Arylpiperazines and their use as metalloproteinase inhibiting agents (MMP)

A compound of the formula I

• 69
• wherein ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring comprising up to 12 ring atoms and containing one or more heteroatoms independently chosen from N, O, and S;
• alternatively ring B may be biphenyl;
• ring B may optionally be linked to ring A by a C1-4 alkyl or a C1-4 alkoxy chain linking the 2-position of ring B with a carbon atom alpha to X2;
• each R3 is independently selected from hydrogen, halogen, NO2, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, —S—C1-6 alkyl, —SO—C1-6 alkyl, —SO2-C1-6 alkyl, C1-6 alkoxy and up to C10 aryloxy, n is 1,2 or 3;
• P is —(CH2)n- wherein n=0, 1, 2:
• or P is an alkene or alkyne chain of up to six carbon atoms;
• where X2 is C;
• P may be -Het-, —(CH[R6])n-Het-, -Het-(CH[R6]n-or -Het-(CH[R6])n-Het-, wherein Het is selected from —CO—, —S—, SO—, —SO2-, —NR6-, or —O— wherein n is 1 or 2;
• or P may be selected from —CO—N(R6)-, —N(R6)-CO—, —SO2-N(R6)- and —N(R6)-SO2-, and R6 is hydrogen, C1-6 alkyl, up to C10 aralkyl or up to C9 heteroalkyl;
• Ring A is a 5-7 membered aliphatic ring and may optionally be mono- or di-substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, each substituent being independently selected from halogen, C1-6 alkyl or an oxo group.
• X1 and X2 are independently selected from N and C, where a ring substituent on ring A is an oxo group this is preferably adjacent a ring nitrogen atom;
• Y is selected from —SO2- and —CO—;
• Z is —CONHOH, Y is —CO— and Q is selected from —C(R6)(R7)-, —C(R6)(R7)-CH2-, —N(R6)-, and —N(R6)-CH2- wherein R6 is as defined above, and solely in relation to Q as here defined, R6 may also represent up to C10 aryl and up to C9 heteroaryl, and R7 is H, C1-6 alkyl, or together with R6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S;
• Z is —CONHOH, Y is —SO2- and Q is selected from —C(R6)(R7)-, and —C(R6)(R7)-CH2-;
• or Z is —N(OH)CHO and Q is selected from —CH(R6)-, —CH(R6)-CH2-;
• and —N(R6)-CH2-;
• R1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10heteroaryl, up to C12aralkyl, or up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from NO2, CF3, halogen, C1-4alkyl, carboxy(C1-4)alkyl, up to C6cycloalkyl, —OR4, —SR4, C1-4alkyl substituted with —OR4, SR4 (and its oxidised analogues), NR4, N—Y—R4, or C1-4alkyl-Y—NR4, with the proviso that where R1 is —OH, —OR4, —SR4, or NR4, or N—Y—R4 then Z is not —N(OH)CHO, or R1 is 2,3,4,5,6-pentafluorophenyl;
• R4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl or up to C9 aralkyl, each independently optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, —S—C1-6 alkyl, —SO—C1-6 alkyl, —SO2-C1-6 alkyl or C1-6 alkoxy;
• R2 is H, C1-6 alkyl, or together with R1 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S;
• also the group Q can be linked to either R1 or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S and N;
• and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.