New aryl amide compounds are kinase inhibitors useful for the treatment and/or prophylaxis of e.g. tumors, psoriasis, rheumatoid arthritis, contact dermatitis, inflammations, endometriosis, scar and benign prostatic hyperplasia
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New aryl amide kinase inhibitors were developed, demonstrating antiangiogenic activity by inhibiting vascular endothelial growth factor stimulated mitogenesis, with potential applications for treating endometriosis and other inflammatory or proliferative diseases.
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Abstract
Aryl amide compounds (I) and their salts, derivatives, solvates and/or stereoisomers including their mixtures in all ratios are new. - Aryl amide compounds (I) of formula (Ar1-N(R2)-CH(=Y)-Ar2-Z-Ar3) and their salts, derivatives, solvates and/or stereoisomers including their mixtures in all ratios are new. - Ar1-Ar3 = aromatic (optionally substituted with R1) or Het - Het = 1-2 aromatic heterocyclic ring with 1-4 N-, O- and/or S- - R1 = H, A, aryl, OR4, SR4, Oaryl, Saryl, N(R4)2, NHaryl, Hal, NO2, CN, (CH2)mCOOR4, (CH2)mCOOaryl, (CH2)mCON(R4)2, (CH2)mCONHaryl, COR4, COaryl, S(O)mA, S(O)maryl, NHCOA, NHCOaryl, NHSO2A, NHSO2aryl, SO2N(R4)2, O(CH2)n, N(R4)2, O(CH2)nNHR3, O(CH2)n-oxo-piperazine, O(CH2)n-oxomorpholine, O(CH2)n-oxopyrrolidine, O(CH2)nC(CH2)2(CH2)nN(R4)2, N(CH2)nC(CH3)2(CH2)nN(R4)2, O(CH2)nN(R4)SOmA, O(CH2)nN(R4)SOmN(R4)A, O(CH2)nN(R4)SOmaryl, (CH2)nN(R4)SOmA, (CH2)nN(R4)SOmN(R4)A, (CH2)nN(R4)SOmaryl, O(CH2)nSOmA, O(CH2)nSOmN(R4)A, O(CH2)nSOmaryl, (CH2)nSOmA, (CH2)nSOmN(R4)A and/or (CH2)nSOmaryl - Y = O, S, C-NO-2, C(CN)2 or N-R3 - Z = G1n, G1nEG2m, EG1nG2m or G1nG2mE - R2-R4 = H, A or -alkylene-aryl - A = 1-10C alkyl (where 1-2 CH2- group is replaced with O-, S and/or with -CH=CH- and/or 1-7H atom is replaced with Hal), aryl (optionally substituted with A), phenyl, OA, SA, Ophenyl, NH2, NA2, hal, NO2, CN, (CH2)mCOOR4, (CH2)mCON(R4)2, COR4, COaryl, S(O)mA, NHCOA or NHSO2A substituted phenyl - E = O, SOm, NR1, CO, C=N or alkene - G1, G2 = CR1R1 or E - Hal = F, Cl, Br or I - n = 0-5 and - m = 0-2. - Independent claims are also included for: - (1) the preparation of (I) - (2) medicament comprising (I), carriers and/or adjuvants and optionally at least additional drug active agents - (3) a set (kit) comprising divided packings of (I) and additional drug active agents and - (4) use of (I) in combination with radiotherapy and a compound (estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic drug, antiproliferative agents, prenyl-proteintransferase inhibitors, 3-hydroxy 3-methyl glutaryl coenzyme A reductase inhibitors, HIV-protease inhibitors, reverse transcriptase inhibitors, growth factor receptor inhibitors and angiogenesis inhibitors) for preparing medicaments for the treatment and/or prophylaxis of diseases. - ACTIVITY - Antiangiogenic Cytostatic Antidiabetic Ophthalmological Osteopathic Antiarthritic Antipsoriatic Antirheumatic Antiinflammatory Dermatological Gynecological Vulnerary Immunostimulant Immunosuppressive. - MECHANISM OF ACTION - Kinase activator Kinase inhibitor Tyrosine kinase inhibitor Raf-kinase inhibitor. The ability of (I) to inhibit tyrosine kinase activity using biological assays. The results showed that (I) inhibited vascular endothelial growth factor stimulated mitogenesis in a culture containing human endothelial cells at HK-50 value of 0.01-5 microM.
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