MXPA00012096A - Combination of aldose reductase inhibitors and antihypertensive agents for the treatment of diabetic complications - Google Patents

Abstract

This invention is directed to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug. This invention further relates to methods of using those pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy.

Description

COMBINATION OF INHIBITORS OF ALDOSA REDUCTASE AND ANTIHYPERTENSIVE AGENTS FOR THE TREATMENT OF DIABETIC COMPLICATIONS BACKGROUND OF THE INVENTION This invention relates to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and an antihypertensive agent, a prodrug thereof or a salt pharmaceutically acceptable of said antihypertensive agent or said prodrug. This invention also relates to methods for using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy. Aldose reductase inhibitors work by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and Other animals. In this way, the undesirable accumulations of galactitol in the crystallites of galactosemic subjects and of sorbitol in the crystallins, peripheral nerve marrow and kidneys of several diabetic subjects are prevented or reduced. Therefore, inhibitors of aldose reductase are of therapeutic value to control certain diabetic complications, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy. Several classes of compounds are known to have activity as antihypertensive agents. These include calcium channel blockers, A-II antagonists, diuretics, beta-adrenergic receptor blockers. The publication of the international patent application No. W099 / 02189, published January 21, 1999, describes the use of ACE inhibitors in combination with aldose reductase inhibitors to treat diabetic complications such as diabetic neuropathy, diabetic nephropathy and diabetic retinopathy.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to pharmaceutical compositions comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent. The invention is also directed to methods for treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth below. In particular, diabetic complications, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy can be treated by the methods of this invention. This invention is also directed to methods for treating a diabetic complication in a mammal the administration to said mammal of an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug. This invention is especially directed to methods wherein the ARI, prodrug thereof or pharmaceutically acceptable salt of said ARI or said prodrug, and the antihypertensive agent, prodrug thereof or pharmaceutically acceptable salt of said antihypertensive agent, are administered separately. This invention is also especially directed to methods wherein the ARI, prodrug thereof or pharmaceutically acceptable salt of said ARI, or said prodrug, and the antihypertensive agent, prodrug thereof or pharmaceutically acceptable salt of said antihypertensive agent or said prodrug are administered together . This invention is also directed to kits comprising: a) a first unit dosage form comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a carrier, vehicle or pharmaceutically acceptable diluent; b) a second unit dosage form comprising an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent; and c) a container. In the compositions, methods and kits of this invention, it is preferred that said ARI be fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug. It is especially preferred that said ARI be zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt thereof or said prodrug. In the compositions, methods and kits of this invention, it is preferred that said antihypertensive agent be a compound by selecting from the following classes of antihypertensive agents: calcium channel blockers, A-II antagonists, diuretics, endopeptidase inhibitors, blockers of beta-adrenergic receptors and alpha-adrenergic receptor blockers.

Preferred calcium channel blockers include verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifenipine, amiodipine, nimodipine, nisoldipine, nitrendipine and felodipine, prodrugs thereof and pharmaceutically acceptable salts of said calcium channel blockers and said prodigies. Preferred A-ll antagonists include losarían, irbesartan and valsartan, prodrugs thereof and pharmaceutically acceptable salts of said A-ll antagonists and said prodrugs. Preferred diuretics include amiloride and bendroflumethiazide, prodrugs thereof and pharmaceutically acceptable salts of said diuretics and said prodrugs. Inhibitors of endopeptidase can be neutral endopeptidase inhibitors or can be neutral endopeptidase / ACE inhibitors. Preferred neutral endopeptidase inhibitors include candoxatril and candoxatrilat, prodrugs thereof and pharmaceutically acceptable salts thereof and said prodrugs. Preferred neutral endopeptidase / ACE inhibitors include sampatrilat and omapatrilat, prodrugs thereof and pharmaceutically acceptable salts thereof and said prodrugs. Sampatrilat and omapatrilat are dual inhibitors of the neutral endopeptidase-ACE. Omapatrilat is also known as a vasopeptidase inhibitor.

