ia, or a pharmaceutically acceptable salt thereof,
wherein the phenyl ring may optionally have —N═ in place of the —(CH)═ at the unsubstituted position that is ortho to the methylene group in formula Ia;
A 1 is phenyl, which is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) C 1-5 alkyl optionally substituted with 1-5 halogens and optionally 1 group —OH, (c) —OC 1-3 alkyl optionally substituted with 1-3 halogens, (d) C 2-4 alkenyl optionally substituted with 1-3 halogens, and (e) optionally one group selected from phenyl and C3-6cycloalkyl, said phenyl and cycloalkyl being optionally substituted with 1-3 substituents independently selected from halogen, —CO 2 H, —CO 2 C 1-3 alkyl optionally substituted with 1-3 halogens, C 1-3 alkyl optionally substituted with 1-3 halogens and optionally one —OH, and —OC 1-3 alkyl optionally substituted with 1-3 halogens;
A 2 is phenyl optionally substituted with 1-3 groups independently selected from halogen, C 1-3 alkyl optionally substituted with 1-3 halogens, —OCH 3 and —OCF 3 ;
each R a is independently selected from the group consisting of halogen, C 1-4 -alkyl optionally substituted with 1-3 halogens, C 2-3 alkenyl optionally substituted with 1-3 halogens, —OCH 3 , and —OCF 3 , wherein two R a groups on adjacent carbon atoms of the phenyl ring optionally may be joined to form a bridging moiety selected from —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, and —CH═CH—CH═CH—, thereby yielding a cyclopentyl, cyclohexyl, or phenyl ring fused to the phenyl ring, said cyclopentyl, cyclohexyl, and phenyl ring being optionally substituted with 1-2 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R 6 is C 1-3 alkyl optionally substituted with 1-3 halogens;
p is an integer from 1-3; and
n is an integer from 0-2.
2. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
3. The compound of claim 1 , which is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
wherein R is selected from the group consisting of:
4. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.
5. A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.
6. A method of lowering LDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.
7. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more active ingredients selected from the group consisting of:
(a) PPAR gamma agonists and partial agonists;
(b) biguanides;
(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,
(d) dipeptidyl peptidase IV (DP-IV) inhibitors;
(e) insulin or insulin mimetics;
(f) sulfonylureas;
(g) α-glucosidase inhibitors;
(h) one or more compounds selected from the group consisting of (a) HMG-CoA reductase inhibitors; (b) bile acid sequestrants; (c) niacin, nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof; (d) PPARα agonists; (e) cholesterol absorption inhibitors; (f) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors; (g) phenolic anti-oxidants, such as probucol, and (h) a microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;
(i) PPAR α/γ dual agonists;
(j) PPAR δ agonists;
(k) antiobesity compounds
(l) ileal bile acid transporter inhibitors;
(m) anti-inflammatory agents;
(n) glucagon receptor antagonists;
(o) GLP-1,
(p) GIP-1, and
(q) GLP-1 analogs.