ALDOSE REDUCTASE INHIBITORS USEFUL IN GLAUCOMA THERAPY

Abstract: Method of treating glaucoma comprising the topical or systemic application of an aldose reductase inhibitor.

Description: Background of the Invention This invention relates to methods and compositions useful in the therapy of primary open angle glaucoma. Specifically, this invention relates to compositions comprising an aldose reductase inhibitor; and methods of treatment comprising administering these compositions to treat the glaucoma syndrome, a leading cause of blindness. While Applicant is bound by no theory, it appears that an important mechanism underlying open angle glaucoma is one associated with the enzyme aldose reductase and/or related aldehyde reductases. Certain cells of the trabecular meshwork, lamina cribrosa and lamina vasculosa of the eye contain the enzyme aldose reductase and/or related reductaces. These reductaces under conditions of hypreglycemia or hyperglactosemia cause the accumulation of certain polyols such as sorbitol or galactitol respectively. The inhibition of the enzyme aldose reductase and related reductaces results in the retardation of abnormal polyol accumulation at the expense of NADPH in such ocular cells. Such inhibition preserves normal or near normal reduced glutathione status, Na+/K+ ATPase activity and amino acid transport within said cells. Furthermore, this inhibition promotes or preserves normal collagen production in and around these cells of the trabecular meshwork which are susceptible to high aldose concentrations. This includes cells of the lamina cribrosa and lamina vasculosa in mammalian eyes, particularly those of man. Trabecular meshwork cells are important in preserving proper aqueous humor outflow facility of the eye. Intraocular pressure or tension in part corresponds to outflow facility. In certain conditions of elevated intraocular pressure, the outflow of the trabecular meshwork may be impaired due to abnormal collagen metabolism and insufficient trabecular meshwork cell population. The rheological characteristics of the trabecular meshwork are linked to the normal functions of its cells. Pathological alterations in collagen production and support in the posterior segments of the eye, which include the lamina cribrosa and lamina vasculosa, are associated with impaired retinal function and vision loss in glaucoma. This weakening of the posterior support structures of the eye is suggested to arise from abnormally elaborated collagen. Aldose reductase inhibitors, such as those disclosed in the present invention, have been demonstrated to prevent an abnormal elaboration of collagen associated with hyperglycemia and/or hypergalactosemia. Hyperglycemia is believed to be associated with the complications of glaucoma in diabetes mellitus patients. It follows that moderate glucose intolerance as is associated with aging may be contributory to glaucoma. Therefore, a potent aldose reductase inhibitor will have therapeutic utility in the therapy and/or prevention of glaucoma. Thus, it is an object of the present invention to provide methods of treatment and pharmaceutical compositions which will retard or delay the progressive field of vision loss associated with glaucoma; wherein the active in such methods and compositions is an aldose reductase inhibitor. Detailed Description of the Invention Aldose reductase inhibitors which are particularly suitable for the method of the present invention and pharmaceutical compositions comprising these inhibitors are disclosed in the prior patent art, many of the patents being owned by the Applicant. Preferred aldose reductase inhibitors which may be used in the invention are disclosed in Applicant's U. S. Patent Nos. 4,537,892 and 4,436,745. Also disclosing suitable aldose reductase inhibitors for use in the invention are U. S. Patents 4,438,272, 3,821,383, 4,117,230, 4,130,714 and 4,181,782. The complete disclosures of these prior patents are incorporated herein by reference. U. S. Patent No. 4,537,892 corresponds to European Patent Application No 84110855.8, filed September 12, 1984. It should be understood that the invention is inclusive of any aldose reductase inhibitor which is useful in the treatment of glaucoma and particularly, primary open angle glaucoma. Classes of aldose reductase inhibitors which may be used in the present invention include spirocyclic aromatic imides (U. S. Patent 4,537,892); spirohydantoin compounds (U. S. Patent Nos. 4,130,714, 4,117,230, 4,436,745, 4,438,272 and 4,209,630); spiro-oxazolidinediones (U. S. Patent 4,226,875) and spiro-polycyclicimidanzolidinediones (U. S. Patent 4,181,728), as well as other aldose reductase inhibitors known in the art. A particularly preferred group of aldose reductase inhibitors useful in the invention are the spirocyclic aromatic imides described in U. S. Patent No. 4,537,892 which are of the following general formula: and the pharmaceutically acceptable metal salts and in cases, where basic aromatic nitrogens are in the A, and/or B rings, the pharmaceutically acceptable organic and inorganic acid salts thereof, wherein A and B are aromatic or heterocyclic rings connected through two adjacent positions to a central cycloalkyl ring, the A and B rings being selected from the group consisting of those of the formula: and wherein U is selected from the group consisting of O, S, N-R¹; X is selected from the group consisting of H, F, lower alkyl sulfide (e.g., -S-CH₃), lower alkylsulfinyl (e.g., -S(O)CH₃); Y is selected from the group consisting of H, -OH, and -O-C-R³, F, Cl, lower alkyl, lower alkoxy, lower alkylsulfide (e.g., -S-CH₃), lower alkyl-sulfinyl (e.g., -S(O)-CH₃), lower alkylsulfonyl (e.g., -SO₂CH₃), -CF₃, -S-CF₃, -SO₂CF₃, CO-N(R¹)-R², lower alkyl alcohol (e.g., -CH₂-OH), lower alkyl ether (e.g., -CH₂OCH₃), nitro, lower alkyl sulfide lower alkyl (e.g., -CH₂S- CH₃), lower alkylamine (e.g., -CH₂NH₂), lower alkyl esters (e.g., -CH₂-O-COCH₃), carboxylic acids and lower alkyl esters (e.g., -COOR³), lower alkyl carboxylic acids and esters (e.g., -CH(CH₃)-COOR¹), and lower cycloalkyl (e.g., cyclopropyl); R¹ and R² are selected from the group consisting of H and lower alkyl (preferably methyl or ethyl); R³ is lower alkyl (preferably methyl or ethyl); Z is selected from the group consisting of H, lower alkyl (preferably methyl), and halogen (fluoro, chloro, bromo, iodo); and t is selected from the group consisting of NH, O, S, and CHR¹. In a more preferred embodiment, the spiro-cyclic aromatic imides of the present invention are of the following general formula: wherein A, B, U, X, Y, R¹, R², R³, Z and t are as described above. In more preferred embodiments, the cycloalkyl groups have 4 to 7 carbon atoms and lower alkyl groups have 1 to 6 carbon atoms. In an especially preferred emodiment, Ring A is selected from the foregoing group and Ring B is selected from the group consisting of the following: wherein X, U, and Z are described above. In the compounds of Formulae I and I-A, Rings A and B are attached to the central five-membered ring at positions 1,2 and 3,4. The compounds of this type have important geometric and chemical similarities. These similarities include a planar, rigid tricyclic fluorene or fluorene-like aromatic ring system spiro-coupled to a five-membered imide (or cyclic secondary amide) ring such as succinimide, hydantoin, thiazolidinedione or oxazolidinedione. These spirocyclic derivatives of the various tricycles each contain a polarizable and hydrogen-bondable secondary amide, also called imide, radical (-CO-NH-CO-). In those instances where, according to general Formulae I and I-A, A does not equal B, the spiro carbon is chiral. Activity of any such racemic mixture may be attributable to only one isomer. Resolution, or direct synthesis, of the enantiomers, as is known in the art, is recognized as a method to isolate or prepare the active or the more active enantiomer. It is also recognized that certain patterns of substitution on A and/or B according to Formulae I and I-A may create asymmetry, and the resulting diastereomeric mixtures may be separated by chromatography or solvent recrystallizations, as is known and practiced in the art. For example, if A has a methylsulfoxyl substituent and A is different from B, then there are at least two chiral centers: the spiro carbon and the sulfoxide sulfur. Physical separation of this diastereomeric mixture by chromatography or other methods practiced in the art will yield two racemic mixtures, each containing a pair of enantiomers. Stereospecific oxidation of a methylsulfide on A to yield a methylsulfoxide (e.g., via sodium metaperiodate and albumin) when A is different than B (according to Formula I) will yield a diastereomeric mixture, which then can be separated by conventional physical methods known in the art, such as liquid chromatography or differential solvent solubility, to yield the purified diastereomers which are themselves purified optical isomers. Reduction of the two optically active sulfoxide diastereomers will yield the optically active pair of enantiomers of mirror image isomers. Other useful aldose reductase inhibitors to be used in the invention are disclosed in the following patents and patent publications, the disclosures of which are also incorporated herein by reference: 1. European Patent Application No. EP-180421-A, Pfizer, Inc. 2. Japanese Patent Application No. J61-056175-A, Yamanouchi Pharm. KK 3. European Patent Application No. EP-173497-A, Pfizer, Inc. 4. European Patent Application No. EP-172719-A, Pfizer, Inc. 5. European Patent Application No. EP-171213-A, Pfizer, Inc. 6. European Patent Application No. EP-159143-A, Pfizer, inc. 7. U. S. Patent No. 4,540,700, Alcon Labs, Inc. 8. U. S. Patent No. 4,533,667, Pfizer, Inc. 9. U. S. Patent No. 4,593,092, Kyorin Pharm. Ltd 10. Canadian Patent No. 1,187,093, Ayerst McKenna & HA 11. European Patent Application No. EP143461-A, Kaken Pharm. Co. Ltd. 12. European Patent Application No. EP136143-A, Pfizer, Inc. 13. Japanese Patent Application No. JP0001173-A, Tanaka C. 14. U. S. Patent No. 4,587,256, Hoffmann-La Roche AG 15. French Patent No. 2544317-A, ADIR 16. U. S. Patent No. 4,471,124, Pfizer, Inc. 17. European Patent Application No. EP117035-A, Pfizer, Inc. 18. European Patent Application No. EP127412-A, Pfizer, Inc. 19. European Patent Application No. EP115133-A, Pfizer, Inc. 20. U. S. Patent No. 4,457,941, Syntex, Inc. 21. European Patent Application No. EP112620-A, Pfizer, Inc. 22. U. S. Patent No. 4,452,806, Pfizer, Inc. 23. U. S. Patent No. 4,442,118, Ayerst McKenna Corp. 24. European Patent Application No. EP104078-A, Ayerst McKenna Corp. 25. Canadian Patent No. 1,162,856, Ayerst McKenna & HA 26. U. S. Patent No. 4,585,789, Fujisawa Pharm. KK. 27. Japanese Patent Application No. J58213717-A, Eisai KK 28. German Patent Application DE 3315106-A, ADIR 29. U. S. Patent No. 4,464,385, Alcon Labs, Inc. 30. European Patent Application No. EP-91761-A, Takeda Chem. Ind. KK 31. U. S. Patent No. 4,443,465, ICI 32. U. S. Patent No. 4,490,381, ICI To the extent that these applications and patents disclose aldose reductase inhibitors which are useful in the practice of the present invention, they are incorporated herein by reference in their entirety. The following specific compounds and their optical isomers are specifically preferred aldose reductase inhibitors for use in the invention: Spiro-(7-fluoro-4 H -indeno[1,2-b]thiophen-4,4′-­ imidazolidine)-2′,5′-dione; Spiro-(2-fluoro-9 H -fluoren-9,4′-imidazolidine)-­ 2′,5′-dione; Spiro-(2-fluoro-9 H -fluoren-9,3′-succinimide); Spiro-(7-fluoro-5 H -indeno[1,2-b]-pyridin-5,4′-­ imidazolidine)-2′,5′-dione; Spiro-(7-chloro-5 H -indeno[1,2-a]pyridin-9,4′-­ imidazolidine)-2′,5′-dione; Spiro-(7-chloro-9 H -pyrrolo[1,2-a]indol-9,4′-­ imidazolidine)-2′,5′-dione; Spiro-(2,7-difluoro-9 H -fluoren-9,4′-­ imidazolidine)-2′,5′-dione; Spiro-(2,7-difluoro-9 H -fluoren-9,3′-succinimide); Spiro-(2,7-difluoro-9 H -fluoren-9,5′-oxazolidine)-­ 2′,4′-dione; Spiro-(7-fluoro-5 H -indeno-[1,2-b]pyridine-5,3′-­ succinimide); Spiro-(7-chloro-5 H -indeno-[1,2-b]pyridine-5,3′-­ succinimide); Spiro-(7-methylthio-5 H -indeno-[1,2-b]pyridine-­ 5,3′-succinimide); The preferred route of administration for the compositions of the present invention is topically to the eye or per oral. The exact dosage regimen is left to the routine discretion of clinician taking into consideration the host's age, sex, weight, and his history accounting for or attributing to the glaucoma in question. The most preferred compositions will have the aldose reductase inhibitor of choice present at a concentration ranging from 0.1% to 2.0 weight % in a vehicle selected from buffered water, aqueous buffered carbopol gel, or a perfluoroalkane-type vehicle such as a fluorocarbon. Typical systemic routes of administration are fully disclosed and claimed in copending owned U. S. Patent No. 4,436,745 and 4,537,892, which are discussed above. The following representative examples illustrate suitable pharmaceutical compositions for topical or oral delivery of the involved aldose reductase inhibitors for glaucoma therapy. Example 1 Gel composition for topical, ocular administration: The following topical, ocular formulations are physically in the form of suspensions: The following formulation is a selected representative of a solution for the ophthalmic indications of the present invention: Example 2 A dry solid pharmaceutical composition is prepared by mixing the following materials together in the proportions by weight specified: The dry composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 100 mg of the active ingredient. Other tablets are also prepared in a likewise manner containing 10, 25 and 200 mg of active ingredient, respectively, by merely using an appropriate quantity by weight of the spiro-hydantoin in each case. Likewise other related examples of spiro-imidazolidinedions, spiro-thiazolidinediones, spiro-oxazolidinediones, spiro-succinimides can be formulated as tablets on a respective weight proportion. The dry solid pharmaceutical composition is prepared by combining the following materials together in the weight proportions indicated below: The dry solid mixture is thoroughly mixed until uniform in composition. The powdered product is then used to fill soft elastic and hard-gelatin capsules so as to provide capsules containing 200 mg of the active ingredient.

Claims: 1. Aldose reductase inhibitor compositions useful for the treatment of glaucoma. 2. A use according to claim 1 characterized in that the composition is used for a host which is human and diabetic. 3. The use according to claim 1 characterized in that the composition is used for a host which is human and exhibits ocular hypertension. 4. The use according to claim 1 characterized in that the glaucoma is primary open angle glaucoma. 5. The use according to claim 1 characterized in that the composition is administered topically, orally, or systemically. 6. The use according to claim 5 characterized in that the aldose reductase inhibitor is contained in a pharmaceutically acceptable vehicle in a concentration ranging from 0.1 to 2.0 weight percent of the vehicle. 7. The use according to claim 6 characterized in that the vehicle is selected from the group consisting of buffered water, aqueous buffered carbopol gel, and a perfluoroalkane. 8. The use according to claim 1 characterized in that the composition is in the form of a gel, suspension, solution, tablet or capsule. 9. The use according to claim 1 characterized in that the aldose reductase inhibitor is a spiro imide compound. 10. The use according to claim 1 characterized in that the aldose reductase inhibitor is a spirocyclic aromatic imide, a spirohydantoin, a spiro­ oxazolidinedione, or a spiropolycyclicimidazolidine­ dione.

Inventors: YORK, BILLIE MURRAY, JR.
Applicants: ALCON LABORATORIES INC
Application year: 1986
Main classification: A61K31
IPC codes: A61K31