New acyltryptophanols useful for fertility control in men or in women, and for preventing or treating osteoporosis

摘要

Acyltryptophanols are new. Acyltryptophanols of formula (I) are new. R 1H, 1-6C alkyl, 3-6C alkenyl, 3-6C alkynyl, 3-7C cycloalkyl, 1-6C alkyloxy-1-6C alkylene, 3-7C cycloalkyloxy-1-6C alkylene, 1-6C alkylamino-1-6C alkylene, di(1-6C alkyl)amino-1-6C alkylene or phenyloxy-1-6C alkylene (hydrocarbon chains is optionally substituted by at least one T 1, OH or amino); T 1piperazin-1-yl, piperidin-1-yl or [1,4]diazepan-1-yl (substituted at 4th position by 0-6C alkyl), F, cyano, pyrrolidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, or 1,1-dioxo-thiomorpholin-4-yl; R 2H, halogen, cyano, -SO 2Me, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkyloxy or benzyloxy (hydrocarbon chains is optionally substituted by at least one F); R 3H, OH, halogen, nitro, amino, cyano, 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl, 3-7C cycloalkyl, hydroxy-1-6C alkylene, hydroxy-3-6C alkenylene, hydroxy-3-6C alkynylene, 1-6C alkyloxy, 1-6C alkyloxy-1-6C alkylene, 3-7C cycloalkyloxy, 3-7C cycloalkyl-1-6C alkyleneoxy, 3-7C cycloalkyloxy-1-6C alkylene, 1-6C alkyloxy-3-6C alkenylene, 1-6C alkyloxy-3-6C alkynylene, 1-6C alkyloxyphenyl-1-6C alkylene, 1-6C alkylamino-1-6C alkylene, di(1-6C alkyl)amino-1-6C alkylene, phenyloxy-1-6C alkylene (hydrocarbon chains is optionally substituted by at least one T 1, OH or amino ); R 4- R 6H, OH, halogen, nitro, amino, cyano, phenyl, 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkylene, or 3-7C heterocycloalkyl (hydrocarbon chains is optionally substituted by at least one T 1) or hydroxy-1-6C alkylene, hydroxy-3-6C alkenylene, hydroxy-3-6C alkynylene, 1-6C alkyloxy, 3-7C cycloalkyloxy, 3-7C cycloalkyl-1-6C alkyleneoxy, 1-6C alkyloxy-1-6C alkylene, 3-7C cycloalkyloxy-1-6C alkylene, 1-6C alkyloxy-3-6C alkenylene, 1-6C alkyloxy-3-6C alkynylene, 1-6C alkyloxyphenyl-1-6C alkylene, phenyloxy-1-6C alkylene, 1-6C alkylamino, di(1-6C alkyl)amino, 1-6C alkylamino-1-6C alkylene, di-1-6C alkylamino-1-6C alkylene, 3-7C cycloalkyl-(0-6C alkyl)amino, 1-6C acyl-(0-6C alkyl)amido, 1-6C alkylaminocarbonyl, di-1-6C alkylaminocarbonyl, 3-7C cycloalkyl aminocarbonyl, di-3-7C cycloalkyl aminocarbonyl, 3-7C cycloalkyl-1-6C alkylene aminocarbonyl, 1-6C alkylcarbonyl, 3-7C cycloalkylcarbonyl, carboxy, carboxamido [-C(O)NH 2], 1-6C alkyloxycarbonyl, 1-3C alkylsulphanyl, 1-6C alkysulphonyl, 3-7C cycloalkylsulphonyl, 3-7C cycloalkyl-1-6C alkylenesulphonyl, 1-6C alkylaminosulphonyl, di(1-6C alkyl)aminosulphonyl, 3-7C cycloalkyl aminosulphonyl, di(3-7C cycloalkyl)aminosulphonyl, 3-7C cycloalkyl-1-6C alkyleneaminosulphonyl, 1-6C alkylsulphonylamido, -N(0-6C alkyl)-C(O)-1-6C alkyl, -N(0-6C alkyl)-C(O)-3-7C cycloalkyl, -N(0-6C alkyl)-C(O)-N-di(0-6C alkyl), -N(0-6C