MXPA99007842A - Polymopher of monopidrate of zopolres - Google Patents
Polymopher of monopidrate of zopolresInfo
- Publication number
- MXPA99007842A MXPA99007842A MXPA/A/1999/007842A MX9907842A MXPA99007842A MX PA99007842 A MXPA99007842 A MX PA99007842A MX 9907842 A MX9907842 A MX 9907842A MX PA99007842 A MXPA99007842 A MX PA99007842A
- Authority
- MX
- Mexico
- Prior art keywords
- solution
- oxo
- trifluoromethyl
- dihydro
- methyl
- Prior art date
Links
- -1 zopolrestat monohydrate Chemical class 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 210000004369 Blood Anatomy 0.000 claims abstract description 9
- 239000008280 blood Substances 0.000 claims abstract description 9
- 150000002632 lipids Chemical class 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 239000003021 water soluble solvent Substances 0.000 claims description 13
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000002798 polar solvent Substances 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 210000001519 tissues Anatomy 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 102000016912 EC 1.1.1.21 Human genes 0.000 claims description 7
- 108010053754 EC 1.1.1.21 Proteins 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 208000000538 Diabetic Cardiomyopathy Diseases 0.000 claims description 4
- 206010012647 Diabetic cardiomyopathy Diseases 0.000 claims description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Trioxopurine Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 4
- 229940116269 Uric Acid Drugs 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000003902 lesions Effects 0.000 claims description 4
- 230000000747 cardiac effect Effects 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 206010002383 Angina pectoris Diseases 0.000 claims description 2
- 210000004556 Brain Anatomy 0.000 claims description 2
- 208000007342 Diabetic Nephropathy Diseases 0.000 claims description 2
- 206010061835 Diabetic nephropathy Diseases 0.000 claims description 2
- 210000003734 Kidney Anatomy 0.000 claims description 2
- 210000004185 Liver Anatomy 0.000 claims description 2
- 210000004072 Lung Anatomy 0.000 claims description 2
- 210000002027 Muscle, Skeletal Anatomy 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- 210000000496 Pancreas Anatomy 0.000 claims description 2
- 230000000968 intestinal Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 8
- IDVJTJYJLCVOAY-UHFFFAOYSA-M C(C)(=O)[O-].[Na+].C1=NN=CC2=CC=CC=C12 Chemical compound C(C)(=O)[O-].[Na+].C1=NN=CC2=CC=CC=C12 IDVJTJYJLCVOAY-UHFFFAOYSA-M 0.000 claims 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 2
- RIIVBOIBIOLLPO-UHFFFAOYSA-N 2-phthalazin-1-ylacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=NN=CC2=C1 RIIVBOIBIOLLPO-UHFFFAOYSA-N 0.000 claims 1
- 210000000936 Intestines Anatomy 0.000 claims 1
- 210000000952 Spleen Anatomy 0.000 claims 1
- MZAJBVDZKSUSGH-UHFFFAOYSA-N acetic acid;phthalazine Chemical compound CC(O)=O.C1=NN=CC2=CC=CC=C21 MZAJBVDZKSUSGH-UHFFFAOYSA-N 0.000 claims 1
- 231100001012 cardiac lesion Toxicity 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000002207 retinal Effects 0.000 claims 1
- 229950005346 Zopolrestat Drugs 0.000 abstract description 60
- 208000001636 Diabetic Neuropathy Diseases 0.000 abstract description 4
- 206010012680 Diabetic neuropathy Diseases 0.000 abstract description 4
- 206010007749 Cataract diabetic Diseases 0.000 abstract description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 abstract description 3
- 201000007025 diabetic cataract Diseases 0.000 abstract description 3
- 208000002249 Diabetes Complications Diseases 0.000 abstract 1
- 206010012655 Diabetic complications Diseases 0.000 abstract 1
