| 摘要 |
Pyrido- and pyrimido- fused azinones of formula (I) and their salts are new. The DEKG ring is 6 or 7 membered, contains 1-3 double bonds, 0-2 heteroatoms from O, N, S, and 0-2 CO or CS groups, provided that there are not two adjacent double bonds; A = N or CR7; B = NR1R2, CR1R2R10, C(=CR2R11)R1, NHCR1R2R10, OCR1R2R10, SCR1R2R10, CR2R10NHR1, CR2R10OR1, CR2R10SR1, or COR2; G = N or CR4 when singly bonded to all atoms, or C when doubly bonded to K; K = N or CR6 when doubly bonded to G or E; or O, S, CO, CS, CR6R12 or NR8 when singly bonded to adjacent ring atoms; or K = a two atom spacer, one unit of which is O, N, S, CO, CS, CR6R12, NR6, or CR6, the other is CR6R12 or CR9; D, E = CO, CS, S, O, CR4R6, or NR8 when singly bonded to adjacent ring atoms, or N or CR4 when doubly bonded to adjacent ring atoms; R1 = 1-6C alkyl (optionally substituted by 1 or 2 OH, halo, 1-4C alkoxy or alkylthio, CF3, 2-5C alkylcarbonyl, alkoxycarbonyl, or alkylcarbonyloxy, (1-4C alkyl)(1-2C alkyl)aminocarbonyloxy(2-5C alkanoylamido), COOH, CONH(1-4C alkyl), CON(1-4C alkyl)(1-2C alkyl), CN, NO2, 1-4C alkylsulphinyl or alkylsulphonyl, SO2NH(1-4C alkyl), or SO2NH(1-4C alkyl)(1-2C alkyl)), in which all alkyl groups optionally contain 1 or 2 double or triple bonds; halo = Br, Cl, I or F; R2 = 1-12C alkyl, optionally containing 1-3 double or triple bonds, aryl or 1-4C alkylene(aryl); 3-8C cycloalkyl, or 3-8C cycloalkyl(1-6C alkylene) (all optionally substituted by 1-3 of Cl, F, OH or 1-4C alkyl, or one of 1-6C alkoxy or alkylthio, 2-7C alkoxycarbonyl or OCON(1-4C alkyl)(1-2C alkyl), amino, 1-2C alkylamino, (1-4C alkyl)(1-2C alkyl)amino, 2-5C alkanoylamido, N-(1-4C alkyl)-(2-5C alkanoyl)amido, carboxy, 2-5C alkoxycarbonyl or alkylaminocarbonyl, N-(1-2C alkyl)(2-5C alkylaminocarbonyl), thiol, CN, NO2, 1-4C alkylsulphinyl, alkylsulphonyl, or alkylamino-sulphonyl, or N,N-(1-2C alkyl)(1-4C alkyl)aminosulphonyl; aryl = phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolo-pyridyl, oxazolyl, or benzoxazolyl; cycloalkyl optionally has one or two C atoms replaced by O, S, or NZ; or NR1R2 or CR1R2R10 = a 3-8 membered ring radical, of which the 5-8 membered rings optionally contain 1 or 2 double bonds and/or one or two ring C atoms can be replaced by O, S or NZ; Z = H, 1-4C alkyl, or benzyl; R3 = H, 1-4C alkyl, alkoxy, alkylthio, or alkylsulphonyl, or halo; R8, R9, R12 = H or 1-2C alkyl; R6 attached to N = H or 1-4C alkyl; R4, and R6 attached to C = H, 1-6C alkyl, halo, hydroxy, 1-2C hydroxyalkyl, CF3, CN, NO2, amino, 1-4C alkoxy or alkylthio, N,N-(1-2C alkyl)(1-4C alkyl)amino, CH2SMe, CHO, or 2-5C alkylcarbonyl or alkoxycarbonyl, and in which all 1-2C alkyl optionally contain one double or triple bond; R5 = phenyl, naphthyl, pyridyl, or pyrimidyl (all substituted by 2-4 substituents, of which 1-3 are selected from Cl, 1-6C alkyl or alkoxy, or 1-6C alkylene-O-1-6C alkyl, and one from Br, I, CN, NO2, formyl, CF3, amino, 1-4C alkylamino, N,N-(1-2C alkyl)(1-6C alkyl)amino, 2-5C alkylcarbonyl or alkoxycarbonyl, carboxy, aminosulphonyl, 1-4C alkylamino-sulphonyl, N,N-(1-2C alkyl)(1-4C alkyl)aminosulphonyl, 1-4C alkyl-sulphonamido, (1-2C alkylthio, alkylsulphinyl, or alkylsulphonyl)-J, or 1-4C hydroxyalkylene, in which all 1-4C and 1-6C alkyl optionally contain 1 or 2 substituents from F, OH, amino, methylamino, dimethylamino or acetyl; J = 0-1C alkylene; R7 = H, Me, halo, OH, MeO, 2-3C alkylcarbonyl or alkoxycarbonyl, hydroxymethyl, CF3 or formyl; R10 = H, OH, MeO or F; and R11 = H or 1-4C alkyl. Also new are quinolines either (a) having at the 4-position a hydroxy group, of formula (IVA); or (b) a leaving group, of formula (IIA). T = Cl, Br, I, or triflyl-oxy. #CMT#USE : #/CMT# (I) are corticotrophin releasing factor (CRF) and hormone (CRH) antagonists, with uses in both clinical and veterinary practice, e.g. stress-induced immune dysfunctions, as in porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, confinement stress of chickens, shearing stress in sheep, or human/animal stress in dogs; or stress, inflammatory, mood, eating, sleep, neurodegenerative and allergic disorders; e.g. rheumatoid arthritis, osteoarthritis, pain, asthma, psoriasis, allergies, anxiety, panic, phobias, obsessive-compulsive or post-traumatic stress disorders, stress-induced sleep disorders, fibromyalgia, various depressions, premenstrual syndrome, dysthemia, cyclothymia, bipolar disorder, chronic fatigue syndrome, headache, cancer, irritable bowel, Crohn's disease, spastic colon, post-operative ileus, ulcer, diarrhoea, stress induced fever, HIV infections, Alzheimer's, Parkinson's, or Huntington's diseases, gastrointestinal disease, anorexia, bulimia, haemorrhagic stress, drug dependency and withdrawal (including alcohol, cocaine, heroin, and benzodiazepines), psychosis, euthyroid sick syndrome, antidiuretic hormone problems, obesity, infertility, head or spinal cord trauma, ischaemic or excitotoxic neuronal damage, epilepsy, stroke, muscular spasm, urinary incontinence, senile or multi-infarct dementia, amyotrophic lateral sclerosis, hypertension, tachycardia, congestive heart failure, osteoporosis, premature birth, and hypoglycaemia. (IIA) and (IVA) are intermediates for (I). |
