Patent
Quinoline compounds
| العنوان: | Quinoline compounds |
|---|---|
| Patent Number: | 8,008,306 |
| تاريخ النشر: | August 30, 2011 |
| Appl. No: | 12/430397 |
| Application Filed: | April 27, 2009 |
| مستخلص: | To provide a novel LXRβ agonist that is useful as a preventative and/or therapeutic agent for atherosclerosis; arteriosclerosis such as those resulting from diabetes; dyslipidemia; hypercholesterolemia; lipid-related diseases; inflammatory diseases that are caused by inflammatory cytokines; skin diseases such as allergic skin diseases; diabetes; or Alzheimer's disease. A quinoline compound represented by the following general formula (1) or salt thereof, or their solvate. [chemical expression included] |
| Inventors: | Koura, Minoru (Higashimurayama, JP); Okuda, Ayumu (Higashimurayama, JP); Matsuda, Takayuki (Higashimurayama, JP); Yamaguchi, Yuki (Higashimurayama, JP); Sumida, Hisashi (Higashimurayama, JP); Kurobuchi, Sayaka (Higashimurayama, JP); Watanabe, Yuichiro (Higashimurayama, JP); Enomoto, Takashi (Higashimurayama, JP); Shibuya, Kimiyuki (Higashimurayama, JP) |
| Assignees: | Kowa Company, Ltd. (Nagoya-shi, Aichi, JP) |
| Claim: | 1. A quinoline compound represented by the following general formula (1) or salt thereof: [chemical expression included] (wherein R 1 represents a hydrogen atom, halogen atom, C 1-8 alkyl group, C 3-8 cycloalkyl group, C 2-8 alkenyl group, C 3-8 cycloalkenyl group, C 3-8 cycloalkenyl-C 1-8 alkyl group, C 1-8 alkoxy group, C 6-10 aryl group, C 6-10 aryl C 1-8 alkyl group, C 6-10 aryl C 2-6 alkenyl group, C 1-8 acyl group, C 6-10 arylcarbonyl group, C 1-8 alkylthio group, C 1-8 alkylsulfinyl group, C 1-8 alkylsulfonyl group, C 6-10 arylsulfonyl group, nitro group, amino group, mono C 1-8 alkylamino group, di C 1-8 alkylamino group, C 3-8 cycloalkyl C 1-8 alkyl group, C 3-8 cycloalkyl C 2-8 alkenyl group, C 3-8 cycloalkyl C 2-8 alkynyl group, halo C 1-8 alkyl group, or cyano group, wherein the C 6-10 aryl may be substituted with 1 to 3 same or different substituents selected from the following group A; R 2 represents a hydrogen atom, C 1-8 alkyl group, halo C 1-8 alkyl group, or halogen atom; R 3 , R 4 , R 5 , and R 6 each independently represents a hydrogen atom, halogen atom, or C 1-8 alkyl group; R 7 and R 8 each independently represents a hydrogen atom, C 1-8 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl C 1-8 alkyl group, C 6-10 aryl group, or 5- to 11-membered heterocyclic group, wherein the C 6-10 aryl and 5- to 11-membered heterocycle may be substituted with 1 to 3 same or different substituents selected from the following group A, or R 7 and R 8 may together form a 5- to 7-membered carbocycle; R 9 represents a hydrogen atom, C 1-8 alkyl group, halo C 1-6 alkyl group, C 3-8 cycloalkyl group, or C 3-8 cycloalkyl C 1-8 alkyl group; X represents a bond or a C 1-8 alkyl chain, C 6-10 aryl chain, or 5- to 11-membered heteroaryl chain; Y represents a —O—, —S—, or —N(R 10)—; R 10 represents a hydrogen atom or C 1-8 alkyl group; and L represents a C 1-8 alkyl chain or C 2-8 alkenyl chain), [Group A: halogen atom, C 1-8 alkyl group, halo C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, cyano group, nitro group, hydroxy group, amino group, mono C 1-8 alkylamino group, di C 1-8 alkylamino group, C 1-8 alkoxy group, halo C 1-8 alkoxy group, C 1-8 acyl group, carboxyl group, C 1-8 acyloxy group, C 1-8 alkoxycarbonyl group, carbamoyl group, C 6-10 aryl group, 5- to 11-membered heteroaryl group, C 6-10 aryl C 1-8 alkoxy group, C 1-8 alkylthio group, C 1-8 alkylsulfinyl group, C 1-8 alkylsulfonyl group, C 6-10 arylthio group, C 6-10 arylsulfinyl group, and C 6-10 arylsulfonyl group]. |
