Method for treating glaucoma IC

A method of decreasing intraocular pressure or improving ocular accommodation in an animal, including a human, comprising administering an intraocular pressure decreasing or accommodation improving amount of (A) a compound of the formula I:

• 19
• wherein
• a. R1 and R2 are
• 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, 4-[C6 or C10]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C6 or C10 aryl or a 5- or 6-membered heteroaryl ring, wherein 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring can be fused to a benzene, pyridine, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Ar)}, Ar-alkyl, Ar—O, ArSO2—, ArSO—, ArS—, ArSO2NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R1 and R2 comprise methylenedioxy;
• or
• 2. together with their ring carbons form a C6- or C10-aromatic fused ring system;
• or
• 3. together with their ring carbons form a C5-C7 fused cycloalkyl ring having up to two double bonds including any fused double bond of the -olium or -onium containing ring, which cycloalkyl ring can be substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo substituents;
• or
• 4. together with their ring carbons form a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroarvy ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring may be optionally substituted with one or more 1-pyrrolidinyl-, 4-[C6 or C10]arylpiperazin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C10-C3)alkylenedioxy groups;
• or
• 5. together with their ring carbons form a five to eight membered heterocycle, wherein the heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, and S(O)n, where n=0, 1, or 2;
• b. Z is
• 1. hydrogen, alkyl, Ar—CH2;
• 2. a group of the formula —NR3R4, wherein R3 and R4 may be independently hydrogen, alkyl, Ar, or Ar-alkyl-;
• 3. a group of the formula —CH(OR11)R12, wherein R11 is hydrogen, methyl, ethyl or CH3C(O)—;
• and R12 is [C1 to C6]alkyl, Ar, or CO2R13 wherein R13 is hydrogen methyl or ethyl;
• 4. a group of the formula —C(CO2R13)(OR11)R12
• 5. a group of the formula —CH2WAr, wherein W is —(C═O)— or —S(O)n— where n=1 or 2;
• or
• 6. a group of the formula —CH2C≡C—R14, wherein R14 is (C1-C6)alkyl;
• c. Y is
• 1. amino, or
• 2. a group of the formula —CH(R5)—R6 wherein
• (a) R5 is hydrogen, alkyl-, cycloalkyl-, alkenyl-, alkynyl-, aminoalkyl-, dialkylaminoalkyl-, (N-[C6 or C10]aryl)(N-alkyl)aminoalkyl-, piperidin-1-ylalkyl-, 1-pyrrolidinylalkyl, azetidinylalkyl, 4-alkylpiperazin-1-ylalkyl, 4-alkylpiperidin-1-ylalkyl, 4-[C6 or C10]arylpiperazin-1-ylalkyl, 4-[C6 or C10]arylpiperidin-1-ylalkyl, azetidin-1-ylalkyl, morpholin-4-ylalkyl, thiomorpholin-4-ylalkyl, piperidin-1-ylalkyl, [C6 or C10]aryl, or independently the same as R6;
• (b) R6 is
• (1) hydrogen, alkyl (which can be substituted by alkoxycarbonyl), alkenyl, alkynyl, cyano- or Rs, wherein Rs is a C6 or C10 aryl or a heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
• or
• (2) a group of the formula —W—R7, wherein R7 is alkyl, alkoxy, hydroxy or Rs, wherein W is —C(═O)— or —S(O)n— where n=1 or 2;
• (3) a group of the formula —W—OR8 wherein R8 is hydrogen or alkyl,
• (4) a group of the formula —CH(OH)Rs;
• or
• (5) a group of the formula —W—N(R9)R10, wherein
• [a] R9 is hydrogen and R10 is an alkyl or cycloalkyl, optionally substituted by
• (i) [C6 or C10]aryl, or
• (ii) a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, said heteroaryl ring can be optionally substituted with one or more 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, and morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C1-C3)alkylenedioxy groups, or fused to a substituted phenyl or pyridine ring, wherein the ring fusion is at a carbon-carbon double bond of the heteroaryl ring, or
• (iii) a heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
• or
• [b] R9 is hydrogen or lower alkyl and R10 is Ar;
• or
• [c] R9 is hydrogen or lower alkyl, and R10 is a heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur, said heterocycle;
• or
• [d] R9 and R10 are both alkyl groups;
• or
• [e] R9 and R10 together with N form a heterocycle containing 4-10 ring atoms which can incorporate up to one additional heteroatom selected from the group of N, O or S in the ring, wherein the heterocycle is optionally substituted with (C6- or C10)aryl, (C6-or C10)arylalkyl, or a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each such heteroaryl can be optionally substituted with one or more 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C1-C3)alkylenedioxy;
• or
• [f] R9 and R10 are both hydrogen;
• or
• d. Q is N, O or S;
• e. M is absent when Q is O or S;
• f. M is alkyl, vinyl or allyl, or independently the same as Y;
• and
• g. X is a pharmaceutically acceptable anion, or
• (B) a pharmaceutically acceptable salt of the compound,
• wherein aryl or Ar can be substituted with, in addition to any substitutions specifically noted, one or more substituents selected from the group consisting of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, ArO—, Ar—, Ar-alkyl-, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl-, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl;
• and
• wherein heterocycles, except those of Ar, can be substituted with, in addition to any substitutions specifically noted, acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)—, ArO—, Ar—, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl.