| 摘要 |
#CMT# #/CMT# Quinoline derivatives of formula (I), their enantiomers, diastereoisomers, and their acid or base addition salts, are new. #CMT# : #/CMT# Quinoline derivatives of formula (I), their enantiomers, diastereoisomers, and their acid or base addition salts, are new. R 11-6C alkyl (substituted by COOR 3 or -NR 4R 5), preferably -(CH 2) 3-COOR 3, -(CH 2) 2-C(Me) 2-COOR 3 or -CH 2-NR 4R 5; R 4-COOR 3 a or 1-6C alkyl (substituted by COOR 3 a); R 3, R 3 aH or 1-6Calkyl; R 51-6C alkyl (substituted by phenyl (optionally substituted by 1-3 substituents of 1-6C alkoxy, 1-6C (polyhalo)alkyl or halo)); R 2phenyl (optionally substituted by 1-6C alkyl, 1-6C alkoxy or 1-6C polyhaloalkyl or halo); and n : 0-8. Independent claims are included for: (1) the preparation of (I); and (2) a combination containing (I) and an antioxidant agent. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Antidiabetic; Antilipemic; Metabolic; Cardiovascular-Gen.; Cardiant; Vasotropic; Nephrotropic; Ophthalmological; Antipsoriatic; Gynecological; Nootropic; Osteopathic; Gastrointestinal-Gen; Antiarteriosclerotic; Anorectic; Eating-Disorders-Gen.; Cytostatic; Muscular-gen; Anabolic. #CMT#MECHANISM OF ACTION : #/CMT# Aldose reductase inhibitor. #CMT#USE : #/CMT# (I) are useful for the treatment and/or prevention of hyperglycemia, dyslipidemia, particularly non-insulin dependent type-II diabetes, insulin resistance, glucose intolerance, disorders related to syndrome X, coronary arterial diseases and other cardiovascular diseases, kidney disease, retinopathies, disorders related to the activation of the endothelial cells, psoriasis, polycystic ovarian syndrome, dementia, osteoporosis, intestinal inflammatory diseases, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma, type I diabetes, obesity, appetite regulation, anorexia nervosa, bulimia, cancerous pathologies, particularly hormone-dependent cancers such as the breast cancer and colon cancer and as angiogenesis inhibitors. (I) are useful to treat and/or prevent weight overloads by a body mass index higher than 25 and lower than 30, particularly weight overloads/obesity induced by a therapeutic treatment such as a treatment of type I or type II diabetes (claimed). (I) are useful to reduce total cholesterol, body weight, plasmatic glucose, triglycerides, low density lipoprotein and very low density lipoprotein. Tests details are described but no results given. #CMT#ADVANTAGE : #/CMT# (I) has a synergistic effect. (I) are excellent hypoglycemic agents and hypolipemiant agents. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises: converting 2-chloro-3-formyl-quinoline (II) into 2-chloro-3-dimethoxymethyl-quinoline (III), reacting (III) with an alcohol compound of formula R 2-(CH 2) n-OH (IV) in the presence of sodium hydride to obtain a 3-dimethoxymethyl-quinoline compound of formula (V), reacting (V) in an acid medium to form a quinoline-3-carbaldehyde compound of formula (VI), reacting (VI) with propargyl magnesium bromide to form a quinolin-3-yl-but-3-yn-1-ol compound of formula (VII), reacting (VII) with tert-butyldimethylsilyl chloride to obtain a 1-(tert-butyl-dimethyl-silanyloxy)-but-3-ynyl-quinoline compound of formula (VIII), reacting (VIII) with trimethoxy compound of formula Br-A-C(OMe) 3 (IX) to form a 1-(tert-butyl-dimethyl-silanyloxy)-but-3-ynyl-quinoline compound of formula (X), either reacting (X) in the presence of tetrabutylammonium chloride to form a 1-quinolin-3-yl-but-3-yn-1-ol compound of formula (A1) or saponification of (X) to form a 1-quinolin-3-yl-but-3-yn-1-ol compound of formula (A2); or condensation of (VIII) and an alcohol compound of formula Br-A-OH (XI) to form a 3-[1-(tert-butyl-dimethyl-silanyl)-but-3-ynyl]-quinoline compound formula (XII), reacting (XII) with methyl tetrabromide to obtain a bromide compound of formula (XIII), condensation of an amine compound of formula HNR 4 aR 5 on (XIII) to form a 3-[1-(tert-butyl-dimethyl-silanyl)-but-3-ynyl]-quinoline compound formula (XIV) and either reacting (XIV) in the presence of tetrabutylammonium chloride to form a 1-quinolin-3-yl-but-3-yn-1-ol compound of formula (A3) or saponification of (XIV) to form a 1-quinolin-3-yl-but-3-yn-1-ol compound formula (A4). (A1)-(A4) are representatives of (I). (I) can be purified using classic separation technique, transformed into additive salts and optionally separated into isomers using classic separation technique. A : 1-6C alkylene; R 0 a1-6C alkyl; and R 4 a, R 4 bR 4. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#PHARMACEUTICALS : #/CMT# Preferred Components: The antioxidant is coenzyme Q10. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.1 mg to 1 g/day, orally, parenterally, nasally, transcutaneously, rectally or perlingually. #CMT#SPECIFIC COMPOUNDS : #/CMT# 1 Compound (I) is specifically claimed i.e. 8-hydroxy-8-{2-[(5-phenylpentyl)oxy]-3-quinolinyl}-5-methyl octynoate of formula (Ia). #CMT#EXAMPLE : #/CMT# 2-(Benzyloxy)-3-(1-([tert-butyl(dimethyl)silyl]oxy)-3-butynyl)quinoline (1.28 g) was added to freshly distilled tetrahydrofuran solution (8 ml) and the reaction medium was brought to - 78[deg] C. The solution of n-butyllithium (1.6 M) in tetrahydrofuran (2.25 ml) was then slowly added and agitation was maintained for 30 minutes after the addition, during which time the temperature was brought to - 65/- 60[deg] C. The hexamethylphosphoramide and trimethyl orthobutyrate (1.5 equivalents) were added quickly. The temperature was raised at room temperature very slowly and agitation was continued for 12 hours. The reaction medium was hydrolyzed by adding a saturated aqueous ammonium chloride solution and further worked up to obtain methyl-8-[2-(benzyloxy)-3-quinolinyl]-8-{[tert-butyl(dimethyl)silyl]oxy}-5-octynoate. Then the methyl-8-[2-(benzyloxy)-3-quinolinyl]-8-{[tert-butyl(dimethyl)silyl]oxy}-5-octynoate (1.47 mmol) was added to distilled tetrahydrofuran (8 ml). The tetrabutylammonium chloride (1M) in tetrahydrofuran (2.05 mmol) solution was added and the reaction mixture was agitated for 2 hours at 45[deg] C. The solvents were filtered and further worked up to obtain a methyl-8-[2-(benzyloxy)-3-quinolinyl]-8-hydroxy-5-octynoate. |
