Patent EP-2316830-A2 (EP)
Inventor: STUERZEBECHER UTE
IPC: C07D295/185
Filed: 2004-05-17
Abstract: N-sulfonated amino acid derivatives (I) and their salts and prodrugs are new. N-sulfonated amino acid derivatives of formula (I) and their salts and prodrugs are new R 1-(CH 2) j-SO 2-NH-CH(CONX 1X 2-(CH 2) k-R 2 (I) X 1 and X 2hydrogen or 1-3C alkyl, but at least one must be a group (i), or X 1 and X 2 together form a ring of formula (ii); R 1optionally partly hydrogenated (hetero)aryl, of 5-20C and one or more oxygen, nitrogen or sulfur, or 1-10C linear branched or cyclic alkyl, all optionally substituted by x; x : one or more of halo, pseudohalo, 1-10C linear, branched or cyclic alkyl, alkoxy or alkylthio (themselves optionally substituted by one or more halo, pseudohalo, hydroxy, amino, cyano, amidino, guanidino or carboxy, optionally esterified with 1-10C alkyl), and alkyl groups may include at least one S, O, or N, and/or substituents are 5-20C (hetero)aryl (optionally substituted by one or more 1-10C linear, branched or cyclic alkyl, COR' 2, COOR' 2, halo, pseudohalo, 1-10C alkoxy or alkylthio, nitro and/or 1-10C haloalkyl) linked to R 1 through a 1-3C alkylene, O or S; and/or substituents are at least one hydroxy, amino, cyano, amidino, guanidino, carboxy(1-10C alkyl), where amino may be acylated and/or the carboxy is esterified with 1-10C alkyl or amidated; R 21-10C aryl (sic) having at least one substituent, optionally with at least one C replaced by sulfur, nitrogen or oxygen, at least one substituent is R 4, and optionally also substituted by hydroxy, COR' 2 or COOR' 2; R' 21-10C linear, branched or cyclic alkyl; j : 0-2; k : 0-3; m and n : 0-5, totalling 3-5; R 3-A 1-T-A 2-R 4; Q : CH or N; A 1 is absent or : 1-4C alkylene, optionally substituted by R 1a>; R 1a>at least halo, pseudohalo, 1-10C linear, branched or cyclic alkyl, 5-10C aryl or aralkyl, 3-10C cycloalkyl and/or hydroxy, cyano, 1-10C alkoxy or alkylthio, carboxy(1-10C alkyl), where carboxy is esterified with 1-10C alkyl or amidated; T : absent or CO, COO, CONR 5, SO 2, CS, CS-O- or CS-NR 5; R 5hydrogen, 1-10C alkyl or, with A 2, is a 1-6C ring-forming alkylene, optionally including at least one heteroatom; A 21-10C linear, branched or cyclic alkylene, or 1-10C (sic) aryl, heteroaryl or aralkylene, all optionally substituted with R 2a>; t : 0 or 1; R 2a>at least one of halo, pseudohalo, 1-10C linear, branched or cyclic alkyl, 5-10C aryl or aralkyl, 3-10C cycloalkyl and/or hydroxy, cyano, 1-10C alkoxy or alkylthio, carboxy(1-10C alkyl), where carboxy is optionally esterified with 1-10C alkyl or amidated; R 4-NHR 6, -(O) t-C(NHR 6)=NR 8>, -(O) t-NR 7>-C(NHR)=NR8 or -S-C(NHR 6)+NR 8>; R 6 and R 7hydrogen, 1-6C alkyl or 1-5C alkylene (forming a ring with A 2), hydroxy, amino, or 1-6C alkylamino, acyl or alkoxycarbonyl; and R 8hydrogen, 1-3C alkyl or 1-3C alkylene that forms a ring with R 6. In (i) and (ii) at least one methylene group indicated by n and m is optionally substituted at least once by hydroxy, halo, pseudohalo or COOR' 2, and/or optionally replaced by S, N or O, and/or at least one cyclic group includes a double bond. The compounds (II), with s = 0-2, and (III), with s = 0 or 1, are excluded. [Image] An independent claim is also included for a method for preparing (I) by reacting an amino acid with R 1-(CH 2) j-SO 2-Cl, at the amino group, then converting the carboxy group to an amide. ACTIVITY : Cytostatic. MECHANISM OF ACTION : Selective inhibition of matriptase, specifically MT-SP1 (membrane-type serine protease-1). The compound anthracenesulfonyl-(3-amidinophenylalanyl)-piperazide-beta -alanine bis(trifluoroacetate) had inhibition constant for matriptase of 0.27 MicroM.