Compounds with activity on muscarinic receptors

A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (I):

• 12
• wherein
• X1, X2, X3, X4 and X5 are selected from C, N and O;
• k is 0 or 1;
• t is 0 or 1;
• R1 is straight or branched-chain C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —SH, C1-8 thioalkyl, —O—CH2—C5-6 aryl, —C(O)—C5-6 aryl substituted with C1-3 alkyl or halo;
• C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O (89620);
• —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —CR3R4, —OC(O)R3, —C(O)(CH2)sNR3R4 or —(CH2)sNR3R3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and s is an integer from 0 to 8;
• A is C5-12 aryl or C5-7 cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
• R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, —C(O)R3R4, —O(CH2)qNR3, —CNR3R4 or —(CH2)qNR3R4;
• where q is an integer from 1 to 6;
• n is 0, 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, NR7 or —CH═N—, and R7 is H or C1-4 alkyl;
• or absent;
• and
• Z is CR8R9 wherein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A pharmaceutical composition comprising an effective amount of a compound of formula (I):

• 14
• wherein
• X1, X2, X3, X4 and X5 are selected from C, N and O;
• k is 0 or 1;
• t is 0 or 1;
• R1 is straight or branched-chain C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —SH, C1-8 thioalkyl, —O—CH2—C5-6 aryl, —C(O)—C5-6 aryl substituted with C1-3 alkyl or halo;
• C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;
• —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —CR3R4, —OC(O)R3, —C(O)(CH2)sNR3R4 or —(CH2)sNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and s is an integer from 0 to 8;
• A is C5-12 aryl or C5-7 cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
• R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, —C(O)R3R4, —O(CH2)qNR3, —CNR3R4 or —(CH2)qNR3R4;
• where q is an integer from 1 to 6;
• n is 0, 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, NR7 or —CH═N—, and R7 is H or C1-4 alkyl;
• or absent;
• Z is CR8R9 wherein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof;
• and
• a pharmaceutically acceptable carrier.

A method of identifying agents capable of reducing intraocular pressure, said method comprising:

• contacting a putative agent with an m1 muscarinic receptor subtype;
• contacting the putative agent with an m3 muscarinic receptor subtype;
• comparing the increase in activity of each receptor subtype;
• and
• identifying agents selective for the m1 muscarinic receptor subtype;
• thereby identifying agents capable of reducing intraocular pressure.