- 230000002378 acidificating Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- BCSVCWVQNOXFGL-UHFFFAOYSA-N 3,4-DIHYDRO-4-OXO-3-((5-TRIFLUOROMETHYL-2-BENZOTHIAZOLYL)METHYL)-1-PHTHALAZINE ACETIC ACID Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 BCSVCWVQNOXFGL-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N 1-Hexanol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- HGIGQRVGJPKKIJ-UHFFFAOYSA-N 2-(4-methylphthalazin-1-yl)acetic acid Chemical compound C1=CC=C2C(C)=NN=C(CC(O)=O)C2=C1 HGIGQRVGJPKKIJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 208000003067 Myocardial Ischemia Diseases 0.000 description 1
- 210000004165 Myocardium Anatomy 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 210000001525 Retina Anatomy 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
This invention relates to zopolrestat monohydrate and its polymorphs, this invention further relates to processes for preparing zopolrestat monohydrate, for preparing its polymorphs and for preparing zopolrestat anhydride, this invention further relates to compositions comprising zopolrestat monohydrate and methods of use of zopolrestat monohydrate and compositions thereof to treat diabetic complications such as diabetic cataracts, retinopathy or neuropathy, reduce blood lipid levels or the acidic level, in blood
Description
MONOPIDRATE POLYMORPHATE OF ZOPOLRESTAT
BACKGROUND OF THE INVENTION
This invention relates to zopolrestat monohydrate, its polymorphs and processes for the preparation of polymorphs. This invention further relates to methods for using the polymorphs to prepare anhydrous zopolrestat and to methods of using the polymorphs and to compositions comprising the polymorph to treat, prevent or reverse complications derived from diabetes mellitus. Zopolrestat, also known as 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetic acid, is the compound of formula I:
Zopolrestat is described in U.S. Patent No. 4,939,140, together with its utility in the inhibition of aldose reductase, more especially as having utility in the treatment of complications derived from diabetes mellitus such as cataracts, retinopathy and Diabetic neuropathy.
Subsequently, zopolrestat has been described because it has utility in reducing blood lipid levels (U.S. Patent No. 5,391,551) and for reducing levels of uric acid in blood (U.S. Patent No. 5,064). .830).
SUMMARY OF THE INVENTION
This invention provides a polymorph of zopolrestat monohydrate and methods for its preparation. The use of the present polymorph of zopolrestat monohydrate allows a faster filtration process and an improved production cycle of zopolrestat monohydrate. This invention also provides the polymorph having the characteristic X-ray powder diffraction pattern, shown in Table 1 below. This invention further provides processes for the preparation of the polymorph, hereinafter referred to as "processes A and B".
Process A comprises: (a) reacting 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetic acid ethyl ester (hereinafter referred to as "zopolrestat ethyl ester") with aqueous sodium hydroxide in a polar solvent inert to the reaction to form a first solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl -1-phthalazinacetate sodium;
(b) adjusting said first solution to a pH ranging from about 7.5 to about 8.5 to form a second solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) - 2-benzothiazolyl) methyl-1-phthalazineacetate sodium; (c) adding to said second solution a suitable water-soluble solvent to form a third solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetate sodium Y
(d) adjusting said third solution to a pH ranging from about 1.5 to about 2.5 with a strong inorganic acid such as concentrated aqueous hydrochloric acid to form a solution of said polymorph. A particularly preferred process in the framework of process A comprises the further step of filtering said solution of said polymorph to obtain 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-monohydrate. -benzothiazolyl) methyl-1-phthalazine acetic acid. A still more particularly preferred method in the context of the method of the preceding paragraph comprises a process in which said suitable water-soluble solvent of step (c) is ethyl acetate, a C-C alcan alkanol or tetrahydrofuran.
