| 摘要 |
#CMT# #/CMT# Pyrrole derivatives (I), in the form of base or acid addition salts, hydrates or solvates, are new. #CMT# : #/CMT# Pyrrole derivatives of formula (I), in the form of base or acid addition salts, hydrates or solvates, are new. A : 1-6C alkylene (optionally substituted by 1-3C alkyl) or a phenyl moiety of formula (Iz); m : 0-2; p : 0-1; either R 1H or 1-4C alkyl; R 23-10C alkyl (optionally substituted by CF 3), 3-12C non-aromatic carbocyclic (optionally substituted by 1-4C alkyl, OH, CN, 1-4C alkoxy or -COR 12), indanyl, 1,2,3,4-tetrahydronaphtalenyl -1 or -2, 5-7 membered mono-oxygenated or mono-sulfidized heterocyclic (optionally substituted by 1-4C alkyl), 5-7 membered mono-nitrogenized heterocyclic (optionally substituted by 1-4C alkyl, the nitrogen atom is substituted by 1-4C alkyl, 1-4C alkoxycarbonyl, 1-4C alkanoyl or phenyl or benzyl( both optionally substituted by halo, 1-4C alkyl, CF 3, OH or 1-4C alkoxy), benzothiophenyl or indolyl (both optionally substituted by 1-4C alkyl), 1-3C alkylene carrying 3-10C non-aromatic carbocyclic radical (optionally substituted by 1-4C alkyl, OH, 1-4C alkoxy, CN, or -COR 12), 1-3C alkylene carrying a 5-7 membered hetero(aromatic)cyclic radical (optionally substituted by 1-4C alkyl), 1-3C alkylene (optionally substituted by OH, Me or OMe, or -COR 12) carrying an indolyl or a benzothiophenyl radical (optionally substituted by 1-4C alkyl), 1-3C alkylene carrying 1-4C alkylthio group), phenyl-1-3C alkylene (optionally substituted on alkylene by Me, OH, hydroxymethyl, OMe, methoxymethyl or COR 12, and optionally substituted on the phenyl by halo or 1-4C alkyl, CF 3, 1-4C alkoxy or CF 3), benzydryl or benzydrylmethyl or NR 10R 11; or NR 1R 2morpholinyl, piperazin-1-yl or 1,4-diazepan-1-yl (optionally substituted by phenyl, benzyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl or COR 12 or -CH 2COR 12), piperidin-1-yl or pyrrolidin-1-yl (optionally mono or gem disubstituted by F, or phenyl, benzyl, piperidin-1-yl, pyrrolidin-1-yl, 1-4C alkyl, OH, CN or COR 12, -NR 13R 14, -NHCOR 15, -CH 2COR 12, -SO 2-Alk or -SO 2-NR 13R 14, where phenyl and benzyl are optionally substituted by halo, Me, -CF 3, hydrolyl or 1-4C alkoxy); R 3-R 8H or halo, 1-5C alkoxy, S(O) n-Alk2, -OS(O) n-Alk2 or 1-7C alkyl (optionally substituted by F, O-Alk2, S(O) nAlk2 or OS(O) nAlk); R 9OH, CN, -COOH, -NR 13R 14, -CONR 13R 14, -CONHNH 2, -CONHOH, -CONHSO 2-Alk, -S(O) n-Alk, -SO 2CF 3, -SO 2-NR 13R 14, -NHSO 2-Alk, -NHSO 2CF 3, -NH-SO 2-NR 13R 14 or 3-hydroxy-3H-imidazole-4-yl, 1H-tetrazol-5-yl, 3-hydroxy-1H-pyrazol-5-yl, 3-hydroxy-isoxazol-5-yl, 3-hydroxy-isothiazol-5-yl, 2-oxo-2,3-dihydro-2lambda-4-[1,2,3,5]oxathiadiazole-4-yl, 5-hydroxy-isoxazole-4-yl or 2-Hydroxy-2H-pyrazole-3-yl; either R 10H or Me; R 113-6C alkyl, phenyl or 3-10C cycloalkyl, where the phenyl and 3-10C cycloalkyl are optionally substituted by halo, 1-4C alkyl or -CF 3; or NR 10R 114-11 membered heterocyclic radical optionally comprising a spirannic carbon and optionally containing a second heteroatom of O or N, optionally substituted by OH, 1-4C alkyl, 1-4C alkoxycarbonyl or phenyl (optionally substituted by halo or 1-4C alkyl); R 121-4C alkyl, phenyl, benzyl, 1-4C alkoxy, CF 3 or NR 13R 14; either R 13, R 14H or 1-4C alkyl; NR 13R 144-7 membered heterocyclic (optionally containing second heteroatom N, O or S); R 15-14C alkyl or CF 3; n : 0-2; Alk2 : 1-4C alkyl (optionally substituted by F); and Alk : 1-4C alkyl. Independent claims are included for: (1) the preparation of (I); and (2) a pyrrole derivative of formula (IIa). X : halo, OH, 1-4C alkoxy or benzyloxy. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Neuroleptic; Nootropic; Tranquilizer; Neuroprotective; Metabolic; Anorectic; Antidiabetic; Analgesic; Antianginal; Antilipemic; Gastrointestinal-Gen; Antiemetic; Antidiarrheic; Antiulcer; Hepatotropic; Immunomodulator; Antiarthritic; Antirheumatic; Antiinflammatory; Antiparkinsonian; Antismoking; Antidepressant; Hypnotic; Antialcoholic; Antimigraine; Anticonvulsant; Muscular-Gen.; Inotropic; Vasotropic; Cerebroprotective; Antiaddictive; Eating-Disorders-Gen; Cardiovascular-Gen; Uropathic; Virucide; Endocrine-Gen; Hypertensive; Antiarteriosclerotic; Antibacterial; Immunosuppressive; Antiasthmatic; Respiratory-Gen; Ophthalmological; Antiinfertility; Gynecological; CNS-Gen; Osteopathic. #CMT#MECHANISM