| Claim: | 2. The quinoline compound or salt thereof according to claim 1 , wherein R 1 is a C 1-8 alkyl group or C 6-10 aryl C 1-8 alkyl group. |
| Claim: | 3. The quinoline compound or salt thereof according to claim 1 , wherein R 2 is a halo C 1-8 alkyl group. |
| Claim: | 4. The quinoline compound or salt thereof according to claim 1 , wherein R 7 and R 8 are each independently a C 1-8 alkyl group, C 6-10 aryl group, or 5- to 11-membered heterocyclic group, wherein the C 6-10 aryl and 5- to 11-membered heterocycle may be substituted with 1 to 3 same or different substituents selected from the following group A, [Group A: halogen atom, C 1-8 alkyl group, halo C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, cyano group, nitro group, hydroxy group, amino group, mono C 1-8 alkylamino group, di C 1-8 alkylamino group, C 1-8 alkoxy group, halo C 1-8 alkoxy group, C 1-8 acyl group, carboxyl group, C 1-8 acyloxy group, C 1-8 alkoxycarbonyl group, carbamoyl group, C 6-10 aryl group, 5- to 11-membered heteroaryl group, C 6-10 aryl C 1-8 alkoxy group, C 1-8 alkylthio group, C 1-8 alkylsulfinyl group, C 1-8 alkylsulfonyl group, C 6-10 arylthio group, C 6-10 arylsulfinyl group, and C 6-10 arylsulfonyl group]. |
| Claim: | 5. A medicine composition comprising a therapeutically effective amount of the quinoline compound or salt thereof according to claim 1 as an active ingredient. |
| Claim: | 6. The medicine composition according to claim 5 , which is a therapeutic agent for atherosclerosis, arteriosclerosis resulting from diabetes, dyslipidemia, hypercholesterolemia, diabetes, or Alzheimer's disease. |
| Claim: | 7. An LXR regulator containing the quinoline compound or salt thereof according to claim 1 as an active ingredient. |
| Claim: | 8. A pharmaceutical composition comprising the quinoline compound or salt thereof according to claim 1 and a pharmaceutically acceptable carrier. |
| Claim: | 9. A method for treating atherosclerosis, arteriosclerosis resulting from diabetes, dyslipidemia, hypercholesterolemia, diabetes, or Alzheimer's disease, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the quinoline compound or salt thereof according to claim 1 . |
| Claim: | 10. A medicine composition according to claim 5 , wherein the medicine composition is administered in the form of an oral preparation, injection, suppository, ointment, inhalation, eye-drops, nasal preparation, or adhesive patch. |
| Claim: | 11. The LXR regulator according to claim 7 , wherein said LXR regulator has a higher selectivity for activating LXRβ expression than a LXRα expression. |
| Current U.S. Class: | 51425/505 |
| Patent References Cited: | 2005/0215577 September 2005 Dehmlow 527433 February 1993 2002-539155 November 2002 2004-509161 March 2004 00/54759 September 2000 02/24632 March 2002 03/082192 October 2003 2004/024161 March 2004 2004/058717 July 2004 2004/072046 August 2004 2005/023188 March 2005 2005/058834 June 2005 |
| Other References: | Byrn et al. Solid-State Chemistry of Drugs, 2d, Chapter 11 Hydrates and Solvates, 233-247 (1999). cited by examiner Morissette et al. Adv. Drug Delivery Rev. 2004, 56, 275-300. cited by examiner A.M. Rouhi, Chem. & Eng. News, Feb. 24, 2003, 81(8), 32-35. cited by examiner Schafer et al. Drug Discovery Today, 13:913 (2008). cited by examiner Horig et al. Journal of Translational Medicine, 2:44 (2004). cited by examiner G. Cao et al., “Antidiabetic Action of a Liver X Receptor Agonist Mediated by Inhibition of Hepatic Gluconeogenesis”, The Journal of Biological Chemistry, Jan. 10, 2003, pp. 1131-1136, vol. 278, No. 10. cited by other M. N. Bradley et al., “LXR: A nuclear receptor target for cardiovascular disease?”, Drug Discovery Today: Therapeutic Strategies, 