Process B comprises: (a) reacting the anhydrous 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazineacetic acid (hereinafter referred to as "anhydrous zopolrestat") ) with aqueous sodium hydroxide in a polar solvent inert to the reaction to form a first solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetate sodium (b) adjusting said first solution to a pH ranging from about 7.5 to about 8.5 to form a second solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2- benzothiazolyl) methyl-1-phthalazinacetate sodium; (c) adding to said second solution a suitable water-soluble solvent to form a third solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetate sodium (hereinafter referred to as "zopolrestat sodium carboxylate"); and (d) adjusting said third solution to a pH ranging from about 1.5 to about 2.5 with a strong inorganic acid such as concentrated aqueous hydrochloric acid to form a solution of said polymorph. A particularly preferred process in the framework of process B comprises the further step of filtering said solution of said polymorph to obtain 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl monohydrate. ) solid methyl-1-phthalazine acetic acid. A still more particularly preferred method in the context of the method of the preceding paragraph comprises a process in which said suitable water-soluble solvent of step (c) is ethyl acetate, a Ci-Cβ alkanol or tetrahydrofuran. This invention also provides a process for preparing anhydrous zopolrestat, which comprises recrystallizing a polymorph of zopolrestat monohydrate in a mixture of a water-soluble solvent and water. Preferred water soluble solvents include ethyl acetate, a C 1 -C 2 alkanol and tetrahydrofuran. It is particularly preferred that the ratio of ethyl acetate to water varies from 1: 4 to 1:12; that the ratio of C-i-Cβ alkanol to water varies from 1: 0.85 to 1: 1, 15 and that the ratio of tetrahydrofuran to water varies from 1: 0.85 to 1: 1, 15. This invention further provides a process for preparing anhydrous zopolrestat, which comprises drying a polymorph of zopolrestat monohydrate, optionally by heating the polymorph in water before drying. In addition, the invention includes a method of treating diabetic cardiomyopathy in a human subject in need of such treatment, which comprises administering a therapeutically effective amount of zopolrestat monohydrate to said subject, a method of reducing lesions to noncardiac tissue resulting from ischemia, which comprises administering to a mammal in need of such treatment an amount of zopolrestat monohydrate effective to reduce non-cardiac ischemic lesions, a method of reducing levels of uric acid in blood in a mammal in need of such reduced levels, which comprises administering to said mammal. mammal means an amount of zopolrestat monohydrate that reduces levels of uric acid in blood, a method for reducing blood lipid levels in a human being in need of such treatment, which comprises administering to said human an effective amount of zopolrestat monohydrate , a procedure inhibitor of aldose reductase activity in a diabetic subject, comprising administering to said diabetic subject an effective amount of zopolrestat monohydrate, a method of treating or preventing angina pain by direct action on the myocardium in a mammal, which comprises administering to said mammal a therapeutically effective amount of zopolrestat monohydrate, a method for preventing cardiac injury derived from myocardial ischemia in a mammal, comprising administering to said mammal a therapeutically effective amount of zopolrestat monohydrate and a method of treating the diabetic nephropathy in a mammal in need of such treatment, which comprises administering to said mammal a therapeutically effective amount of zopolrestat monohydrate. This invention further relates to a pharmaceutical composition comprising zopolrestat monohydrate and a pharmaceutically acceptable carrier or diluent. This invention further includes a pharmaceutical composition for inhibiting aldose reductase, comprising zopolrestat monohydrate and a pharmaceutically acceptable carrier or diluent. This invention also includes a pharmaceutical composition for treating, preventing or reversing complications derived from diabetes mellitus, comprising zopolrestat monohydrate and a pharmaceutically acceptable carrier or diluent.
DETAILED DESCRIPTION OF THE INVENTION
In this specification and the appended claims, the term "polymorph" refers to a form of a substance in which the substance has different forms, preferably in a solution. In this specification, the term "C 1 -C 6 alkanol" refers to (C 1 -C 6 alkyl) -OH, including straight or branched chain alkyl groups such as, for example, but not limited to methanol, ethanol, n-propanol , So-propanol, n-butanol, so-butanol, tert-butanol, n-pentanol or n-hexanol. In this specification, the term "room temperature" refers to 25 ° C. In this specification, the term "solvent inert to the reaction" refers to a solvent or mixture of solvents that does not interact with the starting materials, reagents, intermediates or products in a manner that adversely affects the performance of the desired product. The zopolrestat monohydrate can be prepared by the following procedures. According to the process A (a) of this invention, the zopolrestat sodium carboxylate can be obtained by a process comprising suspending zopolrestat ethyl ester in a polar solvent inert to the reaction, followed