A preferred beta-adrenergic receptor blocker is carvedilol, prodrugs thereof and pharmaceutically acceptable salts of said beta-adrenergic receptor blockers and said prodrugs. Preferred alpha-adrenergic receptor blockers include doxazosin, and trimazosin, prodrugs thereof and pharmaceutically acceptable salts of said alpha-adrenergic receptor blockers and said prodrugs.

DETAILED DESCRIPTION OF THE INVENTION The methods, compositions and kits of this invention are useful for treating diabetic complications, including, but not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy. The term "treat", as used herein, refers to retarding, stopping or reversing the progress of a disorder or condition, or alleviating or avoiding one or the other to which the term "treating" is applied, or one or more symptoms of such disorder or condition The term "treatment" as used herein refers to the act of treating a disorder, symptom or condition, as the term "treating" is defined above.Any inhibitor of aldose reductase can be used in the pharmaceutical compositions, methods and kits of this invention The term "aldose reductase inhibitor" refers to a compound which inhibits the bioconversion of glucose to sorbitol catalyzed by the enzyme, aldose reductase. Such inhibition is easily determined by those skilled in the art. according to standard tests (J. Malone, Diabetes, 29: 861-864, 1980. "Sorbitol Cellular Red, a diabetic control indicator") .The following: patents and patent applications, incorp All of which are herein incorporated by reference, exemplify aldose reductase inhibitors which can be used in the compositions, methods and kits of this invention, and relate to methods of preparing these aldose reductase inhibitors: US Pat. No. 4,251,528; patent of E.U.A. No. 4,600,724; patent of E.U.A. No. 4,464,382; patent of E.U.A. No. 4,791,126; patent of E.U.A. No. 4,831,045; patent of E.U.A. No. 4,734,419; patent of E.U.A. No. 4,883,800; patent of E.U.A. No. 4,883,410; patent of E.U.A. No. 4,883,410; patent of E.U.A. No. 4,771,050; patent of E.U.A. No. 5,252,572; patent of E.U.A. No. 5,270,342; patent of E.U.A. No. 5,430,060; patent of E.U.A. No. 4,130,714; patent of E.U.A. No. 4,540,704; patent of E.U.A. No. 4,338,272; patent of E.U.A. No. 4,436,745; patent of E.U.A. No. 4,438,272; patent of E.U.A. No. 4,436,745; patent of E.U.A. No. 4,438,272; patent of E.U.A. No. 4,436,745; patent of E.U.A. No. 4,438,272; patent of E.U.A. No. 4,980,357; patent of E.U.A. No. 5,066,659; patent of E.U.A. No. 5,447,946; patent of E.U.A. No. 5,037,831. A variety of aldose reductase inhibitors are specifically described and referenced below, however, other aldose reductase inhibitors will be known to those skilled in the art. Also, common USAN chemical names or other designations are in parentheses where they are applicable, along with the reference to the appropriate patent literature describing the compound. Accordingly, examples of aldose reductase inhibitors useful in the compositions, methods and kits of this invention include: 1. 3- (4-Bromo-2-fluorobenzyl) -3,4-dihydro-4-oxo-1- acid phthalazine acetic (ponalrestat, US 4,251, 528); 2. N [[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl) -N-methylglycine (tolrestat, E.U.A. 4,600,724); 3. 5 - [(Z, E) -β-methylcinnamilidene] -4-oxo-2-thioxo-3-thiazolidenacetic acid (epalrestat, E.U.A. 4,464,382, E.U.A. 4,791,126, E.U.A. 4,831, 045); 4. 3- (4-Bromo-2-fluorobenzyl) -7-chloro-3,4-dihydro-2,4-d-oxo-1 (2H) -quinazoyneacetic acid (zenarestat, E.U.A. 4,734,419 and E.U.A. 4,883,800); 5. 2R, 4R-6,7-dichloro-4-hydroxy-2-methyl-chroman-4-acetic acid (U.S. 4,883,410); 6. 2R, 4R, 6,7-dichloro-6-fluoro-4-hydroxy-2-methyl-chroman-4-acetic acid (E.U.A., 4,883,410); 7. 3,4-Dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (E.U.A. 4.771, 050); 8. 3,4-Dihydro-3-oxo-4 - [(4,5,7, -trifluoro-2-benzothiazolyl) methyl] -2H-1,4-benzothiazine-2-acetic acid (SPR-210, USA) 5,252,572) 9. N- [3,5-dimethyl-4 - [(nitromethyl) sulfonylphenyl] -2-methyl-benzeneacetamide (ZD5522, US 5,270,342 and US 5,430,060); 10. (S) -6-fluoroespiro [chroman-4,4-imidazolidine] -2,5'-dione (sorbinyl, E.U.A. 4,130,714); 11. d ^ -methyl-? -fluoro-spirochroman ^ '^' - imidazolidine ^ '-dione (E.U.A. 4,540,704); 12. 2-fluoro-spiro (9H-fluorene-9,4t-α-dazolidine) -2'-5, -dione (E.U.A.4,438,272); 13. 2,7-di-fluoro-spiro (9H-fluorene-9,4, -imidazolidine) -2 ', 5'-dione (E.U.A., 4,436,745, E.U.A., 4,438,272); 14. 2,7-di-fluoro-5-methoxy-spiro (9H-fluorene-9,4'-imidazolidine) -2 \ 5'-dione (E.U.A.4, 436,745, E.U.A. 4,438,272); 15. 7-Fluoro-spiro (5H-indenol [1,2-b] pyridine-5,3'-pyrrolidine) -2,5'dione (E.U.A. 4,436,745, E.U.A. 4,438,272); 16. d-cis-d-chloro ^ '. S'-dihydro ^ -methyl-spiro-imidazolidine ^^' - 4? -pyran (2,3-b) pyridine) -2,5-dione (US 4,980,357); 17. Spiro [imidazolidn-4,5 '(6H) -quinol] -2,5-dione-3'-chloro-7', 8'-d-hydro-7'-methyl - (US 5,066,659); 18. (2S, 4S) -6-fluoro-2 ', 5, -dioxospiro (chroman-4,4-amidazolidine) -2-carboxamide (fidarestat, E.U.A. 5,447,946); and 19. 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluorospiro [isoquinoline-4 (1 H), 3, -pyrrolidine] -1, 2'-3,5, (2H) -tetrone (Minalrestat, USA 5,037,831).

Other inhibitors of aldose reductase include compounds of formula A, and pharmaceutically acceptable salts thereof, wherein Z in the compound of formula A is O or S; R1 in the compound of formula A is hydroxyl or a group capable of being removed in vivo to produce a compound of formula A wherein R1 is OH; and X and Y in the compound of the formula A are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro. A preferred subgroup within the above group of aldose reductase inhibitors include compounds numbered 1, 2, 3, 4, 5, 6, 9, 10, and 17, and the following compounds of formula A: Acid 3,4 -dihydro-3- (5-fluorobenzothiazol-2-imethyl) -4-oxophthalazin-1-yl-acetic acid [R * = hydroxyl, X = F; Y = H]; 21. 3- (6,7-Difluorobenzothiazol-2-ylmethyl) -3,4-dydrohydro-4-oxophthalazin-1-acetic acid [R1 = hydroxyl; X = Y = F]; 22. 3- (5-Chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R = hydroxyl; X = CI; Y = H]; 23. 3- (5,7-Chlorobenzothiazol-2-ylfmethyl) -3,4-dydro-4-q-o -talazin-1-acetic acid [R 1 = hydroxyl; X = Y = CI]; 24. 3,4-dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) -1-ylacetic acid [R1 = hydroxyl; X = CF3; Y = H]; 25. 3,4-Dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-yl-acetic acid [R1 = hydroxyl; X = F; Y = H]; 26. 3- (5,7-Difluorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophtalazin-1-acetic acid [R1 = hydroxyl; X = Y = F]; 27. 3- (5-Chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxyl; X = CI; Y = Hj; 28. 3- (5,7-Dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxyl; X = Y = CI]; and 29. Zopolrestat; 1-phthalazine acetic acid, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] - [R 1 = hydroxy]; X = trifluoromethyl; Y = H]. In compounds 20-23 and 29, Z is S. In compounds 24-28, Z is O. From the above subgroup, compounds 20-29 are more preferred with compound 29 being especially preferred. Said compounds of the formula A are prepared as described in the patent of E.U.A. No. 4,939,140.

The aldose reductase inhibitor compounds of this invention are readily available or can be readily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly in view of the specifications of the relevant patent. The antihypertensive agents that can be used according to this invention are members of different classes of antihypertensive agents, including calcium channel blockers, A-II antagonists, diuretics, beta-adrenergic receptor blockers, vasodilators and alpha-blockers. adrenergic Calcium channel blockers which are within the scope of this invention include, but are not limited to: bepridil, which may be prepared as described in US Pat. No. 3,962,338 or E.U.A. No. 30,577 re Reissue; clentiazem, which can be prepared as described in the patent of E.U.A. No. 4,567,175; diltiazem, which can be prepared as described in the patent of E.U.A. No. 3,562,257; Fendiline, which can be prepared as described in the US patent. No. 3.62.977; gallopamil, which can be prepared as described in the patent of E.U.A. No. 3,261, 859; mibefradil, which can be prepared as described in the patent of E.U.A. No. 4,808,605; prenylamine, which can be prepared as described in the US patent. No. 3,152,173; semotiadil, which can be prepared as described in the patent of E.U.A. No. 4,786,635; terolidine, which can be prepared as described in the patent of E.U.A. No. 3,371,014; vérapamif, which can be prepared as described in the patent of E.U.A. No. 3,261, 859; amiodipine, which can be prepared as described in the patent of E.U.A. No. 4,572,909; aranipine, which can be prepared as described in the US patent. No. 4,572,909; barnipidin which can be prepared as described in the patent of E.U.A. No. 4,220,649; benidipine, which can be prepared as described in European Patent Application Publication No. 106.275; cilnidipine, which can be prepared as described in the patent of E.U.A. No. 4,672,068; Efonidipine, which can be prepared as described in the patent of E.U.A. No. 4,885,284; Elgodipine, which can be prepared as described in the patent of E.U.A. No. 4,952,592; felodipine, which can be prepared as described in the patent of E.U.A. No. 4,264,611; isradipine, which can be prepared as described in the patent of E.U.A. No. 4,466,972; lacidipine, which can be prepared as described in the patent of E.U.A. No. 4,801, 599; lercanidipine, which can be prepared as described in the patent of E.U.A. No. 4,705,797; manidipine, which can be prepared as described in the patent of E.U.A. No. 4,892,875; nicardipine, which can be prepared as described in the patent of E.U.A. No. 3,985,758; nifenipine, which can be prepared as described in the patent of E.U.A. No. 3,485,847; nilvadipine, which can be prepared as described in the patent of E.U.A. No. 4,338,322; nimodipine, which can be prepared as described in the patent of E.U.A. No. 3,799,934; pis? fdiprna, which can be prepared as described in the patent of E.U.A. No. 4,154,839; nitrendipine, which can be prepared as described in the patent of E.U.A. No. 3,799,934; cinnarizine, which can be prepared as described in the patent of E.U.A. No. 2,882,271; flunarizine, which can be prepared as described in the patent of E.U.A. No. 3,773,939; lidoflazine, which can be prepared as described in the patent of E.U.A. No. 3,267,104; Lomerizine, which can be prepared as described in the patent of E.U.A. No. 4,663,325; benziclan, which can be prepared as described in Hungarian patent No. 151, 865; etafenoma, which can be prepared as described in the German patent. No. 1, 265, 758; and perhexiline, which can be prepared as described in British Patent No. 1, 025,578. Amiopidine besilate, a preferred salt of amiopidine, is described in the U.S. patent. No. 4,879,303. The descriptions thereof are incorporated herein by reference. Antagonists of the angotensin-ll receptors (antagonists A-11) that are within the scope of the invention include, but are not limited to: candesartan, which can be prepared as described in the US patent. No. 5,196,444; eprosartan, which can be prepared as