PYRIMIDINE DERIVATIVES USEFUL FOR THE TREATMENT OF DISEASES MEDIATED BY CRTH2

摘要

Pyrimidinylacetic acid derivatives (I) are new. Pyrimidinylacetic acid derivatives of formula (I), their tautomeric or stereoisomeric forms and salts are new. [Image] R 1 : -C(O)-(CH 2) n-Y', -C(O)-CH=CH-Y', -SO 2-(CH 2) n-Y', -CH 2-(CH 2) n-Y', -CH 2-CH=CH-Y', or -C(O)-NH-(CH 2) n-Y'; n : 0-6; Y' : H, 3-8C cycloalkyl (optionally substituted by 1-6C alkyl or optionally fused by benzene), or (hetero)aryl (optionally substituted by CN, halo, nitro, guanidino, pyrrolyl, sulfamoyl, 1-6C alkylaminosulfonyl, di(1-6C alkyl)aminosulfonyl, phenyloxy, phenyl, amino, 1-6C alkylamino, di-1-6C alkylamino, 1-6C alkoxycarbonyl, 1-6C alkanoyl, 1-6C alkanoylamino, carbamoyl, 1-6C alkylcarbamoyl, di-(1-6C alkyl)carbamoyl, 1-6C alkylsulfonyl, 1-6C alkyl (optionally mono- to tri-substituted by halo), 1-6C alkoxy (optionally mono- to tri-substituted by halo), 1-6C alkylthio (optionally mono- to tri-substituted by halo), or aryl (fused by 1,3-dioxolane)); R 2 : H or 1-6C alkyl; R 3 : q : 1-3; R 3 c : H, OH, carboxy, or 1-6C alkyl (optionally substituted by OH, carboxy, or (phenyl-substituted C1-6 alkyl)carbamoyl); X a : -O-, -S- or -N(R 3 d)-; R 3 d : 1-6C alkyl or -N(R 3 a)(R 3 b); R 3 a, R 3 b : 3-8C cycloalkyl, or 1-6C alkyl (optionally substituted by carboxy, 3-8C cycloalkyl, carbamoyl, 1-6C alkylcarbamoyl, aryl-substituted 1-6C alkylcarbamoyl, 1-6C alkylcarbamoyl, di(1-6C alkyl)carbamoyl, 3-8C cycloalkylcarbamoyl, 3-8C heterocyclocarbonyl, 1-6C alkylamino, di-1-6C alkylamino or 1-6C alkoxy); and R 4 : H, halo, 1-6C alkoxy, di(1-6C alkyl)amino or 1-6C alkyl (optionally mono- to tri-substituted by halo). ACTIVITY : Antiasthmatic; Antiallergic; Antiinflammatory; Dermatological; Ophthalmological; Cytostatic. MECHANISM OF ACTION : G-Protein-coupled chemoattractant receptor, expressed on Th2 cells (CRTH2) antagonist. [2-(4-Benzoylamino-benzyl)-4-chloro-6-(cyclopentylcarbamoylmethyl-methyl-amino)-pyrimidin-5-yl]-acetic acid (A) was tested for binding activity of human CRTH2 receptor. A cell suspension (2X10 5> cells) (100 mu l), [ 3>H]-labeled PGD 2, and (A) were mixed with 96-well U-bottom polypropylene plate and incubated for 60 minutes at room temperature to allow binding. After incubation, the cell suspension was transferred to a filtration plate and washed 3 times with binding buffer. Non-specific binding was determined. IC 5 0 of (A) was found to be = 0.5 nM.