by the reaction with aqueous sodium hydroxide. The inert polar solvent for the suitable reaction may be a Ci-Cβ alkanol or tetrahydrofuran (THF) and, preferably, is ethanol. The formation of the suspension can be carried out at a temperature in the range of 10 ° to 60 ° C, preferably at room temperature. The suspension thus obtained is added to aqueous sodium hydroxide to form a reaction mixture which is stirred at a temperature in the range of 10 ° to 60 ° C, preferably 30 ° to 40 ° C, for about 30 minutes to 12 hours, preferably 2 to 4 hours. The zopolrestat sodium carboxylate thus obtained can optionally be filtered according to procedures well known to those skilled in the art. Alternatively, the zopolrestat sodium carboxylate can be obtained by the process B (a) of this invention. According to process B (a), anhydrous zopolrestat is reacted with aqueous sodium hydroxide in a polar solvent inert to the reaction as a C-i-Cß or THF alkanol. An inert polar solvent for the reaction is ethanol. The volume ratio of inert polar solvent for the reaction to water ranges from 6: 1 to 0.5: 1. Preferably, the ratio in volume is 1: 1. The reaction is carried out at a temperature in the range of 10 ° to 60 ° C, preferably at room temperature, at a pH in the range of about 10 to about 14, preferably 11, for about 30 minutes to 12 hours. The zopolrestat sodium carboxylate can be isolated according to procedures well known to those skilled in the art. The zopolrestat sodium carboxylate solution obtained by any of processes A (a) or B (a) is treated with an acid until the pH of the solution is adjusted to a pH of about 7.5 to about 8.5, preferably at a pH of about 7.8 to about 8.2. A suitable acid is a strong inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid. A suitable organic solvent is added to the solution thus obtained. Suitable organic solvents are water-soluble solvents, for example, esters such as ethyl acetate or Ci-Cβ alkanols such as methanol, THF or ethanol. A preferred solvent is ethyl acetate. The pH of the obtained solution is adjusted to a pH ranging from 1.5 to 2.5, preferably to approximately pH 2 with a suitable acid to crystallize the polymorph of zopolrestat monohydrate as a suspension. The suitable acid is a strong inorganic acid such as concentrated aqueous hydrochloric acid, hydrobromic acid or sulfuric acid, preferably concentrated hydrochloric acid. This crystallization can be carried out at a temperature in the range of 5 ° to 60 ° C., preferably from 20 ° to 35 ° C. The polymorph suspension of zopolrestat monohydrate thus obtained is filtered and washed with a suitable solvent such as Ci-Cβ alkanol, ester, water or a mixture thereof. In a preferred embodiment of this invention, the recrystallization of zopolrestat monohydrate to prepare the anhydrous zopolrestat is carried out in a solvent comprising a solvent soluble in water and water, such as ethyl acetate and water, a Ci-Cβ alkanol and water or THF and water. Preferred solvents are those comprising ethyl acetate and water in a ratio of 1: 4 to 1: 12 and a C? -C6 alkanol and water or THF and water in a ratio of 1: 0.85 to 1: 1, fifteen. The most preferred solvents are those comprising ethyl acetate and water in a ratio of 1: 7 to 1: 9 and an alkanol CI-CT and water or THF and water in a ratio of 1: 0.95 to 1: 1, 05 An even more preferred solvent is a solvent comprising ethyl acetate and water in a ratio of 1: 8. A polymorph of zopolrestat monohydrate of this invention can be converted to the anhydrous form by drying. The polymorph can be dried in a drying apparatus such as a drying oven at a temperature of about 40 ° to about 90 ° C, at atmospheric pressure or under vacuum, until the water is practically eliminated (i.e., up to a concentration of water of approximately 0%). The concentration of water can be measured by a technique known as the Kari Fischer procedure. A polymorph of zopolrestat monohydrate of this invention can be heated in water before drying. A polymorph and water ratio of the mixture ranges from about 1: 1 to about 1:10. The mixture is heated from about 70 ° C to about the reflux temperature of the mixture for about 30 minutes to 6 hours. A preferable temperature of heating is approximately 90 ° C. The mixture can be stirred while heating. In the methods described above, filtering methods known to those skilled in the art may be used. The filtrations can be carried out by centrifugation, or using a Buchner type filter, a Rosenmund filter or a plate filter press, preferably the Buchner type filter, the Rosenmund filter or a plate filter press are used. The anhydrous zopolrestat and the zopolrestat ethyl ester can be prepared according to a known method (for example, B. L. Mylari et al., J. Med. Chem., 1991, 34, 108-122). For example, the zopolrestat ethyl ester is prepared by contacting or reacting the 3- (cyanomethyl) -3,4-dihydro-4-oxo-1-phthalazine acetic acid ethyl ester with 2-amino-4-hydrochloride. trifluoromethyl) benzenethiol. The reaction is carried out in an inert solvent for the reaction as ethanol at about the reflux temperature of the reaction mixture for about 1 to 12 hours. The ester thus obtained is hydrolyzed by treatment of the ester with sodium or potassium hydroxide in an alkanol such as methanol, followed by treatment with a mineral acid such as hydrochloric acid in water. The polymorph of zopolrestat monohydrate thus obtained is new and useful in the manufacture