described in the US patent. No. 5,185,351; irbesartan, which can be prepared as described in the patent of E.U.A. 5,270,317; losarían, which can be prepared as described in the patent of E.U.A. No. 5,138,069; and valsarían, which can be prepared as described in the patent of E.U.A. No. 5,399,578. The descriptions of the above patents incorporated herein by reference. Blockers of the beta-adrenergic receptors (beta- or β-blockers) which are within the scope of this invention include, but are not limited to: acebutolol, which can be prepared as described in the patent of E.U.A. No. 3,857,952; alprenolol, which can be prepared as described in the Netherlands patent application No. 6,605,692; amosulatol, which can be prepared as described in the patent of E.U.A. No. 4,217,305; arotinolol, which can be prepared as described in the patent of E.U.A. No. 3,932,400; atenolol, which can be prepared as described in the patent of E.U.A. No. 3,663,607 or 3,836,671; befunolol, which can be prepared as described in the patent of E.U.A. No. 3,853,923; betaxolol, which can be prepared as described in the patent of E.U.A. No. 4,252,984; bevantolol, which can be prepared as described in the patent of E.U.A. No. 3,857,981; bisoprolol, which can be prepared as described in the patent of E.U.A. No. 4,171, 370; bopindolol, which can be prepared as described in the patent of E.U.A. No. 4,340,541; bucumuiol, which can be prepared as described in the patent of E.U.A. No. 3,663,570; bufetolol, which can be prepared as described in the patent of E.U.A. No. 3,723,476; bufuralol, which can be prepared as described in the U.S. patent. No. 3,929,836; bunitrolol, which can be prepared as described in the patents of E.U.A. No. 3,940,489 and No. 3,961,071; buprándolol, which can be prepared as described in the patent of E.U.A. No. 3,309,406; butyridine hydrochloride, which can be prepared as described in French Patent No. 1, 390,056; Butofilolol, which can be prepared as described in the patent of E.U.A. No. 4,252,825; carazolol, which can be prepared as described in the German patent. No. 2,240,599; carteolol, which can be prepared as described in the patent of E.U.A. No. 3,910,924; carvedilol, which can be prepared as described in the patent of E.U.A. No. 4,503,067; celiprolol, which can be prepared as described in the patent of E.U.A. No. 4,034,009; cetamolol, which can be prepared as described in the patent of E.U.A. No. 4,059,622; chloranolol, which can be prepared as described in German Patent No. 2,213,044; dilevalol, which can be prepared as described in Clifton, Journal of Medicinal Chemistry (Journal of Medicinal Chemistry), 1982, 25, 670; epanolol, which can be prepared as described in European Patent Publication No. 41,491; indenolol, which can be prepared as described in the patent of E.U.A. No. 4,045,482; labetalol, which can be prepared as described in the patent of E.U.A. No. 4,012,444; levobunolol, which can be prepared as described in the patent of E.U.A. No. 4,463,176; mepindolol, which can be prepared as described in Seeman Helv. Chim. Acta. 1971, 241; metipranolol, which can be prepared as described in the Czechoslovak patent application No. 128,471; metoprolol, which can be prepared as described in the patent of E.U.A. No. 3,873,600; moprolol, which can be prepared as described in the patent of E.U.A. No. 3,501, 769; nadolol, which can be prepared as described in the patent of E.U.A. No. 3,935,267; nadoxolol, which can be prepared as described in the patent of E.U.A. No. 3,819,702; nebivalot, which can be prepared as described in the patent of E.U.A. No. 4,654,362; nipradilol, which can be prepared as described in the patent of E.U.A. No. 4,394,382; oxprenolol, which can be prepared as described in British Patent No. 1, 077,603; perbutolol, which can be prepared as described in patents No. 469,002 and 472,404; practolol, which can be prepared as described in the patent of E.U.A. No. 3,408,387; pronetalol, which can be prepared as described in British Patent No. 909,357; propanolol, which