Claims
- 1. A method of decreasing intraocular pressure or improving ocular accommodation in an animal, including a human, comprising administering an intraocular pressure decreasing or ocular accommodation improving amount of a compound of the formula I:
- 2. The method of claim 1, wherein
a. Het is a five or six membered heterocycle having a first ring nitrogen and optionally, a second or third ring nitrogen, with the remaining ring atoms being carbon, oxygen, or sulfur; provided that Het is not thiazole, imidazole, oxazole, or dihydro or tetrahydro analogs thereof; b. Het can be substituted on carbon atoms with
1. one or more substituents independently selected from hydrogen, acylamino, alkanoyl, alkanoylalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, 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, alkylthio, alkylsulfonyl, alkylsulfinyl, alkylsulfonamido, trifluoromethyl, morpholin-4-yl, thiomorpholin-4-yl, 4-[C6 or C10]arylpiperidin-1-yl, 4-[C6 or C10]arylpiperazin-1-yl, piperidin-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 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 optionally fused to a substituted benzene, pyridine, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Het)}, Ar*-alkyl, Ar*-O, Ar*SO2—, Ar*SO—, Ar*S—, Ar*SO2NH—, Ar*NH, (N—Ar*)(N-alkyl)N—, Ar*C(O)—, Ar*C(O)NH—, Ar*NH—C(O)—, and (N—Ar*)(N-alkyl)N—C(O)—; or 2. two adjacent substitutions together with their ring carbons form a fused C6 or C10 aryl ring which aryl ring can be substituted as set forth below; or 3. two adjacent substitutions together with their ring carbons form a C5-C7 fused cycloalkyl ring having no double bonds except any fused double bond of the Het group, which cycloalkyl ring can be substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo; and c. Het can be substituted on ring nitrogen atoms with
1. hydrogen, alkyl, alkoxycarbonylalkyl-, Ar*, Ar*alkyl-, Ar*C(O)alkyl-, ArS*(O)alkyl-, Ar*S(O)2alkyl-, so long as the ring nitrogen atoms are not quaternized; 2. amino; or 3. at most one nitrogen with oxido (—O−) to form an N-oxide; and d. Y is substituted on a ring carbon adjacent to the first or second ring nitrogens and is
1. hydrogen, oxo, alkyl, mercapto, alkylthio, amino, amino(C1-C5)alkyl, or aminophenyl, wherein the amino of the latter three groups can be (a) 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 S(O)2 or (c) formyl or alkanoyl, 2. —NHC(O)(CH2)n—D—ReRf, wherein D is oxygen, sulfur or nitrogen, wherein when 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 formulaHetδ-wherein Hetδ is independently the same as Het, (3) a C3-C8 cycloalkyl ring having up to one double bond with the proviso that the carbon linking the cycloalkyl ring to D is saturated, which cycloalkyl ring can be substituted by one or more alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxo-substituents, where multiple substituents are located on different carbon atoms of the cycloalkyl ring, except in the case of alkyl, alkoxycarbonyl, and fluoro substituents, which can be located on the same or different carbon atoms; or (4) hydrogen, (C2-C6)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkoxyimino), alkoxycarbonyl, Ar*, or Ar*-alkyl-; and (b) Rf is independently hydrogen, hydroxy(C2-C6)alkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), alkoxycarbonyl, independently a group Ar* or Ar*-alkyl; wherein aryl or Ar* in addition to any substitutions specifically noted can be substituted with one or more substituents selected from the group of alkyl, amino, dialkylamino, 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 Het or Ar*, can be substituted with, in addition to substitutions specifically noted, one or more substituents selected from acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, Ar*C(O)—, Ar*O—, Ar*-, Ar*-alkyl, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, 4-[C6 or C10]arylpiperidin-1-yl, 4-[C6 or C10]arylpiperazin-1-yl. (C1-C3)alkylenedioxy, oxo, sulfamoyl, and trifluoromethyl; or a pharmaceutically acceptable salt of said compounds.
- 3. The method of claim 1, wherein Het-Y is
- 4. The method of claim 3, wherein Het-Y is
- 5. The method of claim 3, wherein Het-Y is
- 6. The method of claim 3, wherein Het-Y is
- 7. The method of claim 1, wherein Het-Y is
- 8. The method of claim 7,
a. wherein L is N; b. G is C—Rj; C. M is C—Rk; d. Q is C—Rl; and e. Y is amino, amino(C1-C5)alkyl, or aminophenyl, wherein the amino of all three groups can be substituted with
(1) Ar*, (2) Ar*-Z—, Ar*-alkyl-Z—, Ar*-Z-alkyl-, Ar*-amino-Z—, Ar*-aminoalkyl-Z— or Ar*-oxyalkyl-Z—, wherein Z is a carbonyl or S(O)2 or (3) formyl or alkanoyl.
- 9. The method of claim 7,
a. wherein L and Q are N; b. G is C—Rj; c. M is C—Rk; and d. Y is amino, amino(C1-C5)alkyl, or aminophenyl, wherein the amino of all three groups can be substituted with
(1) Ar*, (2) Ar*-Z—, Ar*-alkyl-Z—, Ar*-Z-alkyl-, Ar*-amino-Z—, Ar*-aminoalkyl-Z— or Ar*-oxyalkyl-Z—, wherein Z is a carbonyl or S(O)2 or (3) formyl or alkanoyl.
- 10. The method of claim 3,
a. wherein Q is N; b. G is N—Rg; c. M is C—Rh; and d. Y is amino, amino(C1-C5)alkyl, or aminophenyl, wherein the amino of all three groups can be substituted with
(1) Ar*, (2) Ar*-Z—, Ar*-alkyl-Z—, Ar*-Z-alkyl-, Ar*-amino-Z—, Ar*-aminoalkyl-Z— or Ar*-oxyalkyl-Z—, wherein Z is a carbonyl or S(O)2 or (3) formyl or alkanoyl.
Parent Case Info
[0001] This application claims the priority of U.S. Applications No. 60/296,434, filed Jun. 6, 2001, and 60/259,427, filed Dec. 29, 2000.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60296434 |
Jun 2001 |
US |
|
60259427 |
Dec 2000 |
US |