of zopolrestat. Said polymorph decreases the time necessary to carry out the overall procedure by accelerating the filtration process. The zopolrestat monohydrate and the polymorphs thus obtained have utility in the treatment of complications derived from diabetes mellitus such as diabetic cataracts, retinopathy and neuropathy. More especially, zopolrestat monohydrate and the polymorphs thereof are useful for the treatment comprising reversing diabetic cardiomyopathy, reducing tissue lesions in the brain, liver, kidney, lung, stomach, skeletal muscle or pancreas, the tissue of the retina or intestinal tissue, more especially in a human being, in particular, in a human being suffering from diabetes. A therapeutically effective amount of zopolrestat monohydrate and the polymorphs thereof of this invention can be administered to a human subject. Said administration comprises any known method for therapeutically providing an active compound to a human subject, including conventional routes such as oral, transdermal, intraduodenal or parenteral. For the purposes of the process of the present invention, oral administration is generally preferred. In carrying out the objects of the process of this invention, an amount of a compound of this invention that is effective to treat or reverse the particular disorder is initiated. Typically, an effective dose for a compound of this invention ranges from about 0.1 mg per day to about 1,000 mg per day in a single dose (eg, once a day) or in several doses. Preferred dose ranges for a compound of this invention range from about 250 mg per day to about 1,000 mg per day in a single oral dose. However, depending on the disorder of the patient being treated, some variation of the dosage will be necessary. In any case, the responsible of the administration will determine the amount of appropriate dose for the particular subject that requires treatment. A compound of this invention is used either alone, together in combination with another inhibitor of aldose reductase, or in combination with a pharmaceutically acceptable carrier. Suitable carriers can include solid diluents or fillers, sterile aqueous solutions and various physiologically compatible organic solvents. Pharmaceutical compositions formed by combining the active compound and pharmaceutically acceptable carriers are thus administered in a variety of dosage forms such as tablets, powders, tablets, syrups, injectable solutions and similar forms. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavors, binders, excipients and the like. For the purposes of choosing the preferred route of administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used, together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinyl pyrrolidone. , sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for the preparation of tablets. Solid compositions of a similar type can also be used as fillers in hard and soft filled gelatin capsules. Preferred materials for this use include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient may be combined with various sweetening or flavoring agents, coloring materials or pigments and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerol and various combinations thereof. For parenteral administration, solutions of the compounds useful in this invention, in sesame or peanut oil, in aqueous propylene glycol or in aqueous solution may be employed. Such aqueous solutions may be suitably buffered if necessary and the liquid diluent first made isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous media employed are all readily available by techniques known to those skilled in the art. The anhydrous zopolrestat obtained by drying zopoirestat monohydrate or its polymorph of this invention can be used to inhibit aldose reductase, more especially in the treatment of complications derived from diabetes mellitus such as diabetic cataracts, retinopathy and neuropathy. The anhydrous zopolrestat can be administered to a human being in a manner similar to that described above or described, for example in U.S. Patent No. 4,939,140.
EXAMPLES AND EXPERIMENTAL PART
The present invention is illustrated by the following examples. It will be appreciated, however, that the invention is not limited to the specific details of these examples.
EXAMPLE 1
Stirred at room temperature in an anhydrous zopolrestat reaction flask (20 g, 0.048 mol), ethanol (90 ml) and water (90 ml). A 50% aqueous sodium hydroxide solution was added slowly to the crystalline suspension until a pale yellow solution formed at approximately pH
11, 0. In this example, 2.6 ml of 50% aqueous sodium hydroxide was used. A drop of concentrated hydrochloric acid was added to the pale yellow solution so that the pH dropped to 7.8. Ethyl acetate (22.5 ml) was added to the solution at pH 7.8. Concentrated hydrochloric acid was added to reduce the pH of the solution to 2. The crystallization was started and a thick white suspension was obtained which could be stirred at 27 ° C. The suspension was cooled to 5 ° C, granulated for a while and the crystals were isolated by filtration and washed with a solution mixture of ethanol (18 ml), water (18 ml) and ethyl acetate.
(4.5 ml). The product was air dried to give crystals of the product zopoirestat monohydrate, 21 g, 100% with a characteristic X-ray powder diffraction pattern, shown in Table 1.
p.f. 188-190 ° C, water content 4.1% by the Karl Fischer method (theoretical 4.1%).
