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(12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani Et Al US 200800 19978A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani et al. (43) Pub. Date: Jan. 24, 2008 (54) NITROGEN-CONTAINING HETEROCYCLIC (57) ABSTRACT COMPOUNDS AND METHODS OF USE The present invention provides compounds of Formula (I): THEREOF (75) Inventors: Anandan Palani, Bridgewater, NJ (US); Jing Su, Scotch Plains, NJ (US); (I) Dong Xiao, Warren, NJ (US); Xianhai Huang, Warren, NJ (US); Ashwin U. Rao, Avenel, NJ (US); Xiao Chen, Edison, NJ (US); Haiqun Tang, Belle Mead, NJ (US); Jun Qin, Edison, NJ (US); Ying R. Huang, Berkeley Heights, NJ (US); Robert G. Aslanian, Rockaway, NJ (US); Brian A. and pharmaceutically acceptable salts, Solvates, esters, and McKittrick, New Vernon, NJ (US); tautomers thereof, wherein: Sylvia J. Degrado, Scotch Plains, NJ Q is selected from the group consisting of: (US) Correspondence Address: SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (73) Assignee: Schering Corporation (21) Appl. No.: 11/771.538 (22) Filed: Jun. 29, 2007 (b) Related U.S. Application Data (63) Continuation-in-part of application No. 1 1/600,216, filed on Nov. 15, 2006, which is a continuation-in-part of application No. 11/432,133, filed on May 11, 2006. (60) Provisional application No. 60/681,848, filed on May 17, 2005. Provisional application No. 60/715,565, filed on Sep. 9, 2005. Provisional application No. 60/731,039, filed on Oct. 28, 2005. (c) Publication Classification (51) Int. Cl. A 6LX 3/59 (2006.01) A 6LX 3L/397 (2006.01) A6 IK 3/56 (2006.01) A6 IK 3L/60 (2006.01) A6 IK 38/16 (2006.01) A 6LX 39/395 (2006.01) (d) A6IP I/00 (2006.01) A6IP II/00 (2006.01) A6IP 3/00 (2006.01) A6IP 3/10 (2006.01) A6IP 35/00 (2006.01) A6IP 9/00 (2006.01) C07D 239/70 (2006.01) (52) U.S. Cl. ........................ 424/158.1: 514/12: 514/165; 514/171; 514/210.02; 514/210.05; 514/260.1; 544/278 US 2008/0019978 A1 Page 2 -continued -continued (g) (e) b R3 R O s Ra * R4. (h) i N O y s and O I. and f (i) L is selected from the group consisting of O ey (f) I. O O s pharmaceutically compositions comprising one or more compounds of formula (I), and methods of using the com pounds of formula (I). US 2008/00 19978 A1 Jan. 24, 2008 NITROGEN-CONTAINING HETEROCYCLC 0006 WO 2005/000217 describes combination therapies COMPOUNDS AND METHODS OF USE THEREOF for the treatment of dyslipidemia comprising the adminis tration of a combination of an anti-obesity agent and an REFERENCE TO PRIORITY APPLICATIONS anti-dyslipidemic agent. However, WO 2005/000217 fails to 0001. This application is a continuation-in-part of U.S. describe nicotinic acid receptor agonists, or combinations of patent application Ser. No. 1 1/600,216, filed Nov. 15, 2006, one or more nicotinic acid receptor agonists with a second which is a continuation-in-part of U.S. patent application therapeutic agent. Ser. No. 11/4327,133, filed May 11, 2006, which claims the benefit of priority from U.S. provisional patent applications, 0007 WO 2004/110375 describes combination therapies Ser. Nos. 60/681,848 filed May 17, 2005; 60/715,565 filed for the treatment of diabetes comprising the administration Sep. 9, 2005; and 60/731,039 filed Oct. 28, 2005, each of of a combination of an anti-obesity agent and an anti which is incorporated herein by reference in its entirety. diabetic agent. However, WO 2004/110375 fails to describe nicotinic acid receptor agonists, or combinations of one or FIELD OF THE INVENTION more nicotinic acid receptor agonists with a second thera 0002 The present invention relates to nicotinic acid peutic agent. receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders 0008 US 2004/0122033 describes combination therapies of the peripheral and central nervous system, hematological for the treatment of obesity comprising the administration of diseases, cancer, inflammation, respiratory diseases, gastro a combination of an appetite Suppressant and/or metabolic enterological diseases, diabetes, and non-alcoholic fatty rate enhancers and/or nutrient absorption inhibitors. How liver disease; pharmaceutical compositions comprising Such ever, US 2004/0122033 fails to describe nicotinic acid compounds; pharmaceutical compositions comprising nico receptor agonists, or combinations of one or more nicotinic tinic acid receptor agonist compounds in combination with acid receptor agonists with a second therapeutic agent. US other therapeutic agents; and methods of treatment using the 2004/0229844 describes combination therapies for treating compounds and compositions to treat conditions such as atherosclerosis comprising the administration of a combi metabolic syndrome, dyslipidemia, cardiovascular diseases, nation of nicotinic acid or another nicotinic acid receptor disorders of the peripheral and central nervous system, agonistanda DP receptor antagonist. However, the nicotinic hematological diseases, cancer, inflammation, respiratory acid agonists of US 2004/02298.44 are quite different from diseases, gastroenterological diseases, diabetes, hepatic Ste those of the present invention. atosis and non-alcoholic fatty liver disease. 