Benzothiadiazepine derivatives, processes for their preparation and pharmaceutical compositions containing them

A compound of formula (I):

• wherein:
• Rv is selected from hydrogen or C1-6alkyl;
• One of R1 and R2 are selected from hydrogen or C1-6alkyl and the other is selected from C1-6alkyl;
• Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C1-6alkoxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkylS(O)a wherein a is 0 to 2;
• Rz is selected from halo, nitr, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6-alkyl)sulphamoyl and N,N—(C1-6alkyl)2sulphamoyl;
• v is 0–5;
• one of R4 and R5 is a group of formula (IA):
• R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl and N,N—(C1-6alkyl)2sulphamoyl;
• wherein R3 and R6 and the other of R4 and R5 may be optionally substituted on carbon by one or more R17;
• X is —O—, —N(Ra)—, —S(O)b— or —CH(Ra)—;
• wherein Ra is hydrogen or C1-6alkyl and b is 0–2;
• Ring A is aryl or heteroaryl;
• wherein Ring A is optionally substituted on carbon by one or more substituents selected from R18;
• R7 is hydrogen, C1-6alkyl, carbocyclyl or heterocyclyl;
• wherein R7 is optionally substituted on carbon by one or more substituents selected from R19;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R20;
• R8 is hydrogen or C1-6-alkyl;
• R9 is hydrogen or C1-6alkyl;
• R10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkynyl, C2-10alkynyl, C1-10alkoxy, C1-10alkanoyl, C1-10alkanoyloxy, N—(C1-10alkyl)amino, N,N—(C1-10alkyl)2amino, N,N,N—(C1-10alkyl)3ammonio, C1-10alkanoylamino, N—(C1-10alkyl)carbamoyl, N,N—(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N—(C1-10alkyl)sulphamoyl, N,N—(C1-10alkyl)2sulphamoyl, N—(C1-10alkyl)sulphamoylamino, N,N—(C1-10alkyl)2sulphamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)p-R21—(C1-10alkylene)q- or heterocyclyl-(C1-10alkylene)r-R22—(C1-10alkylene)s-;
• wherein R10 is optionally substituted on carbon by one or more substituents selected from R23;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R24;
• or R10 is a group of formula (IB):
• wherein:
• R11 is hydrogen or C1-6-alkyl;
• R12 and R13 are independently selected from hydrogen, halo, carbamoyl, sulphamoyl, C1-10alkyl, C2-10alkynyl, C2-10alkynyl, C1-10alkanoyl, N—(C1-10alkyl)carbamoyl, N,N—(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N—(C1-10alkyl)sulphamoyl, N,N—(C1-10alkyl)2sulphamoyl, N—(C1-10alkyl)sulphamoylamino, N,N—(C1-10alkyl)2sulphamoylamino, carbocyclyl or heterocyclyl;
• wherein R12 and R13 may be independently optionally substituted on carbon by one or more substituents selected from R25;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R26;
• R14 is selected from hydrogen, halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkanoyl, N—(C1-10alkyl)carbamoyl, N,N—(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N—(C1-10alkyl)sulphamoyl, N,N—(C1-10alkyl)2sulphamoyl, N—(C1-10alkyl)sulphamoylamino, N,N—(C1-10alkyl)2sulphamoylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)p-R27—(C1-10alkylene)q- or heterocyclyl-(C1-10alkylene)r-R28—(C1-10alkylene)s-;
• wherein R14 may be optionally substituted on carbon by one or more substituents selected from R29;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R30;
• or R14 is a group of formula (IC):
• R15 is hydrogen or C1-6alkyl;
• and R16 is hydrogen or C1-6alkyl;
• wherein R16 may be optionally substituted on carbon by one or more groups selected from R31;
• or R15 and R16 together with the nitrogen to which they are attached form a heterocyclyl;
• wherein said heterocyclyl may be optionally substituted on carbon by one or more R37;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R38;
• n is 1–3;
• wherein the values of R7 may be the same or different;
• R17, R18, R19, R23, R25, R29, R31 and R37 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkanoyl, C1-10alkanoyloxy, N—(C1-10alkyl)amino, N,N—(C1-10alkyl)2amino, N,N,N—(C1-10alkyl)3ammonio, C1-10alkanoylamino, N—(C1-10alkyl)carbamoyl, N,N—(C1-10alkyl)2carbamoyl, C1-10alkylS(O)a wherein a is 0 to 2, N—(C1-10alkyl)sulphamoyl, N,N—(C1-10alkyl)2sulphamoyl, N—(C1-10alkyl)sulphamoylamino, N,N—(C1-10alkyl)2sulphamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl-(C1-10alkylene)p-R32—(C1-10alkylene)q- or heterocyclyl-(C1-10alkylene)r-R33—(C1-10alkylene)s-;
• wherein R17, R18, R19, R23, R25, R29, R31 and R37 may be independently optionally substituted on carbon by one or more R34;
• and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R35;
• R21, R22, R27, R28, R32 or R33 are independently selected from —O—, —NR36—, —S(O)x—, —NR36C(O)NR36—, —NR36C(S)NR36—, —OC(O)N═C—, —NR36C(O)— or —C(O)NR36—;
• wherein R36 is selected from hydrogen or C1-6alkyl, and x is 0–2;
• p, q, r and s are independently selected from 0–2;
• R34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;
• R20, R24, R26, R30, R35 and R38 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• and
• wherein a “heteroaryl” is a totally unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heteroaryl may, unless otherwise specified, be carbon or nitrogen linked;
• wherein a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heterocyclyl may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH2- group can optionally be replaced by a —C(O)— group, and a ring sulphur atom may be optionally oxidised to form an S-oxide;
• and
• wherein a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3–12 atoms;
• wherein a —CH2- group can optionally be replaced by a —C(O) group;
• or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide formed on an available carboxy or hydroxy group thereof.