Cyclic amine substituted oxazolidinone CETP inhibitor
| Title: | Cyclic amine substituted oxazolidinone CETP inhibitor |
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| Patent Number: | 9,221,834 |
| Publication Date: | December 29, 2015 |
| Appl. No: | 13/881896 |
| Application Filed: | October 25, 2011 |
| Abstract: | Compounds having the structure 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 compound of Formula I, A3 is a substituted phenyl group or indanyl group. Formula (I). [chemical expression included] |
| Inventors: | Lu, Zhijian (Clinton, NJ, US); Chen, Yi-Heng (Whippany, NJ, US); Smith, Cameron (Lawrenceville, NJ, US); Li, Hong (Edison, NJ, US); Thompson, Christopher F. (Arlington, MA, US); Hunt, Julianne (Montclair, NJ, US); Kallashi, Florida (Lawrence Harbor, NJ, US); Sweis, Ramzi (Lake Bluff, IL, US); Sinclair, Peter (Doylestown, PA, US); Adamson, Samantha E. (Charlottesville, VA, US); Dong, Guizhen (Dayton, NJ, US); Ondeyka, Debra L. (Fanwood, NJ, US); Qian, Xiaoxia (New York, NY, US); Sun, Wanying (Edison, NJ, US); Vachal, Petr (Summit, NJ, US); Zhao, Kake (Westfield, NJ, US) |
| Assignees: | Merck Sharp & Dohme Corp. (Rahway, NJ, US) |
| Claim: | 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: [chemical expression included] wherein A 3 is represented by Formula II: [chemical expression included] wherein Y is N or CH, wherein CH may be substituted with R c1 if R c1 is present in the structure; R 1 is CH 3 ; Each R a is independently CF 3 , CH 3 , —OCF 3 , Cl, F, cyclopropyl, or —CN; R c is (a) a 4-7 membered monocyclic heterocycle containing one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the monocyclic heterocycle optionally contains 1-2 double bonds, one carbonyl, and 1-2 additional heteroatom groups which are each independently N, O, or S(O) 2 , or (b) a 6-7 membered bicyclic heterocycle containing one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the bicyclic heterocycle optionally contains 1-2 double bonds, one carbonyl, and 1-2 additional heteroatom groups which are each independently N, O, or S(O) 2 , wherein R c as defined in (a) or (b) is optionally substituted with 1-2 substituent groups which are independently halogen, —OH, CH 3 , —OCH 3 , CF 3 , or —OCF 3 ; Each R c1 is independently —CH 3 or Br; R b is H, —C 1-2 alkyl, —OCH 3 , Cl, F, or —O-cyclopropyl; Each R b1 is F; X is: (a) Cl, —CH 2 CN, —(CH 2) 1-3 OH, —(CH 2) 1-3 OCH 3 , —CH(CH 3) 2 optionally substituted with 1-3 F and one —OH, -cyclopentyl-OH, -cyclohexyl-CN, or phenyl substituted with 2 substituents which are —OH and —C(═O)CH 3 ; (b) D 1 , wherein D 1 is —CO 2 H or —CO 2 C 1-4 alkyl; (c) —C 1-4 alkyl-D 2 , wherein D 2 is —CO 2 H, —CO 2 C 1-4 alkyl, or —C(═O)NR 2 R 3 ; (d) —C 3-6 cycloalkyl-D 2 ; (e) —C 3-6 cycloalkyl-CH 2 -D 1 ; (f) -phenyl-D 1 , wherein phenyl is optionally substituted with 1-3 substituents which are independently halogen or; (g) -HET(1)-D 1 -Het-D 1 , wherein HET(1) is a 5-6-membered heteroaromatic ring having 1-2 heteroatom groups which are each independently N, O, or S, wherein HET(1) is optionally substituted with 1-3 groups which are independently halogen, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 ; or (h) —(CH2) 1-2 -HET(2) wherein HET(2) is a 5-membered heteroaromatic ring having 2-4 N atoms, wherein HET(2) is optionally substituted with 1-2 groups which are independently —CH 3 or halogen; R 2 and R 3 are each independently H or —C 1-3 alkyl, or R 2 and R 3 are optionally joined to form a bridging group having 3-5 carbons, thereby yielding a 4-6 membered cyclic amide group; d is an integer from 0-2; e is an integer from 1-3; and f is an integer from 0-2. |
| Claim: | 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein HET(1) is isoxazole, pyrazole, pyrazine, thiophene, furan, thiazole, pyrrole, pyridine, or imidazole. |
| Claim: | 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein HET(2) is triazole, tetrazole, or imidazole. |
