| 摘要 |
<p>#CMT# #/CMT# Annelated cyanopyridine compounds (I) and their nitrogen oxides, salts, solvates, salts of the nitrogen oxides, solvate of the nitrogen oxides or salts, are new, where (I) excludes e.g. 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(2-thienyl)-3-quinoline-carbonitrile, 5,6,7,8-tetrahydro-2-[(2-phenylmethyl)thio]-4-(2-thienyl)-3-quinoline carbonitrile, 5,6,7,8-tetrahydro-2-[(phenylmethyl)thio]-4-phenyl-3-quinoline carbonitrile and 6,7-dihydro-4-(4-hydroxyphenyl)-2-[(phenylmethyl)thio]-5H-cyclopenta[b]pyridin-3-carbonitrile. #CMT# : #/CMT# Annelated cyanopyridine compounds of formula (I) and their nitrogen oxides, salts, solvates, salts of the nitrogen oxides, solvate of the nitrogen oxides or salts, are new, where (I) excludes 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(2-thienyl)-3-quinoline-carbonitrile, 5,6,7,8-tetrahydro-2-[(2-phenylmethyl)thio]-4-(2-thienyl)-3-quinoline carbonitrile, 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(4-pyridyl)-3-quinoline carbonitrile, 5,6,7,8-tetrahydro-2-[(phenylmethyl)thio]-4-phenyl-3-quinoline carbonitrile, 5,6,7,8-tetrahydro-2-[(phenylmethyl)thio]-4-(4-chlorophenyl)-3-quinoline carbonitrile and 6,7-dihydro-4-(4-hydroxyphenyl)-2-[(phenylmethyl)thio]-5H-cyclopenta[b]pyridin-3-carbonitrile. Q : e.g. (a-N=C(R 5>)-N=CH-N(R 3>)-(R 4>)-aa); X : e.g. S; R 1>e.g. (6-10C)-aryl; R 2>e.g. (5-6C)-cycloalkyl; R 3>, R 4>H or (1-4C)-alkyl; R 5>H, (1-4C)-alkyl or amino; a : the bonding point on the C2-atom; and aa : the bonding point on the C3-atom. With provisos. Full Definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with an inert, non-toxic, auxiliary material. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Cardiant; Vasotropic; Antianginal; Antiarrhythmic; Muscular-Gen.; Antidiabetic; Metabolic; Antilipemic; Thrombolytic; Antiinflammatory; Nephrotropic; Gastrointestinal-Gen.; Endocrine-Gen.; Dermatological; Antipsoriatic; Antiseborrheic; Ophthalmological; Vulnerary; CNS-Gen.; Neuroprotective; Cerebroprotective; Nootropic; Antiparkinsonian; Anticonvulsant; Antidepressant; Cytostatic; Antiemetic; Immunostimulant; Antiulcer; Immunosuppressive; Antiarthritic; Antirheumatic; Respiratory-Gen.; Antiasthmatic; Antithyroid; Virucide; Anti-HIV; Anabolic; Osteopathic; Antigout; Uropathic. #CMT#MECHANISM OF ACTION : #/CMT# Selective adenosine A1 receptor ligand; Selective adenosine A2b-receptor ligand. The ability of (I) to bind selective adenosine A1 receptor was tested in Chinese hamster ovary cell line. The results showed that 4-amino-7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-5-[4-(2-hydroxyethoxy)phenyl]-2-methylpyrido[2,3-d]pyrimidin-6-carbonitrile exhibited an EC 5 0value of less than 0.04 nM. #CMT#USE : #/CMT# USE -(I) are useful for the preparation of a medicament to treat and/or prevent diseases, which are coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction, atrial fibrillation, hypertonia, diabetes, metabolic syndrome and dyslipidemia (all claimed), where the heart disease is pulmonary valve insufficiency, myocarditis, chronic myocarditis, acute myocarditis, systolic and diastolic heart failure. (I) are useful to treat or prevent e.g. thromboembolic disorders, reperfusion