can be prepared as described in the patents of E.U.A. No. 3,337,628 and 3,520,119; sotalol, which can be prepared as described in Uloth, Journal of Medicinal Chemistry, 1996, 9, 88; sufinalol, which can be prepared as described in German Patent No. 2,728,641; talindol, which can be prepared as described in the patents of E.U.A. No. 3,935,259 and 4,038,313; tertatolol, which can be prepared as described in the patent of E.U.A. No. 3,960,891; tilisolol, which can be prepared as described in the patent of E.U.A. No. 4,129,565; timolol which can be prepared as described in the patent of E.U.A. No. 3,655,633; toliprolol, which can be prepared as described in the patent of E.U.A. No. 3,432,545; xibenolol, which can be prepared as described in the patent of * - E.U.A. No. 4,018,824. Descriptions of these are "incorporated herein by reference." Endopeptidase inhibitors that are within the scope of this invention include, but are not limited to sampatrilat, which is prepared as described in European patent application publication EP 358398; candoxatril and candoxatrilat, each of which can be prepared as described in European Patent Application Publication No. EP 274234, and ompatrilat, which can be prepared as described in US Patent No. 5,508,272, the descriptions of the same are incorporated herein by reference: Blockers of alpha-adrenergic receptors (alpha- or α-blockers) which are within the scope of this invention include, but are not limited to: amosulalol, which can be prepared as is described in U.S. Patent No. 4,117,307, arolinolol, which may be prepared as described in U.S. Patent No. 3,932,400, depiprazole, which can be prepared as described in the patent of E.U.A. No. 4,252,721; doxazosin, which can be prepared as described in the patent of E.U.A. No. 4,188,390; fenspiride, which can be prepared as described in the patent of E.U.A. No. 3,399,192; indoramin, which can be prepared as described in the U.S. patent. No. 3,527,761; labetolol, which can be prepared as previously revealed; naftopidil, which can be prepared as described in the patent of E.U.A. No. 3,997,666; Nicergoline, which can be prepared as described in the patent of E.U.A. No. 3.28,943; prazosin, which can be prepared as described in the patent of E.U.A. No. 3,511, 836; tamsulosin, which can be prepared as described in the patent of E.U.A. No. 4,703,063; tolazoline, which can be prepared as described in the patent of E.U.A. No. 2,161, 938; trimazosin, which can be prepared as described in the patent of E.U.A. No. 3,669,968; and yohimbine, which can be isolated from natural sources according to methods well known to those skilled in the art. The descriptions thereof are incorporated herein by reference. The term "vasodilator," where it is used, is intended to include cerebral vasodilators, coronary vasodilators and peripheral vasodilators. Brain vasodilators within the scope of this invention include, but are not limited to: benziclan, which may be prepared as disclosed above; cinnarizine, which can be prepared as previously disclosed; citicoline, which can be isolated from natural sources as described in Kennedy, Journal of the American Chemical Society, 1955, 77, 250 or synthesized as described in Kennedy, Journal of Biological Chemistry, 1956. 222, 185; cycldelate, which can be prepared as described in the patent of E.U.A. No. 3,663,597; cycloncate, which can be prepared as described in German Patent No. 1, 910,481; diisopropylamine dichloroacetate, which can be prepared as described in British Patent No. 862,248; eburnamonin, which can be prepared as described in Hermann, Journal of the American Chemical Society, 1979, 101, 1540; fasudil, which can be prepared as described in the patent of E.U.A. No. 4,668,783; phenoxymedil, which can be prepared as described in the patent of E.U.A. No. 3,818,021, flunarizine, which can be prepared as described in the US patent. No. 3,773,939; ibudilast, which can be prepared as described in the patent of E.U.A. No. 3,850,941; ifendropil, which can be