Claims
- 1. The polymorph of 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid monohydrate having the following characteristic x-ray powder diffraction pattern:
- ______________________________________2-theta d/A 2-theta d/A 2-theta d/A______________________________________5.3 16.7 17.6 5.0 26.2 3.45.9 15.1 19.2 4.6 27.3 3.38.0 11.0 20.1 4.4 28.3 3.210.5 8.4 21.2 4.2 29.0 3.111.8 7.5 21.4 4.2 29.5 3.012.3 7.2 22.1 4.0 30.2 3.012.6 7.0 22.5 4.0 30.9 2.913.1 6.8 23.1 3.8 31.7 2.814.3 6.2 23.4 3.8 32.6 2.715.7 5.6 23.8 3.7 33.4 2.716.5 5.4 24.3 3.7 36.6 2.517.1 5.2 25.3 3.5______________________________________
- 2. A process for preparing the polymorph of claim 1 comprising:
- (a) reacting 3,4-dihydro-4-oxo-3-((5-trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid ethyl ester with aqueous sodium hydroxide in a reaction inert polar solvent to form a first solution comprising sodium 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetate;
- (b) adjusting said first solution to a pH of from about 7.5 to about 8.5 to form a second solution comprising sodium 3,4-dihydro-4-oxo-3-((5(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetate;
- (c) adding to said second solution a suitable water soluble solvent to form a third solution comprising sodium 3,4-dihydro-4-oxo-3-((5-trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetate; and
- (d) adjusting said third solution to a pH of from about 1.5 to about 2.5 with a strong inorganic acid to form a solution of said polymorph.
- 3. A process of claim 2 comprising the additional subsequent step of filtering said solution of said polymorph to obtain solid 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid monohydrate.
- 4. A process of claim 3 wherein said suitable water soluble solvent in step (c) is ethyl acetate, a (C.sub.1 -C.sub.6)alkanol or tetrahydrofuran.
- 5. A process for preparing the polymorph of claim 1 comprising:
- (a) reacting anhydrous 3,4-dihydro-4-oxo-3-((5-trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid with aqueous sodium hydroxide in a reaction inert polar solvent to form a first solution comprising sodium 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetate;
- (b) adjusting said first solution to a pH of from about 7.5 to about 8.5 to form a second solution comprising sodium 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl) methyl)-1-phthalazineacetate;
- (c) adding to said second solution a suitable water soluble solvent to form a third solution comprising sodium 3,4-dihydro-4-oxo-3-((5-trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetate; and
- (d) adjusting said third solution to a pH of from about 1.5 to about 2.5 with a strong inorganic acid to form a solution of said polymorph.
- 6. A process of claim 5 comprising the additional subsequent step of filtering said solution of said polymorph to obtain solid 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic monohydrate.
- 7. A process of claim 6 wherein said suitable water soluble solvent in step (c) is ethyl acetate, a (C.sub.1 -C.sub.6)alkanol or tetrahydrofuran.
- 8. A process for preparing anhydrous 3,4-dihydro-4-oxo-3-((5(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid comprising recrystallizing 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic monohydrate from a mixture of a water soluble solvent and water.
- 9. A process of claim 8 wherein said water soluble solvent is ethyl acetate, a C.sub.1 -C.sub.6 alkanol or tetrahydrofuran.
- 10. A process of claim 9 wherein the ratio of ethyl acetate to water is from 1:4 to 1:12, the ratio of a (C.sub.1 -C.sub.6)alkanol to water is from 1:0.85 to 1:1.15 and the ratio of tetrahydrofuran to water is from 1:0.85 to 1:1.15.
- 11. A process for preparing anhydrous 3,4-dihydro-4-oxo-3-((5-(trifluoromethyl)-2-benzothiazolyl)methyl)-1-phthalazineacetic acid comprising drying the polymorph of claim 1.
- 12. A process of claim 11 comprising heating the polymorph in water prior to drying.
- 13. A method of treating diabetic cardiomyopathy in a human subject in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 1 to said subject.
- 14. A method of claim 13 wherein said treatment comprises reversal of said diabetic cardiomyopathy.
- 15. A method of reducing non-cardiac tissue damage resulting from ischemia comprising administering to a mammal in need of such treatment an amount of a compound of claim 1 effective at reducing non-cardiac ischemic damage.
- 16. A method of claim 15 wherein said tissue is brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, retinal tissue or intestinal tissue.
- 17. A method of claim 16 wherein said mammal is a human.
- 18. A method of claim 17 wherein said human has diabetes.
- 19. A method of lowering blood uric acid levels in a mammal in need of such lower levels comprising administering to said mammal a blood uric acid level lowering amount of a compound of claim 1.
- 20. A method of lowering blood lipid levels in a human comprising administering to a human in need of such treatment an effective amount of a compound of claim 1.
- 21. A method of inhibiting aldose reductase activity in a diabetic subject comprising administering to said diabetic subject an effective amount of a compound of claim 1.
- 22. A method of treating anginal pain by direct action on the myocardium in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.
- 23. A method of treating diabetic nephropathy in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.
- 24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
- 25. A pharmaceutical composition for inhibiting aldose reductase comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
- 26. A pharmaceutical composition for treating or reversing complications arising from diabetes mellitus comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
Parent Case Info
This application is filed claiming priority from co-pending Provisional Application No. 60/097,474 filed Aug. 21, 1998.
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