Patent NZ-501635-A (NZ)
Title: Amidino derivatives and their use as thrombin inhibitors
Inventor: KAROLSSON OLLE
IPC: A61K/
Filed: 1998-06-09
Abstract: A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: R1 is OR1d; R1d is H, C(O)R11, SiR12R13R14 or alkyl, which latter group is optionally substituted or terminated by one or more substituent selected from OR15 or (CH2)qR16; R12, R13 and R14 are independently H, phenyl or alkyl; R16 is alkyl, phenyl, OH, C(O)OR'7 or C(O)NHR18; R18 is H, alkyl or CH2C(O)OKR19; R15 and R17 are independently H, alkyl or alkylphenyl; R1a, R1b, R1c, R11 and R19 are independently H or alkyl; q is 0, 1 or 2; Rx is a structural fragment of formula IIa, IIb or IIc, wherein: the dotted lines are independently optional double bonds; A and B are independently 0 or S, CH or CH2 (as appropriate), or N or N(R21) (as appropriate); D is -CH2-, O, S, N(R22), -(CH2)2-, -CH=CH-, -CH2N(R22)-, -N(R22)CH2-, -CH=N-, -N=CH-, -CH2O-, -OCH2-, -CH2S- or -SCH2-; X1 is alkylene, alkylene interrupted by Z; -C(O)-Z-A1; -Z-C(O)-A1-; -CH2-C(O)-A1; -Z-C(O)-Z-A2-; -CH2-Z-C(O)- A2-; -Z-CH2-C(O)- A2-; -Z-CH2-S(O)m- A2-;- -CH2-Z-S(O)m- A2-; -C(O)-A3; -Z- A3-; or - A3-Z-; X2 is alkylene, -C(O)-A4- or -A4-C(O)-; X3 is CH or N; X4 is a single bond, 0, S, C(O), N(R23), -CH(R23)-, -CH(R23)-CH(R24)- or -C(R23)-C(R24)-; A1 is a single bond or alkylene; A2 is a single bond or -CH2-; A3 is alkylene; A4 is C(O) or alkylene; Z is, at each occurrence, 0, S(O)m or N(R25); m is, at each occurrence, 0, 1 or 2; R2 and R4 are independently one or more optional substituents selected from alkyl (which latter group is optionally substituted by one or more halo substituent), alkoxy, methylenedioxy, halo, hydroxy, cyano, nitro, SO2NH2, C(O)OR26 or N(R27)R28); R3 is an optional substituent selected from OH or alkoxy; R21, R22, R23, R24, R25, R26, R27 and R28 are independently H or alkyl; Y is CH2, (CH2)2, CH=CH, (CH2)3, CH2CH=CH or CH=CHCH2, which latter three groups are optionally substituted by alkyl, methylene, oxo or hydroxy; RY is H or alkyl; n is 0, 1, 2, 3 or 4; and B is a structural fragment of formula IIIa or IIIc, wherein: X5, X6, X7 and X8 are independently CH, N or N-O; X9 and X10 are independently is a single bond or CH2; R31 is an optional substituent selected from halo and alkyl; provided that:  (a) A and B are not both 0 or S; (b) B and D are not both 0 or S; (c) when X, is -C(O)-Z-A1, -Z-CH2-S(O)m-A2-, -CH2-Z-S(O)m-A2- or -Z-C(O)-Z-A2, then A1 or A2 (as appropriate) is not a single bond;  (d) when X4 is -CH(R23)-, R1 is not OH. These compounds are useful for inhibiting thrombin, treating thrombosis and as an anticoagulant. A compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein: B' is a structural fragment of formula IIId or IIIf D' and D2 are independently H, OH, ORa, OC(O)Rb, OC(O)ORC, C(O)ORd, C(O)Re; Ra is phenyl, benzyl, alkyl (which latter group is optionally interrupted by oxygen or is optionally substituted by halo) or -C(Rf)(Rg)-OC(O)Rh; Rb is alkyl (which latter group is optionally substituted by alkoxy, acyloxy, amino or halo); alkoxy, cycloalkyl, phenyl, naphthyl or alkylphenyl (which latter five groups are optionally substituted by alkyl or halo); or -[C(Ri)(Rj)]mOC(O)Rk; Rc is alkyl, phenyl, 2-naphthyl (which latter three groups are optionally substituted by alkyl, Si(Raa)(Rab)(Rac) or halo), -[C(Rm)(Rn)]nOC(O)Rp, or -CH2-Ar1; Rd is 2-naphthyl, phenyl, alkylphenyl (which latter three groups are optionally substituted by alkyl, alkoxy, nitro, Si(Rba)(Rbb)(Rbc) or halo), group alkyl (which latter group is optionally substituted by alkoxy, acyloxy or halo), -[C(Rq)(Rr)]pOC(O)Rs or -CH2-Ar2; Re is phenyl, benzyl, alkyl (which latter group is optionally interrupted by oxygen) or -[C(Rt)(Ru)]rOC(O)Rv; Raa, Rab, Rac, Rba, Rbb and Rbc  are independently alkyl or phenyl; Rf, Rg, Ri, Rj, Rm, Rn, Rq, Rr, Rt and Ru are independently H or alkyl; Rh, Rk, Rp, Rs and Rv are independently alkyl (which latter group is optionally substituted by alkoxy, acyloxy or halo); alkoxy, cycloalkyl, phenyl, naphthyl or alkylphenyl (which latter five groups are optionally substituted by alkyl or halo); Ar1and Ar2 are independently the structural fragment X m and r are independently 3 or 4; n and p are independently 1, 2 or 3; and R1, Rx, Y, RY, n, X5, X6, X7, X8, X9, X10 and R31 are as defined for formula I; provided that D' and D2 are not both H.