2005, pp. 97-103, vol. 2, No. 2. cited by other N. Zelcer et al., “Liver X receptors as integrators of metabolic and inflammatory signaling”, The Journal of Clinical Investigation, Mar. 2006, pp. 607-614, vol. 116, No. 3. cited by other N. Terasaka et al., “T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice”, Federation of European Biochemical Societies, 2003, pp. 6-11, Letters 536. cited by other R. K. Tangirala et al., “Identification of macrophage liver X receptors as inhibitors of atherosclerosis”, PNAS, Sep. 3, 2002, pp. 11896-11901, vol. 99, No. 18. cited by other J. R. Schultz et al., “Role of LXRs in control of lipogenesis”, Genes & Development, 2002, pp. 2831-2838. cited by other P. H. E. Groot et al., “Synthetic LXR agonists increase LDL in CETP species”, Journal of Lipid Research, 2005, pp. 2182-2191, vol. 46. cited by other D. J. Peet et al, “Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα”, Cell, May 29, 1998, pp. 693-704, vol. 93. cited by other S. B. Joseph et al., “Reciprocal regulation of inflammation and lipid metabolism by liver X receptors”, Nature Medicine, Feb. 2003, pp. 213-219, vol. 9, No. 2. cited by other E. G. Lund et al., “Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis”, Arterioscler Thromb Vasc Biol, Jul. 2003, pp. 1169-1177. cited by other D. Auboeuf et al., “Tissue Distribution and Quantification of the Expression of mRNAs of Peroxisome Proliferator-Activated Receptors and Liver X Receptor-in Humans”, Diabetes, Aug. 1997, pp. 1319-1327, vol. 46. cited by other S. Alberti et al., “Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice”, The Journal of Clinical Investigation, Mar. 2001, pp. 565-573, vol. 107, No. 5. cited by other B. Hu et al., “Further modification on phenyl acetic acid based quinolines as liver X receptor modulators”, Bioorganic & Medicinal Chemistry, 2007, pp. 3321-3333, vol. 15. cited by other B. Hu et al., “Carboxylic acid based quinolines as liver X receptor modulators that have LXRβ receptor binding selectivity”, Bioorganic & Medicinal Chemistry Letters, 2007, pp. 54-59, vol. 18. cited by other X. Fu et al., “27-Hydroxycholesterol is an Endogenous Ligand for Liver X Receptor in Cholesterol-loaded Cells”, The Journal of Biological Chemistry, 2001, pp. 38378-38387, vol. 276, No. 42. cited by other R. Geyeregger et al., “Liver X receptors in cardiovascular and metabolic disease”, Cellular and Molecular Life Sciences, 2006, pp. 524-539, vol. 63. cited by other B. A. Janowski et al, “An oxysterol signalling pathway mediated by the nuclear receptor LXRα”, Nature, Oct. 24, 1996, pp. 728-731, vol. 383. cited by other B. Hu et al., “Discovery of Phenyl Acetic Acid Substituted Quinolines as Novel Liver X Receptor Agonists for the Treatment of Atherosclerosis”, Journal of Medicinal Chemistry, Sep. 9, 2006, pp. 6151-6154, vol. 49. cited by other T. T. Lu et al., Orphan Nuclear Receptors as eLiXiRs and FiXeRs of Sterol Metabolism, The Journal of Biological Chemistry, 2001, pp. 37735-37738, vol. 276, No. 41. cited by other D. S. Lala, “The liver X receptors”, Current Opinion in Investigational Drugs, 2005, pp. 934-943, vol. 6, No. 9. cited by other J. M. Lehmann et al., “Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway”, The Journal of Biological Chemistry, 1997, pp. 3137-3140, vol. 272, No. 6. cited by other B. A. Laffitte et al., “Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue”, PNAS, Apr. 29, 2003, pp. 5419-5424, vol. 100, No. 9. cited by other |
| Assistant Examiner: | Barker, Michael |
| Primary Examiner: | Chu, Yong |
| Attorney, Agent or Firm: | Westerman, Hattori, Daniels & Adrian, LLP |
| رقم الانضمام: | edspgr.08008306 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |