Method for treating glaucoma IIB

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

• 14
• wherein:
• a. J is oxygen, sulfur, or N—Rd;
• b. the carbon 2 to nitrogen bond is a double bond except when Rc is oxo;
• c. the bond between carbons 4 and 5 is a single bond or a double bond;
• d. Ra and Rb are
• 2. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (1-C3)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), cycloalkyl, dialkylamino, halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, 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 the 6-membered heterodox 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 substituted benzene, pyridine, pyrimidine, pyrazine, pyridazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Ar)}, Ar-alkyl, ArO—, 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 Ra and Rb comprise methylenedioxy-;
• or
• 2. together with their ring carbons form a C6- or C10-aryl fused ring, 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 containing group, which cycloalkyl ring can be substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo;
• or
• 4. together with their ring carbons form a fused 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;
• or
• 5. together with their ring carbons form a fused five to eight membered second heterocycle, wherein the fused heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and S(O)n, wherein n is 1 or 2;
• e. Rd is alkyl, alkenyl, hydrogen, or Ar;
• f. Rc is
• 1. oxo (when Δ2,3 is not present), or (when Δ2,3 is present) hydrogen, alkyl, alkylthio, hydrogen, mercapto, amino, amino(C1-C5)alkyl, or amino(C6 or C10)aryl, or wherein the amino of the last three groups can be substituted with
• (a) Ar,
• (b) Ar—Z—, Ar-alkyl-Z—, Ar—Z-alkyl, Ar-amino-Z—, Ar-aminoalkyl-Z—, or Ar-oxyalkyl-Z—, wherein Z is a carbonyl or —SO2—
• (c) formyl or alkanoyl,
• 2. —NHC(O)(CH2)n—D—ReRf, wherein D is oxygen, sulfur or nitrogen, wherein where D is nitrogen n is 0, 1 or 2, but when D is oxygen or sulfur n=1 or 2, and Rf is present only when D is nitrogen, wherein
• (a) Re is
• (1) Ar,
• (2) a group of the formula
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• wherein E is sulfur, oxygen, or N—Ri, and Rg, Rh and Ri are independently the same as Ra, Rb and Rd, respectively,
• (3) a C3-C8 cycloalkyl ring having up to one double bond with the proviso that the carbon linking the cyloalkyl ring to D is saturated, which cycloalkyl ring can be substituted by one or more alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxo-substituents;
• (4) a 5- or 6-membered heteroaryl ring containing at least one and up to three atoms of N for the 6-membered heteroaryl rings and from one to three atoms of N or one atom of O or S and zero to two atoms of N for the 5-membered heteroaryl rings;
• (5) hydrogen, (C2-C6)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkoxyimino), alkoxycarbonyl, a group Arφ which is C6- or C10-aryl or a 5- or 6-membered, or 9- or 10-membered heteroaryl (wherein the heteroatom is one oxygen, one sulfur or one nitrogen) or Aralkyl;
• and
• (b) Rf is independently hydrogen, (C2-C6)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), alkoxycarbonyl, Arφ, or Arφ-alkyl;
• wherein aryl, Ar, or Arφ can be substituted with, in addition to any substitutions specifically noted one or more substituents selected from the group 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—, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, ArO—, Ar—, Ar—alkyl-, 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
• heterocycles, except those of Ar and Arφ, can be substituted with in addition to any substitutions specifically noted one or more substituents selected from acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C1 to C3)alkylenedioxy, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)—, ArO—, Ar—, Ar-alkyl, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, oxo, sulfamoyl, trifluoromethyl, 4-[C6 or C10]arylpiperidin-1-yl and 4-[C6 or C10]arylpiperazin-1-yl;
• or a pharmaceutically acceptable salt of said compounds, with the proviso that where the compound of formula I is administered to decrease intraocular pressure at least one compound of formula I administered in effective amount is not a thiazole substituted on a ring carbon sulfonamide (the amide of which can be substituted) that has carbonic anhydrase inhibiting activity.