after ischemia, vasculitis, edema, ischemia, such as myocardial infarction, stroke and transient ischemic attack, glomerulonephritis, acute glomerulonephritis, nephropathic diseases such as primary and congenital kidney disease, kidney inflammation by toxic substances induced nephropathy, diabetic nephropathy, and pyelonephritis, irritable bowel syndrome, erectile dysfunction, female sexual dysfunction, disorders such as inflammatory skin disease (psoriasis, acne, eczema, atopic dermatitis, dermatitis, keratitis, scarring, and warts formation), central nervous system diseases and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), cancer (skin cancer, liposarcoma, cancers of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract), nausea, vomiting, inflammation and immune diseases (ulcerative colitis, lupus erythematosus, rheumatoid arthritis), and respiratory diseases, such as chronic obstructive respiratory diseases (chronic bronchitis), asthma, pulmonary emphysema, bronchiectasis, and cystic fibrosis (mucoviscidosis), thyroid disease (hyperthyroidism), diseases of the pancreas (pancreatitis), viral diseases (human papilloma virus, human cytomegalovirus, HIV), cachexia, osteoporosis, gout and incontinence. (I) are useful to promote wound healing. #CMT#ADVANTAGE : #/CMT# (I) are non-toxic. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises either: reacting (A) a substituted 2-amino-pyridine-3,5-dicarbonitrile compound of formula (II) in an inert solvent or without solvent with a carbonyl compound of formula (R 7>-C(=O)-X 1>) (III) to give a substituted 4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile compound of formula (I-A) (representative of (I)), or (B) reacting (II) in an inert solvent or without solvent in the presence of a suitable ammonia source such as ammonium acetate, with a triol compound of formula (R 5>-(C-O-R 11>) 3) (IV) to give a substituted 4-amino-pyrido[2,3-d]pyrimidine-6-carbonitrile compound of formula (I-B) (representative of (I)), or (C) reacting a 2-chloro-nicotinonitrile compound of formula (V) in an inert solvent with an alkali sulfide such as sodium sulfide, to give 3-cyano-pyridine-2-thiol anion compound of formula (VI), and subsequently reacting (VI) in the presence of a suitable base with a leaving group compound of formula (X 2>-CH 2-R 1>) (VII) to give 2-mercapto-nicotinonitrile compound of formula (I-C) (representative of (I)), or (D) reacting (V) in an inert solvent in the presence of a base with a hydroxyl compound of formula (HO-CH 2-R 1>) (VIII) to give 2-hydroxy-nicotinonitrile compound of formula (I-D) (representative of (I)), or (E) reacting a 5-Oxo-5,6-dihydro-[1,6]naphthyridine-3-carbonitrile compound of formula (IX) in an inert solvent in the presence of a suitable base with (VII) to give 2-mercapto-5-oxo-5,6-dihydro-[1,6]naphthyridine-3-carbonitrile compound of formula (I-E) (representative of (I)). X 1>OH or -OC(O)R 7>; R 11>(1-4C)-alkyl; Q : (a-CH(R 7>) 2-CH 2-CH(R8A)(R8B)-aa) or (a-N-(R 6>)-C(=O)-N(R 6>)-C(=O)-aa); R 7>H or (1-4C)-alkyl; either R8A, R8B : H; or R8AR8B : an oxo group; Ak +>an alkali salt; X 2>a suitable leaving group, preferably Cl, Br or I, or mesylate, tosylate or triflate; and R 12>(1-4C)-alkyl. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#PHARMACEUTICALS : #/CMT# Preferred Components: The medicament further comprises active agents, which are lipid metabolism modifying drugs, antidiabetic agents, antihypertensive agents and antithrombotic-active agents. #CMT#DEFINITIONS : #/CMT# Full Definitions: Q : (a-N=C(R 5>)-N=CH-N(R 3>)-(R 4>)-aa), (a-N=C(R 7>)-N(R 6>)-C(=O)-aa), (a-N(R 6>)-C(=O)-N(R 6>)-C(=O)-aa), (a-CH=CH-N(R 6>)-C(=O)-aa), (a-N(R 6>)-C(R 7>) 2-N(R 6>)-C(=O)-aa), (a-CH 2-C(R9A)(R9B)-CH 2-C(R8A)(R8B)-aa), (a-C(R9A)(R9B)-CH 2-C(R8A)(R8B)-aa) or (a-N(R 1> 0>)-NH-C(=O)-aa); R 3>, R 4>H or (1-4C)-alkyl; R 5>H, (1-4C)-alkyl or amino; R 6>H, (1-4C)-alkyl (which is optionally substituted by hydroxy carbonyl, (1-4C)-alkoxy carbonyl or amino) or allyl; R 7>H, (1-4C)-alkyl (which is optionally substituted by 1 or 2 substituents from OH or amino), CF 3, amino, mono(1-4C)-alkyl amino or di-(1-4C)-alkyl amino; either R8A : H, OH, (1-4C)-alkoxy or mono-(1-4C)-alkyl amino, where (2-4C)-alkoxy and mono-(2-4C)-alkyl amino are substituted with OH; and R8B : H; or R8AR8B : oxo-, N-(1-4C)-alkyl imino, N-(1-4C)-alkoxyimino or (1-4C)-alkoxycarbonylmethylidene; either R9A, R9B : H or (1-4C)-alkyl; or CR9AR9B : a spiro linked 3-5-membered cycloalkyl ring; R 1> 0>H, (1-4C)-alkyl (which is optionally substituted by 1 or 2 substituents of OH or amino), or phenyl; X : S or O; R 1>(6-10C)-aryl or 5-10-membered heteroaryl (both are optionally substituted by 1 or 2 substituents of halo, NO 2, CN, (1-6C)-alkyl, trifluoromethyl, OH, (1-6C)-alkoxy, amino, mono-(1-6C)-alkyl amino, di-(1-6C)-alkyl amino, hydroxy carbonyl, (1-6C)-alkoxy carbonyl, amino carbonyl, mono-(1-6C)-alkyl amino carbonyl, di-(1-6C)-alkyl amino carbonyl, pyrrolidino-, piperidino-, morpholino-, piperazino-, N'-(1-4C)-alkylpiperazino-group, phenyl or 5-6-membered heteroaryl (where phenyl and 5-6-membered heteroaryl are optionally substituted by 1-3 substituents of halo, NO 2, CN, (1-6C)-alkyl, difluoromethyl, trifluoromethyl, OH, (1-6C)-alkoxy, difluoromethoxy, trifluoromethoxy, amino, mono-(1-6C)-alkyl amino, di-(1-6C)-alkyl amino, hydroxy carbonyl or (1-6C)-alkoxy carbonyl)); R 2>(5-6C)-cycloalkyl (optionally substituted by 1 or 2 substituents of (1-6C)-alkyl, OH, oxo, (1-6C)-alkoxy, NH 2, mono-(1-6C)-alkyl amino or di-(1-6C)-alkyl amino, where: (1-6C)-alkyl and (1-6C)-alkoxy are optionally substituted by 1 or 2 substituents of OH, (1-4C)-alkoxy or (3-7C)-cycloalkyl, and (3-7C)-cycloalkyl is optionally substituted by 1 or 2 substituents of (1-4C)-alkyl, OH, oxo or (1-4C)-alkoxy), 5-6-membered heterocyclyl (which is optionally substituted by 1-3 substituents of oxo, thioxo, OH, (1-6C)-alkyl (which is optionally substituted by 1-3 substituents of F, oxo, OH, CF 3, (1-4C)-alkoxy, (1-4C)-alkylcarbonyloxy, NH 2, mono-(1-4C)-alkyl amino, di-(1-4C)-alkyl amino or (3-7C)-cycloalkyl (which is optionally substituted by 1 or 2 substituents of (1-4C)-alkyl, OH, oxo or (1-4C)-alkoxy)), (1-6C)-alkoxy, (1-6C) -alkyl carbonyl (which is optionally substituted by OH or (1-4C)-alkoxy), NH 2, mono-(1-6C)-alkyl amino, di-(1-6C)-alkyl amino or (3-7C)-cycloalkyl (which is optionally substituted by 1 or 2 s</p> |