| Claim: | 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R c is (a) a 4-6 membered monocyclic heterocycle containing one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the monocyclic heterocycle optionally comprises one carbonyl and 1 additional heteroatom group which is O, N, or —S(O) 2 —; (b) a 5 membered monocyclic heteroaromatic ring containing one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the 5 membered monocyclic heteroaromatic ring optionally contains 1 additional heteroatom group which is N; or (c) a 6-7 membered bicyclic heterocycle containing one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the bicyclic heterocycle optionally contains 1 additional heteroatom group which is N or O; wherein R c as defined in (a), (b), or (c) is optionally substituted with 1-2 substituent groups which are each independently F, —OH, CH 3 , —OCH 3 , CF 3 , or —OCF 3 . |
| Claim: | 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the substituent R c is azetidine, azetidinone, pyrrolidine, piperidine, morpholine, imidazole, pyrazole, isothiazolidine 1,1-dioxide, a morpholine ring containing a methylene group bridging between two ring members, or a pyrrolidine ring containing a fused cyclopropyl ring, wherein R c is optionally substituted with 1-3 substituents which are each independently halogen, —OH, —CH 3 , —OCH 3 , —CF 3 , or —OCF 3 . |
| Claim: | 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R c is optionally substituted with 1-2 substituents which are each independently F, —CH 3 , —OH, or —OCH 3 . |
| Claim: | 7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure below: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] |
| Claim: | 8. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. |
| Claim: | 9. 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 to said patient, or a pharmaceutically acceptable salt thereof. |
| Claim: | 10. 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 to said patient, or a pharmaceutically acceptable salt thereof. |
| Claim: | 11. 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 to said patient, or a pharmaceutically acceptable salt thereof. |
| Claim: | 12. A method of treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof. |
| Claim: | 13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients which are: (i) HMG-CoA reductase inhibitors; (ii) bile acid sequestrants; (iii) niacin and related compounds; (iv) PPARα agonists; (v) cholesterol absorption inhibitors; (vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors; (vii) phenolic anti-oxidants; (viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors; (ix) anti-oxidant vitamins; (x) thyromimetics; (xi) LDL (low density lipoprotein) receptor inducers; (xii) platelet aggregation inhibitors; (xiii) vitamin B12 (also known as cyanocobalamin); (xiv) folic acid or a pharmaceutically acceptable salt or ester thereof; (xv) FXR and LXR ligands; (xvi) agents that enhance ABCA1 gene expression; or (xvii) ileal bile acid transporters. |
| Claim: | 14. The compound [chemical expression included] or a pharmaceutically acceptable salt thereof. |
| Patent References Cited: | 7652049 January 2010 Ali et al. 7781426 August 2010 Ali et al. 7910592 March 2011 Ali et al. 7915271 March 2011 Ali et al. 8871738 October 2014 Shao et al. 2015/0111866 April 2015 Acton, III et al. 2007/081569 July 2007 2007081569 July 2007 2011/028395 March 2011 |
| Other References: | Abu Khalaf; et al., “Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration”, European Journal of Medicinal Chemistry, vol. 45, pp. 1598-1617; 1599, Sec 2.1, 1604, Sec 2.5, 1605-1606, Sec 4.1.1(2010). cited by applicant |
| Assistant Examiner: | Sackey, Ebenezer O |
| Primary Examiner: | Wilson, James O |
| Attorney, Agent or Firm: | Meade, Eric A. Fitch, Catherine D. |
| Accession Number: | edspgr.09221834 |
| Database: | USPTO Patent Grants |
| Language: | English |
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