New bi-heteroaryl or phenyl-heteroaryl compounds, are PPAR-gamma receptor modulators useful e.g. for treating dermatological, metabolic or immunological disorders or precancerous lesions

摘要

3,4'-Disubstituted 1,1'-biphenyl analogs (I), in which at least one phenyl ring is replaced by a heteroaryl ring, are new. Bi-heteroaryl or phenyl-heteroaryl compounds of formula (I) and their optical or geometric isomers and salts are new. [Image] R1 : (2,4-dioxo-thiazolidin-5-yl)-methyl, (2,4-dioxo-thiazolidin-5-ylidene)-methyl or -CH 2-CHR3R4; R2 : 1-12C alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, 9-fluorenylmethyl or -(CH 2) m-(NR5) n-(C(O,N)) p-R6; R3 : 5-(R7)-1,3,4-oxadiazol-2-yl, -CO-R8 or an azole group; R4 : 1-12C alkyl, OR9, SR9 or NHR9; R5, R7 : H, 1-12C alkyl, aryl, aralkyl, heteroaryl or heterocyclyl; R6, R8 : -O-(CH 2) v-R 10, OH, 1-12C alkyl, aryl, aralkyl, heteroaryl, heterocyclyl,-NR'R'' or -N(R')-(CH 2) v-R 10; R9 : 1-12C alkyl, -C 6H 4-R11 or -(CH 2) m-(CO) n-(Q) p-(CH 2) q-R11 or N-protected alpha -aminoacid residue containing a conventional amino-protecting group (e.g. 9-fluorenylmethylcarbamate, tert. butylcarbamate, benzyl or trifluoroacetyl); m, n, p, q : 0-2; Q : O, S or NR5; V : O or S; W : N or C-R5; Y : N or C; Z : O, N or S; v : 1-3; R10 : 1-12C alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, NHCOR12, NHCOOR12, CR12R13 or NR12R13; R' : H, 1-12C alkyl, heteroaryl or heterocyclyl; R'' : H, 1-12C alkyl, aryl, aralkyl (optionally substituted by one or more halo), heteroaryl, heterocyclyl, -(CH 2) v-R10, NHR10 or N(R10) 2; R11 : H, 1-12C alkyl, aryl, aralkyl, heteroaryl, heterocyclyl or -(CO) s(Z) t-R10; R12 : H, 1-12C alkyl, aryl, aralkyl, heteroaryl or heterocyclyl; R13 : H or 1-12C alkyl; X : -(CH 2) z-(NR14) y-(CO) x-(D) w-; D : O, S, NR15 or CH 2; x, y, z : 0 or 1; w : 0-6; R14, R15 : H or 1-12C alkyl; Ar1, Ar2 : phenyl (but not both phenyl), pyridine, pyrimidine, pyrazine, pyridazine, thiophene, furan, 1-(R13)-pyrrole, isoxazole, isothiazole, 1-(R13)-pyrazole, oxazole, thiazole, 1-(R13)-imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 4-(R13)-4H-1,2,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole or 1-(R13)-1H-1,2,4-triazole (all optionally substituted). ACTIVITY : Dermatological; antiseborrheic; immunosuppressive; antiallergic; antiinflammatory; antipsoriatic; antirheumatic; virucide; cytostatic; vulnerary; keratolytic; anorectic; antilipemic; antidiabetic; antiarthritic; antialopecia; antiasthmatic; neuroprotective; antiarteriosclerotic; hypotensive. MECHANISM OF ACTION : Peroxisome proliferator-activated receptor sub-type gamma (PPARgamma ) modulator. In transactivation tests in cultures of HeLa cells transfected with the plasmids ERE-beta Glob-Luc-SV-Neo (reporter) and PPAR (alpha , beta , gamma ) Gal-hPPAR, N-(3-(5-(2,4-dioxo-thiazolidin-5-ylidenyl-methyl)-benzyl)-N-methyl-octanoylamide (Ia) had a K dapparent value of 500 nM for PPARgamma .