Ophthalmic compositions for treating ocular hypertension

A compound of the structural formula I:

• where
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R represents hydrogen, or C1-6 alkyl;
• X represents —(CHR7)p—, or —(CHR7)pCO—;
• Y represents —CO(CH2)n—, (CH2)n, —CH(OR)—, OR6, or SR6;
• Z=O or S;
• M1, M2, and M3 are independently CH or N;
• Q represents CRy, or N, provided that when Q is N then R2 is not alkyl;
• Ry represents H, C1-6 alkyl, —(CH2)nC3-8 cycloalkyl, —(CH2)nC3-10 heterocyclyl, —(CH2)nC5-10 heteroaryl, or —(CH2)nC6-10 aryl;
• Rw represents H, C1-6 alkyl, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl, —SO2N(R)2, —SO2C1-6 alkyl, —SO2C6-10 aryl, NO2, CN or —C(O)N(R)2;
• R2 represents hydrogen, C1-10 alkyl, OH, C2-6 alkenyl, C1-6 alkylSR, —(CH2)nO(CH2)mOR, —(CH2)n(CHR7)q(CH2)mC1-6 alkoxy, —(CH2)n(CHR7)q(CH2)mC3-8 cycloalkyl, —(CH2)n(CHR7)q(CH2)mC3-8cycloalkenyl, —(CH2)n(CHR7)q(CH2)mC3-10 heterocyclyl, —N(R)2, —COOR, or —(CH2)n(CHR7)q(CH2)mC6-10 aryl, said alkyl, cycloalkyl, heterocyclyl, or aryl optionally substituted with 1-5 groups selected from Ra,
• R3 represents hydrogen, C1-10 alkyl, C2-6 alkenyl, —(CH2)n(CHR7)q(CH2)mC3-8 cycloalkyl, —(CH2)n(CHR7)q(CH2)mcycloalkenyl, —(CH2)n(CHR7)q(CH2)mC3-10 heterocyclyl, —(CH2)n(CHR7)q(CH2)mCOOR, —(CH2)n(CHR7)q(CH2)mC6-10 aryl, —(CH2)n(CHR7)q(CH2)mNHR8, —(CH2)n(CHR7)q(CH2)mN(R)2, —(CH2)n(CHR7)q(CH2)mN(R)3, —(CH2)n(CHR7)q(CH2)mN(R8)2, —(CH2)n(CHR7)q(CH2)mNHCOOR, —(CH2)n(CHR7)q(CH2)mN(R8)CO2R, —(CH2)n(CHR7)q(CH2)mN(R8)COR, —(CH2)n(CHR7)q(CH2)mNHCOR, —(CH2)n(CHR7)q(CH2)mCONH(R8), aryl, —(CH2)n(CHR7)q(CH2)mC1-6 alkoxy, CF3, —(CH2)n(CHR7)q(CH2)mSO2R, —(CH2)n(CHR7)q(CH2)mSO2N(R)2, —(CH2)n(CHR7)q(CH2)mCON(R)2, —(CH2)n(CHR7)q(CH2)mCONHC(R)3, —(CH2)n(CHR7)q(CH2)mCONHC(R)2CO2R, —(CH2)n(CHR7)q(CH2)mCOR8, nitro, cyano or halogen, said alkyl, cycloalkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-5 groups of Ra;
• or, when Q equals CRy or N, R2 and R3 taken together with the intervening CRy or N form a 3-10 membered carbocyclic or heterocyclic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from Ra;
• R4 and R5 independently represent hydrogen, C1-6 alkoxy, OH, C1-6 alkyl, C1-6 alkyl-S, C1-6 alkyl-CO—, C1-6 alkenyl, C3-8 cycloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkyl-S, C3-8 cycloalkyl-CO—, COOR, SO3H, —O(CH2)nN(R)2, —O(CH2)nCO2R, —OPO(OH)2, CF3, —N(R)2, nitro, cyano, C1-6 alkylamino, or halogen;
• R6 represents hydrogen, C1-10 alkyl, —(CH2)n(CHR7)q(CH2)mC6-10 aryl, —(CH2)n(CHR7)q(CH2)mC5-10 heteroaryl, NRcRd, —NR—(CH2)n(CHR7)q(CH2)mC6-10 aryl,
• —N—((CH2)n(CHR7)q(CH2)mC6-10 aryl)2, —(CH2)n(CHR7)q(CH2)mC3-10 heterocyclyl, —NR—(CH2)n(CHR7)q(CH2)mC3-10 heterocyclyl, —N—((CH2)n(CHR7)q(CH2)mC3-10 heterocyclyl)2 (C6-10 aryl)O—, —(CH2)n(CHR7)q(CH2)mC3-8 cycloalkyl, —COOR, —C(O)CO2R, said aryl, cycloalkyl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from Ra;
• Rc and Rd independently represent H, C1-6 alkyl, C2-6 alkenyl, —(CH2)nC6-10 aryl, —(CH2)nC5-10 heteroaryl, C1-6 alkylSR, —(CH2)nO(CH2)mOR, —(CH2)nC1-6 alkoxy, or —(CH2)nC3-8 cycloalkyl;
• or Rc and Rd taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from Ra;
• R7 represents hydrogen, C1-6 alkyl, —(CH2)nCOOR or —(CH2)nN(R)2,
• R8 represents —(CH2)nC3-8 cycloalkyl, —(CH2)n 3-10 heterocyclyl, C1-6 alkoxy or —(CH2)nC5-10 heteroaryl, —(CH2)nC6-10 aryl said cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
• Ra represents F, Cl, Br, I, CF3, N(R)2, NO2, CN, —COR8, —CONHR9, —CON(R8)2, —O(CH2)nCOOR, —NH(CH2)nOR, —COOR, —OCF3, —NHCOR, —SO2R, —SO2NR2, —SR, (C1-C6 alkyl)O—, —(CH2)nO(CH2)mOR, —(CH2)nC1-6 alkoxy, (aryl)O—, —OH, (C1-C6 alkyl)S(O)m—, H2N—C(NH)—, (C1-C6 alkyl)C(O)—, (C1-C6 alkyl)OC(O)NH—, —(C1-C6 alkyl)NRw(CH2)nC3-10 heterocyclyl-Rw, —(C1-C6 alkyl)O(CH2)nC3-10 heterocyclyl-Rw, —(C1-C6 alkyl)S(CH2)nC3-10 heterocyclyl-Rw, —(C1-C6 alkyl)-C3-10 heterocyclyl-Rw, —(CH2)n-Z1-C(=Z2)N(R)2, —(C2-6 alkenyl)NRw(CH2)nC3-10 heterocyclyl-Rw, —(C2-6 alkenyl)O(CH2)nC3-10 heterocyclyl-Rw, —(C2-6 alkenyl)S(CH2)nC3-10 heterocyclyl-Rw, —(C2-6 alkenyl)-C3-10 heterocyclyl-Rw, —(C2-6 alkenyl)-Z1-C(=Z2)N(R)2, —(CH2)nSO2R, —(CH2)nSO3H, —(CH2)nPO(OR)2, —(CH2)nOH, —(CH2)n(CHR7)q(CH2)mOPO(OR)2, C3-10 cycloalkyl, C6-10 aryl, C3-10 heterocyclyl, C2-6 alkenyl, and C1-C10 alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C1-C6 alkyl, CN, NO2, —(CH2)nOH, —(CH2)nOPO(OR)2, CON(R)2 and COOR;
• Z1 and Z2 independently represents NRw, O, CH2, or S;
• m is 0-3;
• n is 0-3;
• p is 0-3 and
• q is 0-1.