Diaminopyrimidines as modulators for an EP2 receptor

摘要

Diaminopyrimidine derivative is new. Diaminopyrimidine derivative of formula (I) or its isomer, diastereomer, enantiomer and salt and cyclodextrin clathrate is new. Y 1CH or C(1-4C alkyl); V 1H or 1-4C alkyl; n : 0-2; W 1A 1or or 3-12-membered, mono-, bi- or tricyclic cycloalkyl radical (optionally mono-substituted by t 1; and the substituents are linked either directly or via a spacer U 1to W 1);or W 1+V 1u 1or u 2; A 16-10-membered, mono- or bicyclic aryl ring, 5-10-membered, mono- or bicyclic heteroaryl ring, 8-12-membered aryl- or heteroaryl-cycloalkyl or -cycloalkenyl, 8-12-membered aryl- or heteroaryl-heterocyclyl or -heterocyclenyl (all optionally mono- to tri-substituted); t 1halogen, cyano, R 4, OR 4, OC(O)R 4, S(O) nR 4, SO 2NR 4R 5, SO 2NR 5C(O)R 4, NR 4R 5, NR 5C(O)R 4, NR 5SO 2R 4, C(O)NR 5SO 2R 4, C(OH)R 4R 5, C(O)R 4, C(NOH)R 4, CO 2R 4, or C(O)NR 4R 5; u 1pyrrolidine, piperidine, morpholine or thiomorpholine residue (all optionally mono-substituted); u 2piperazine residue (optionally N-substituted by t 1and substituents are linked either directly or via a spacer U 1to W 1); U 11-4C alkylene, 2-4C alkenylidene, 2-4C alkynylidene, O-1-4C-alkylene, C(O)-1-4C-alkylene, S(O) n-1-4C-alkylene, N(R 5)-1-4C-alkylene, C(O)-N(R 5)-1-4C alkylene or N(R 5)-C(O)-1-4C-alkylene spacer; R 11-4C alkyl or cyano; R 2,R 3H, halo, cyano or 1-4C alkyl; R 4H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, 3-6C cycloalkyl, CH 2-3-6C-cycloalkyl, 6-membered aryl ring, 5-6-membered heteroaryl ring or CH 2-6-membered aryl or 5- or 6-membered heteroaryl; R 5H or 1-4C alkyl;or R 4+R 53-6-membered cycloalkyl or heteroatom-containing ring. Provided that when n is 0, then W 1+V 1is u 1or u 2. [Image] ACTIVITY : Antiinfertility; Osteopathic; Cytostatic; Ophthalmological; Antibacterial; Virucide; Neuroprotective; Nootropic; Nephrotropic; Gynecological; Antiangiogenic; Antiarteriosclerotic; Hepatotropic; Antiinflammatory; Cardiovascular-Gen.; Vasotropic; Contraceptive. MECHANISM OF ACTION : Prostaglandin E2 (EP2) receptor modulator. Antagonism assay for detection of antagonism of the human EP2 receptor was carried out as follows: N-biphenyl-2-ylmethyl-N'-[2-(7-fluoro-2,4-dimethyl-1H-indol-3-yl)-ethyl]-pyrimidine-4,6-diamine (test compound) (0.75 mu l) was introduced into an assay plate and 30% dimethylsulfoxide (DMSO) was dissolved in KRSB+IBMX (3-isobutyl-1-methylxanthine) stimulation solution and then 15 mu l was transferred into a media-fred cell culture plate. After preincubation at room temperature for 30 minutes, 5 mu l of a 4x PGE2 solution (11 nM) was added and incubated at room temperature for further 60 minutes. The IC 50value for the test compound was found to be 1.4 mu M.