0009 WO2005/077950 describes xanthine derivatives BACKGROUND OF THE INVENTION which are agonists of the nicotinic acid receptor HM74A. However, the xanthine derivatives of WO2005/077950 are 0003 Nicotinic acid has been used to treat metabolic quite different from the compounds of the present invention. syndrome and dyslipidemia. However, nicotinic acid has undesirable side effects such as flushing and diarrhea. It is therefore desirable to provide improved nicotinic acid recep SUMMARY OF THE INVENTION tor agonists with improved efficacy at treating metabolic 0010. In one embodiment, the present invention is syndrome and dyslipidemia, yet without the undesirable side directed to a compound of Formula (I): effects. The compounds of the present invention provide Such improved nicotinic acid receptor agonists. 0004) M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 (I) and M. Ridi, Gazzetta Chim. Ital. (1952) vol. 82, p 23 disclose syntheses of barbituric acid derivatives. FR 2563223 discloses nucleoside analogs. T. Paterson et al. J. Chem. Soc., Perkins Trans. I (1972), vol. 8, pp. 1041-1050 discloses the synthesis of 8-substituted pyrido 2,3-dipyrim idines. S. Rao, Indian J. Chem. (1974), 12(10), pp. 1028 1030 discloses the synthesis of pyrano 2,3-dipyrimidines. M. Skof, Heterocycles, (1999), 51(5), pp. 1051-1058 dis and pharmaceutically acceptable salts, Solvates, esters, and closes one step transformations of (S)-1-benzoyl-3-(E)- tautomers thereof, wherein: dimethylaminomethylidene-5-methoxycarbonyl-pyrroli 0011 Q is selected from the group consisting of: din-2-one into quinolizinyl- and 2H-2-pyranonyl-substituted alanine derivatives. R. Toplak J. Heterocyclic Chem. (1999), 36(1), pp. 225-235 discloses the synthesis of pyran-2-ones. (a) However, the compounds of the above references differ from those of the present invention. * R4 0005 WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combina tion of an anti-obesity agent and an anti-hypertensive agent. ins s However, WO 2004/110368 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic O acid receptor agonists with a second therapeutic agent. US 2008/00 19978 A1 Jan. 24, 2008 -continued -continued (b) (i) 0013) R' is selected from the group consisting of H, alkyl, arylalkyl, -alkylene-S-alkyl, alkenyl, alkynyl, haloalkyl, wherein an alkyl group can be optionally Substituted with one or more of the following groups, (c) which can be the same or different: —OH, cycloalkyl, —C(O)-alkyl, -alkylene-C(O) O-alkyl, -O-R', -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, halogen, -(CH2), N(R), -alkylene-cycloalkyl, or -alkylene-cycloalkenyl, 0014 wherein the cycloalkyl or the cycloalkyl por tion of said -alkylene-cycloalkyl of R' is unsubsti tuted or Substituted with one or more X groups, said aryl or the aryl portion of said -alkylene-aryl of R' is (d) unsubstituted or substituted with one or more Y groups, and said heteroaryl or the heteroaryl portion of said -alkylene-heteroaryl of R is unsubstituted or substituted with one or more Y groups: yer and 0015 R is selected from the group consisting of H, halogen, alkyl, haloalkyl, alkyl substituted with one or more —OH, - C(O)-alkyl, —C(O) O-alkyl, —C(O)—OH, - O R', -alkylene-O-alkyl, unsubsti tuted aryl, aryl substituted with one or more Ygroups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups, and halogen; or (e) 0016) R' and R together with the ring carbon atoms to which they are shown attached, form a 5- or 6-mem bered cycloalkenyl ring or a 5- or 6-membered hetero cyclic ring having 1 or 2 heteroatoms; 0017 R is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, cycloalkyl, -alkylene-cy cloalkyl, -alkylene-C(O) O-alkyl, -alkylene-O- C(O)-alkyl, alkenyl, aryl, and heteroaryl, 0018 wherein the cycloalkyl or the cycloalkyl por 0012 L is selected from the group consisting of: tion of said -alkylene-cycloalkyl of R is unsubsti tuted or Substituted with one or more X groups, said aryl of R is unsubstituted or substituted with one or (f) more Y groups, and said heteroaryl of R is unsub stituted or substituted with one or more Y groups: 0019 R is selected from the group consisting of H, halogen, alkyl, haloalkyl, —O-cycloalkyl, —O-alky (g) nyl, —O R', —C(O) O-alkyl, - S(O), R. - N(R), N(R) NH-C(O)-alkyl, - N(R)- NH C(O) O-alkyl, - O N=C(R') - N(R)- N=C(R'), C(O)-alkyl, unsubstituted heterocyclyl, (h) heterocyclyl Substituted with one or more X groups, —O N(R) C(O) O-alkyl, —C(O) N(R), —CN, N, and —O C(O)-alkyl: 0020 R is selected from the group consisting of H, sy alkyl, -OH, haloalkyl, arylalkyl, —O-alkyl, O-aryl, cycloalkyl, heterocyclyl.
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