EXAMPLE 2
The zopolrestat ethyl ester (50 g, 0.11 mol) and ethanol (200 ml) were stirred at room temperature in a reaction flask to form a white crystalline suspension. Sodium hydroxide (15.11 g, 0.38 mol) and water (200 ml) were mixed with cooling to form an aqueous sodium hydroxide solution. The sodium hydroxide solution was added to the white crystalline suspension and the resulting mixture was stirred in the temperature range of 30 ° to 40 ° C. After a period of 2-4 hours, a red / purple solution was formed. This indicates that the reaction had elapsed until its completion. The solution was filtered and treated with concentrated hydrochloric acid until the pH was adjusted to 8.1. In this example, 20 ml of concentrated HCl was needed to effect the pH adjustment. Ethyl acetate was added to the solution at pH 8.1. The pH was then adjusted to pH 2 by the addition of an additional amount of concentrated hydrochloric acid (10.5 ml). The crystallization was started and a thick white suspension was obtained at 33-28 ° C. The suspension was cooled to 5 ° C, granulated for a time and the crystals were isolated by filtration and washed with a solution mixture of ethanol (50 ml), water (50 ml) and ethyl acetate (12.5 ml). ). The product was air dried to give crystals of product zopolrestat monohydrate, 41.4 g, 88%, with a characteristic X-ray powder diffraction pattern shown in Table 1. p.f. 188-190 ° C, water content 4.1% by the Karl Fischer method (theoretical 4.1%). The X-ray powder diffraction pattern of the zopolrestat monohydrate polymorph of this invention prepared in Examples 1 and 2 was measured with a Siemens D5000 X-ray diffractometer with the following conditions:
Anode: Cu Wavelength 1: 1, 54056 Wavelength 2: 1, 54439 Relative intensity: 0,500 Interval n ° Coupling: 3,000 to 4,000 Size of the increment: 0,040 Time of the increase: 1, 00 Modulation width: 0,300 Threshold: 1, 0
The X-ray diffraction pattern thus measured is summarized in Table 1.
TABLE 1
-teta d / A 2-teta d / A 2-teta d / A
, 3 16.7 17.6 5.0 26.2 3.4, 9 15.1 19.2 4.6 27.3 3.3, 0 11.0 20.1 4.4 28.3 3, 2 0.5 8.4 21.2 4.2 29.0 3.1 1.8 7.5 21.4 4.2 29.5 3.0 2.3 7.2 22.1 4.0 30 , 2 3.0 2.6 7.0 22.5 4.0 30.9 2.9 3.1 6.8 23.1 3.8 31.7 2.8, 3 6.2 23.4 3 , 8 32.6 2.7 5.7 5.6 23.8 3.7 33.4 2.7 6.5 5.4 24.3 3.7 36.6 2.5 7.1 5.2 25.3 3.5
Claims (28)
1. - A polymorph of 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazole) methyl-1-phthalazine acetic acid monohydrate. 2. The polymorph of the compound according to claim 1, which has the following characteristic X-ray powder diffraction pattern:
2-theta d / A 2-theta d / A 2-teta d / A 5.3 16.7 17.6 5.0 26.2 3.4 5.9 15.1 19.2 4.6 27.3 3.3 8.0 11.0 20.1 4.4 28, 3 3.2 10.5 8.4 21.2 4.2 29.0 3.1 11.8 7.5 21.4 4.2 29.5 3.0 12.3 7.2 22.1 4 , 0 30.2 3.0 12.6 7.0 22.5 4.0 30.9 2.9 13.1 6.8 23.1 3.8 31.7 2.8 14.3 6.2 23.4 3.8 32.6 2.7 15.7 5.6 23.8 3.7 33.4 2.7 16.5 5.4 24.3 3.7 36.6 2.5 17, 1 5.2 25.3 3.5
3. - A process for preparing the polymorph according to claim 2, comprising: (a) reacting the 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl ethyl ester 1-phthalazine acetic acid with aqueous sodium hydroxide in a polar solvent inert for the reaction to form a first solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazole) Sodium l-1-phthalazinacetate; (b) adjusting said first solution to a pH ranging from about 7.5 to about 8.5 to form a second solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2- benzothiazole) sodium methyl-1-phthalazonacetate; (c) adding to said second solution a suitable water-soluble solvent to form a third solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1 Sodium phthalazine acetate; and (d) adjusting said third solution to a pH ranging from about 1.5 to about 2.5 with a strong inorganic acid to form a solution of said polymorph.