alkyl)-C(O)-O-(0-6C)alkyl, -N(0-6C alkyl)-C(O)-NH-3-7C cycloalkyl, -N(0-6C alkyl)-SO 2-1-6C alkyl, -N(0-6C alkyl)-SO 2-3-7C cycloalkyl, -N(0-6C alkyl)-SO 2-N-di(0-6C alkyl), -N(0-6C alkyl)-SO 2-NH-3-7C cycloalkyl, -C(O)-N(H)-2-6C alkylene-1-6C alkylamine, -C(O)-NH-2-6C alkylene-[di(1-6C alkyl)]amine, -C(O)-N(H) -2-6C alkylene-(3-7C cycloalkyl)amine, -C(O)-N(H)-2-6C alkylene-(3-7C cycloalkyl-1-6C alkyl)amine, -S(O 2)-N(H)-2-6C alkylene-(1-6C alkyl)amine, -S(O 2)-N(H)-2-6C alkylene-[di(1-6C alkyl)]amine, -S(O 2)-N(H)-2-6C alkylene-(3-7C cycloalkyl)amine, -S(O 2)-N(H)-2-6C alkylene-(3-7C cycloalkyl-1-6C alkylene)amine, -O-2-6C alkylene-(1-6C alkyl)amine, -O-2-6C alkylene-[di(1-6C alkylene)]amine, or radicals selected from 35 compounds are given in the specification e.g. pyrrolidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl; R 7and R 8H, methyl, or ethyl (optionally substituted by at least one F); R 5+R 6heterocycloalkyl or cycloalkyl; Q and W : (hetero)aryl; X : bond, 1-4C alkylene, 2-4C alkenylene, 2-4C alkynylene, 1-3C alkyleneoxy, 1-3C alkyleneoxy-1-3C alkylene;and Y : bond or 1-4C alkylene. An independent claim is included for preparation of (I). [Image] ACTIVITY : Antiinfertility; Osteopathic. No biological data is given. MECHANISM OF ACTION : Follicle-stimulating hormone (FSH) receptor antagonist. The follicle-stimulating hormone (FSH) antagonist activity of N-[(R)-2-[1-(4-cyanobutyl)-1H-indol-3-yl]-1-(hydroxymethyl)ethyl]-3'-fluoro-4'-methoxy[1,1'-biphenyl]-3-carboxamide (Ia) was tested as follows: CHO cells stably transfected with human follicle stimulating hormone (hFSH) receptor in 150 mu l of medium were seeded in 96-well plates (3x104 cells per well hFSHR clone 16 cells). (Ia) was diluted in ice-cold buffer 1 containing PBS, calcium chloride (1 mM), magnesium chloride (1 mM), glucose (0.2%), BSA (bovine serum albumin) (0.1%) and IBMX (3-isobutyl-1-methylxanthine) (1 mM) (with or without hFSH), and the substance dilutions were placed on ice until applied to the cells. The cell supernatant was aspirated off, and the cells were washed with buffer 1 (200 mu l). The cells were treated with the test substance (60 mu l) at 37[deg]C for 2h. The cells were lysed with buffer 2 containing triton X-100 (1%) in PBS (without calcium chloride and magnesium chloride). The test conjugates (XL-665 and anti-cAMP cryptate) were diluted in buffer 3 containing potassium phosphate buffer (50 nM, pH 7), potassium fluoride (800 mM), BSA (0.2%). The actual mixture for measurement was pipetted into a black 96-well plate (in each case 15 mu l of the cell lysate diluted with 35 mu l of buffer 1; firstly 25 mu l of XL-665 conjugate were pipetted and, after 10 min, 25 mu l of the anti-cAMP cryptate were added). This was followed by incubation at room temperature for 90 minutes. (Ia) Showed an IC 50value of 100 nM.