Substituted indolealkanoic acids derivative and formulations containing same for use in the treatment of diabetic complications
Disclosed is a compound of the formula (I) its hydrates and/or pharmaceutically acceptable salts, which are useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their preparation.
1 . Hydrates of a compound of the formula:
2 . A compound that is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate.
3 . A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or 2 and at least one pharmaceutically acceptable carrier, solvent, excipient or adjuvant.
4 . A method of preventing or alleviating chronic complications arising from diabetes mellitus, which comprises administering to a mammal in need of such treatment an effective amount of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
5 . A method according to claim 4 , wherein the compound is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate.
6 . A method according to claim 5 wherein the mammal is a human.
7 . A method according to claim 5 wherein the complications are selected from the group consisting of diabetic cataracts, retinopathy, nephropathy and neuropathy.
8 . A method according to claim 5 wherein the complications are diabetic cataracts or retinopathy.
9 . A method according to claim 5 wherein the complications are nephropathy or neuropathy.
10 . A method of treatment according to claim 5 wherein the therapeutically effective amount for oral administration is about 0.01 mg to 100 mg/kilogram of body weight per day.
11 . A method of treatment according to claim 10 wherein the therapeutically effective amount for oral administration is about 0.025 mg to 15 mg/kilogram of body weight per day.
12 . A method of treatment according to claim 11 wherein the therapeutically effective amount for oral administration is about 0.05 mg to 10 mg/kilogram of body weight per day.
13 . A method of treatment according to claim 10 , wherein the therapeutically effective amount for oral administration is about 0.05 mg to 2.5 mg/kilogram of body weight per day.
14 . A method according to claim 5 , wherein the effective amount of the compound is contained within a unit dosage form containing about 1 to 10 mg of the compound.
15 . A method according to claim 14 , wherein the unit dosage form contains between about 0.5 mg to 100 mg of the compound.
16 . A method according to claim 15 wherein the unit dosage form contains about 1 mg to 50 mg of the compound.
17 . A method according to claim 16 wherein the unit dosage form contains about 1 mg to 15 mg of the compound.
18 . A method of reducing sorbitol in tissues comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid or a salt or hydrate thereof.
19 . A methods according to claim 24 wherein the tissue is sciatic nerve, lens, retina, kidney cortex or kidney medulla.
20 . A method of reducing fructose levels in tissues comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl)acetic acid or a salt or hydrate thereof.
21 . A method of increasing myoinositol in tissues comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid or a salt or hydrate thereof.
22 . A method of inhibiting the polyol-induced loss of nerve conduction velocity in the sciatic nerve comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid or a salt or hydrate thereof.
23 . A method of reversing cataract formation comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid or a salt or hydrate thereof.
24 . A method of preventing cataract formation comprising administering from about 0.05 to 0.5 mg/kg/day of a compound which is {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid or a salt or hydrate thereof.
25 . A method according to claim 5 wherein the unit dosage form contains about 5 mg to 10 mg of the compound.
26 . A pharmaceutical composition comprising {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, lactose and polyvinylpyrrolidinone.
27 . A pharmaceutical composition according to claim 26 , wherein the composition is formulated into granules.
28 . A pharmaceutical composition according to claim 27 wherein the granule size is less than 1.0 mm.
29 . A pharmaceutical composition in tablet form comprising, by weight of the tablet, from about 5-75% of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, about 25-85% of lactose monohydrate, about 3-6% polyvinylpyrrolidinone, about 2-4% of croscarmellose sodium, and about 4-8% magnesium stearate.
30 . A pharmaceutical composition in tablet form comprising about 50 mg of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, about 248 mg of lactose monohydrate, about 16 mg polyvinylpyrrolidinone, about 10 mg of croscarmellose sodium, and about 6 mg magnesium stearate.
31 . A pharmaceutical composition in tablet form comprising about 200 mg of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, about 98 mg of lactose monohydrate, about 16 mg polyvinylpyrrolidinone, about 10 mg of croscarmellose sodium, and about 6 mg magnesium stearate.
32 . A pharmaceutical composition in capsule form comprising about 200 mg of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, about 98 mg of lactose monohydrate, and about 16 mg polyvinylpyrrolidinone.
33 . A pharmaceutical composition according to claim 32 , wherein the capsule comprises granules of blended (3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, lactose monohydrate, and polyvinylpyrrolidinone.
34 . A pharmaceutical composition according to claim 33 , where the granules have an average size of about 1 mm.
35 . A process for preparing a pharmaceutical composition according to any of claims 29 - 34 , comprising forming granules of blended {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, lactose monohydrate, and polyvinylpyrrolidinone, where the granules have an average size of about 1 mm.
36 . A process for preparing a compound of claim 1 , comprising forming a solution of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid in acetonitrile and water, and subsequently allowing crystals of the compound of claim 1 to form.
37 . A process according to claim 36 , wherein the solution is heated.
38 . A pharmaceutical composition in tablet form comprising about 20-30 mg of {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl}acetic acid monohydrate, about 270-280 mg of lactose monohydrate, about 10-20 mg polyvinylpyrrolidinone, about 5-15 mg of croscarmellose sodium, and about 3-10 mg of magnesium stearate.
39 . A method normalizing sorbitol levels in tissues in a human patient, which comprises administering to a a patient in need of such treatment an effective amount of a compound according to claim 1.