4. A method according to claim 3, comprising the further step of filtering said solution of said polymorph to obtain the 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2- monohydrate. benzothiazolyl) methyl-1-phthalazine acetic acid.
5. A process according to claim 4, wherein said suitable water-soluble solvent in step (c) is ethyl acetate, a d-Cβ alkanol or tetrahydrofuran.
6. A process for preparing the polymorph according to claim 2, comprising: (a) reacting the acid 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1 anhydrous phthalazine acetic acid with aqueous sodium hydroxide in an inert polar solvent for the reaction to form a first solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1 Sodium phthalazine acetate; (b) adjusting said first solution to a pH ranging from about 7.5 to about 8.5 to form a second solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) - 2-benzothiazolyl) methyl-1-phthalazinacetate sodium; (c) adding a suitable water-soluble solvent to the said second solution to form a third solution comprising 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazole) methyl -1-sodium phthalazinacetate; and (d) adjusting said third solution to a pH ranging from about 1.5 to about 2.5 with a strong inorganic acid to form a solution of said polymorph.
7. A method according to claim 6, comprising the further step of filtering said solution of said polymorph to obtain the 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2- monohydrate. benzothiazolyl) methyl-1-phthalazine acetic acid.
8. A process according to claim 7, wherein said suitable water-soluble solvent in step (c) is ethyl acetate, a Ci-Cβ alkanol or tetrahydrofuran.
9. A process for preparing anhydrous 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetic acid, which comprises recrystallizing 3,4-dihydrohydrohydrate -4-Oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetic acid in a mixture of a water-soluble solvent and water.
10. A method according to claim 9, wherein said water-soluble solvent is ethyl acetate, a C-i-Cβ alkanol or tetrahydrofuran.
11. A process according to claim 10, wherein the ratio of ethyl acetate to water ranges from 1: 4 to 1: 12, the ratio of Ci-Cβ alkanol to water ranges from 1: 0.85 to 1: 1, 15 and the ratio of tetrahydrofuran to water varies from 1: 0.85 to 1: 1, 15.
12. A process for preparing anhydrous 3,4-dihydro-4-oxo-3 - ((5-trifluoromethyl) -2-benzothiazolyl) methyl-1-phthalazine acetic acid, which comprises drying the polymorph according to claim 2.
13. - A method according to claim 12, comprising heating the polymorph in water before drying.
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
15. A pharmaceutical composition for inhibiting aldose reductase, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
16. A pharmaceutical composition for treating, preventing or reversing complications derived from diabetes mellitus, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
17. The use of a compound according to claim 1, in the manufacture of a medicament for treating diabetic cardiomyopathy in a mammal.
18. The use according to claim 17, wherein said treatment comprises the reversion of said diabetic cardiomyopathy.
19. The use of a compound according to claim 1, in the manufacture of a medicament for reducing lesions in non-cardiac tissue in a mammal.
20. The use according to claim 19, wherein said tissue is tissue from the brain, liver, kidney, lung, intestine, skeletal muscle, spleen, pancreas, retinal tissue or intestinal tissue.
21. The use according to claim 20, wherein said mammal is a human.
22. The use according to claim 21, wherein said human is suffering from diabetes.
23. The use of a compound according to claim 1, in the manufacture of a medicament for reducing the levels of uric acid in blood in a mammal.
24. The use of a compound according to claim 1, in the manufacture of a medicament for reducing blood lipid levels in a mammal. i. - The use of a compound according to claim 1, in the manufacture of a medicament for inhibiting the activity of aldose reductase in a mammal. 26. The use of a compound according to claim 1, in the manufacture of a medicament for preventing pain from angina in a mammal. 27. The use of a compound according to claim 1, in _BBHtfNb manufacture of a medicament for preventing cardiac lesions in a mammal. I 28.- The use of a compound according to claim 1, in the manufacture of a medicament for treating diabetic nephropathy in a mammal.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US60/097474 | 1998-08-21 | ||
US097474 | 1998-08-21 |
Publications (1)
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MXPA99007842A true MXPA99007842A (en) | 2000-06-05 |
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