OF ACTION : #/CMT# Cannabinoid CB 1 receptor antagonist. #CMT#USE : #/CMT# (I) are useful to prevent or treat psychiatric disorders, dependence and weaning to a substance, cognitive disorders, disorders of attention and vigilance, acute and chronic neurodegenerative diseases, metabolic disorders, appetite disorders, obesity, type II diabetes, metabolic syndrome, dyslipidemia, pain, neuropathic pain, pain caused by cancer treatment, gastrointestinal disorders, vomiting, diarrhea disorders, ulcers, liver diseases, immune system diseases, rheumatoid arthritis, demyelinating disease, multiple sclerosis, inflammatory diseases, Alzheimers, Parkinson's disease, schizophrenia and tobacco weaning (claimed). (I) are also useful to treat anxiety, depression, mood disorders, insomnia, delirious, obsessive disorders, psychosis, attention deficit hyperactivity disorders in hyperkinetic children, abuse of a substance and/or dependence to a substance, including alcohol dependence and nicotine addiction, migraine, psychosomatic diseases, crises of panic attacks, epilepsy, movement disorders, dyskinesias, tremor and dystonia, memory disorders, cognitive disorders, particularly senile dementia, Alzheimer's disease, ischemia, brain injury, chorea, Huntington's disease, Tourette's syndrome, appetite (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) and/or obesity or bulimia, or non-insulin diabetes and dyslipidemia, cardiovascular risks, gastrointestinal disorders, diarrheal disorders, vesical and urinary disorders, liver diseases such as chronic cirrhosis, fatty liver, steatohepatitis, endocrine disorders, cardiovascular disorders, hypotension, atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, problems with fertility, premature delivery, interruption of pregnancy, inflammatory phenomena, immune system diseases, autoimmune and neuroinflammatory disorders such as rheumatoid arthritis, reactive arthritis, viral infectious diseases such as encephalitis, stroke and as drug for cancer chemotherapy, to treat Guillain-Barre syndrome and bone diseases and osteoporosis. No biological data given. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises treating the acid of formula (II) or its functional derivative with an amine of formula HNR 1R 2 and optionally transforming the group Y 1 into the group -A-R 9. Y 1H, -A-R 9 or a precursor of -A-R 9. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Preferred Definitions: NR 1R 24'-carbamoyl-[1,4']bipiperidinyl-1'-yl, 4-benzo[1,3]dioxol-5-ylmethyl-piperazine-1-yl or 1-methoxymethyl-2-phenyl-ethylamino; R 3, R 4, R 6halo; R 5, R 7, R 8H; A : benzyl or 2-5C alkylene optionally substituted by methyl; and R 9CN, CO 2H, SO 2CH 3, NHSO 2CH 3, NHSO 2CF 3. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is oral (0.01-100 mg/kg/day, preferably 0.02-50 mg/kg/day), sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal. #CMT#SPECIFIC COMPOUNDS : #/CMT# 9 Compounds (I) are disclosed e.g. 6-[5-(4'-carbamoyl-[1,4']bipiperidinyl-1'-carbonyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-pyrrol-1-yl]-hexanoic acid of formula (Ia), 1-({5-[(4-bromophenyl)-4-(2,4-dichlorophenyl)-1,2-(methylsulfonyl)ethyl]-1H-pyrrol-2-yl}carbonyl)-4-phenylpiperidine-4-carboxamide, 1-(1,3-benzodioxol-5-yl-methyl)-4-({5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-1-[2-(methylsulfonyl)ethyl]-1H-pyrrol-2-yl}carbonyl)piperazine, N-(1-benzyl-2-methoxyethyl)-5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-1-[(2-methylsulfonyl)ethyl]-1H-pyrrole-2-carboxamide, 1'-{[5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-{3-[(methylsulfonyl)amino]propyl}-1H-pyrrol-2-yl]carbonyl}-1,4'-bipiperidin-4'-carboxamide. #CMT#EXAMPLE : #/CMT# 6-[5-(4'-Carbamoyl-[1,4']-bipiperidinyl-1'-carbonyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-pyrrol-1-yl]-hexanoic acid ethyl ester (1.1 g) was saponified in the presence of lithium hydroxide (0.66 g) and 9:1 mixture of water an tetrahydrofuran (10 ml). After 24 hours of reflux the mixture was further worked up to obtain 6-[5-(4'-carbamoyl-[1,4']bipiperidinyl-1'-carbonyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-pyrrol-1-yl]-hexanoic acid. |
