| 摘要 |
<p>#CMT# #/CMT# Aminoquinoline derivatives (I) and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) and their salts or solvates are new. #CMT# : #/CMT# Aminoquinoline derivatives of formula (I) and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) and their salts or solvates are new. #CMT#[Image]#/CMT# R 1>H or 1-4C alkyl; R 2>H or 1-4C alkyl; R 3>H, 1-4C alkyl, 3-6C cycloalkyl, phenyl, thienyl or furyl (optionally substituted by 1-4C alkyl, 1-4C alkoxy or halo), 5-6 membered heteroaromatic ring containing 1-3N, 5 membered heteroaromatic ring containing O, N or S (optionally substituted with 1-4C alkyl, 1-4C alkoxy or halo); R 4>, R 5>H, 3-6C cycloalkyl or 1-4C alkyl (optionally containing amino group substituted by 1-2 1-4C alkyl, OH, carboxy or alkyl group substituted with 1-4C alkyl), benzyl, -SO 2OH or 1-4C acyl; NR 4>R 5>a group of formula (a); R 7>, R 8>H, 1-4C alkyl or 3-6C cycloalkyl; R 6>H, 1-4C alkyl, phenyl, benzyl, thienyl or furyl (optionally substituted by methylenedioxy or 1 or more 1-4C alkyl, 1-4C alkoxy, hydroxy, trifluoromethyl, cyano or halo), or 5 or 6 membered heteroaromatic ring (containing either 1-3 N, 1 N and 1 O or 1 N and 1 S, and optionally substituted by 1 or more 1-4C alkyl, 1-4C alkoxy or halo); X : CH 2, NH, NR 9>, S, O, sulfo or sulfoxy; R 9>1-4C alkyl or 3-6C cycloalkyl; Z : O, S, CHR 1> 0> or NR 1>; R 1> 0>H, 1-4C alkyl or 3-6C cycloalkyl; R 1> 1>H, 1-4C alkyl, 3-6C cycloalkyl, SO 2OH or 1-4C acyl; n : 0-2; m, o : 1-3; and p, r : 0-1. Provided that either: (1) R 4> and R 5> are H, 3-6C cycloalkyl or 1-4C alkyl optionally contains amino group substituted 1-2 1-4C alkyl, OH, carboxy or alkyl group substituted with 1-4C alkyl; (2) R 4> is H, 1-4C alkyl or benzyl and R 5> is H, -SO 2OH or 1-4C acyl; or (3) NR 4>R 5> is (a). #CMT#[Image]#/CMT# Independent claims are also included for the following: (1) preparation of (I); and (2) new compounds of formulae (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII'') and (XIII''). #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Cardiant; Nephrotropic; Respiratory-Gen.; CNS-Gen.; Cytostatic; Ophthalmological; Antiinflammatory; Antiasthmatic; Vasotropic; Antidepressant; Antiarrhythmic; Antiparkinsonian; Nootropic; Antiallergic; Dermatological; Antiarthritic; Immunosuppressive; Gastrointestinal-Gen.; Anabolic; Hypertensive; Antipsoriatic; Antirheumatic; Neuroprotective; Antidiabetic. #CMT#MECHANISM OF ACTION : #/CMT# Adenosine A3 ligands. (I) were tested for adenosine A3 ligand activity in HEK-293 cells. The inhibitory constant value of (I) was 0.5-15 nM. #CMT#USE : #/CMT# (I) are useful for the treatment disease of the e.g. heart, kidney, respiratory organs and central nervous system; and for the inhibition of protection of adenosine in growing tumor cells; prevention of mast cell degranulation; inhibition of cytokine production; reduction of intraocular pressure; inhibition of tumor necrosis factor (TNF)-alpha release; inhibition of eosinophil, neutrophil and other immune cell migration; inhibition of bronchoconstriction and plasma extravasation; for the manufacture of antiinflamatory, antiasthmatic, antiischemic, antidepressant, antiarrhythmic, renal protective, antitumor, antiparkinson and cognitive enhancing composition; for the treatment of myocardial reperfusion injury, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS) including chronic bronchitis, pulmonary emphysema or dyspnea, allergic reactions (e.g. rhinitis, poison ivy induced responses, urticaria, scleroderma, arthritis) other autoimmune diseases, inflammatory bowel disease, Addison' s disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurogical function disorders, glaucoma and diabetes (claimed). #CMT#ADVANTAGE : #/CMT# (I) possess good bioavailability. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises: (a) a bis-carboxamide of formula (II) is selectively hydrolyzed and if desired the protective group removed; or (b) for (I) (where R 1> is H, 1-4C alkyl or benzyl, R 5> is 1-4C acyl or N+R 4>+R 5> is formula (a), where Z is NR 1> 1>, where R 1> 1> is 1-4C acyl), a compound of formula (I) (where R 4> is H or 1-4C alkyl or benzyl, R 5> is H or N+R 4>+R 5> is formula (a), where Z is NH) is acylated with carbonyl compound of formula R 1> 2>COY; (c) for (I) (where R 4> is H or 1-4C alkyl or benzyl and R 5> is -SO 2OH or N+R 4>+R 5> is formula (a), where Z is -NF 1> 1>, where R 1> 1> is -SO 2OH), a compound of formula (I) (where R 4> is H, 1-4C alkyl or benzyl and R 5> is H or N+R 4>+R 5> is formula (a), where Z is -NH-) is reacted with a pyridine-SO 3 complex or with ClSO 3H; (d) for (I) (where R 4> is H, 1-4C alkyl or benzyl and R 5> is -SO 2OH), a compound of formula (XIII) is reacted with sodium thiosulfate or sodium bisulfite or is reduced and compound of formula (XIV) is sulfated with a pyridine-SO 3 complex or ClSO 3H, if desired after transforming the R 4> H atom into 1-4C alkyl or benzyl; (e) for (I) (where R 4> is H, 3-6C cycloalkyl, benzyl, 1-4C alkyl optionally containing an amino or amino substituted with 1-4C alkyl, OH, carboxy, alkoxy substituted with a 1-4C alkyl and R 5> is H or N+R 4>+R 5> is formula (a), where R 7> and R 8> is H, 1-4C alkyl or 3-6C cycloalkyl and Z is -NR 1> 1>, where R 1> 1> is H), removing the protective group of (II); N+R 4>+R 5> is formula (a2), where R 7> and R 8> is H, 1-4 C alkyl or 3-6C cycloalkyl and Z is NR 1> 1>, where R 1> 1> is a protecting group; If desired, the substituents of the resulting compound of formula (I) are transformed into each other by known methods, and/or the compound of formula (I) thus obtained is transformed into its salt or solvate; liberated from its salt or solvate; resolved into its optically active isomers; or a given desmotrop is transformed into an other desmotropic form. #CMT#[Image]#/CMT# Preferred Process: The selective hydrolysis is effected with alkali hydroxide dissolved in alcoholic medium (preferably with methanolic potassium or sodium hydroxide solution). #CMT#DEFINITIONS : #/CMT# Preferred Definitions: R 1>, R 2>H or CH 3; R 3>phenyl, thienyl or furyl; R 4>, R 5>H, 3-6C cycloalkyl, 1-4C alkyl optionally containing an amino, amino group optionally substituted with 1-2 1-4C alkyl, OH, COO, alkoxy substituted with 1-4C alkyl; R 4>1-4C alkyl or benzyl; R 5>H, formyl or SO 2OH; R 6>4-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 4-fluorophenyl, 2-thienyl or 2-furyl; X : NH or O; n : 1; m, o : 2; and p, r : 0. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.1-1000 mg, orally, parenterally, transdermally or by inhalation. #CMT#SPECIFIC COMPOUNDS : #/CMT# 21 compounds (I) are specifically claimed, e.g. 4-methoxy-N-[6-(morpholin-4-yl)-4-benzylamino-3-cyanoquinolin-2-yl]-benzamide (Ia). #CMT#[Image]#/CMT# #CMT#EXAMPLE : #/CMT# To the solution of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-10 (morpholin-4-yl)-4-benzylamino-3-cyanoquinolin-2-yl)benzamide (2.3 g) in acetonitrile (20 ml), 1N methanolic potassium hydroxide solution (5 ml) was added. The reaction mixture was heated under reflux conditions for 10 minutes, glacial acetic acid (1.5 ml) was added to it, then it was neutralized with 1M sodium hydrogen carbonate solution (15 ml). The mixture was worked up to give 4-methoxy-N-[6-(morpholin-4-yl)-4-benzylamino-3-cyanoquinolin-2-yl]benzamide (Ia) (1.3 g).</p> |