prepared as described in the patent of E.U.A. No. 3,509,164; Lomerizine, which can be prepared as described in the patent of E.U.A. No. 4,663,325; naphronil, which can be prepared as described in the patent of E.U.A. No. 3,334,096; nicamethate, which can be prepared as described in Blicke, Journal of the American Chemical Society, 1942, 64, 1722; nicergoline, which can be prepared as previously disclosed; nimodipine, which can be prepared as described in the patent of E.U.A. No. 3,799,934; papaverine, which can be prepared as outlined in Goldberg, Chem. Prod. Chem. News, 1954, 17, 371; pentiphylline, which can be prepared as described in German Patent No. 860,217; tinofedrine, which can be prepared as described in the patent of E.U.A. No. 3,563,997; vincamine, which can be prepared as described in the patent of E.U.A. No. 3,770,724; vinpocetine, which can be prepared as described in the patent of E.U.A. No. 4, 035,750; and viquidil, which can be prepared as described in the patent of E.U.A. No. 2,500,444. The descriptions thereof are incorporated herein by reference. Coronary vasodilators within the scope of this invention include, but are not limited to: amotriphene, which can be prepared as described in the U.S. patent. No. 3,010,965; bendazole, which can be prepared as described in J. Chem. Soc. 1958, 2426; benfurodil hemisuccinate, which can be prepared as described in the patent of E.U.A. No. 3,355,463; benciodarone, which can be prepared as described in the patent of E.U.A. No. 3,012,042; chloracizine, which can be prepared as described in British Patent No. 740,932; cromonar, which can be prepared as described in British Patent No. 1, 160,925; clonitrate, which can be prepared from propanediol according to methods well known to those skilled in the art, eg, see Annalen, 1870, 155, 165; chlorichromen, which can be prepared as described in the patent of E.U.A. No. 4,452,811; dilazep, which can be prepared as described in the patent of E.U.A. No. 3,532,685; dipyridamole, which can be prepared as described in British Patent No. 807,826; droprenylamine, which can be prepared as described in German Patent No. 2,521, 113; efloxate, which can be prepared as described in British patents No. 803,372 and 824, 547; Erythrityl tetranitrate, which can be prepared by nitration of erythritol according to methods well known to those skilled in the art; etafenone, which can be prepared as described in German Patent No. 1, 265,758; Fendiline, which can be prepared as described in the US patent. No. 3,262,977; floredil, which can be prepared as described in German Patent No. 2,020,464; glanglefen, which can be prepared as described in U.S.S.R. 115, 905; hexestrol, which can be prepared as described in the U.S. patent. No. 2,357,985; hexobendin, which can be prepared as described in the patent of E.U.A. No. 3,267,103; itramin socylate, which can be prepared as described in Swedish Patent No. 168,308; khellina, which can be prepared as described in Baxter, Journal of the Chemical Society, 1949 S 30; lidoflazine, which can be prepared as described in the patent of E.U.A. No. 3,267,104; mannitol hexanitrate, which can be prepared by nitration of mannitol according to methods well known to those skilled in the art; Medibazine, which can be prepared as described in the patent of E.U.A. No. 3,119,826; nitroglycerine; pentaerythritol tetranitrate, which can be prepared by nitration of pentaerythritol according to methods well known to those skilled in the art; pentinitrol, which can be prepared as described in German Patent No. 638,422-3; perhexilin, which can be prepared as previously disclosed; phyprophylline, which can be prepared as described in the patent of E.U.A. No. 3,350,400; prenylamine, which can be prepared as described in the US patent. No. 3,152,173; propathyl nitrate, which was prepared as described in French patent No. 1, 103, 113; trapidil, which can be prepared as described in the East German Patent No. 55,956; trichromyl, which can be prepared as described in the patent of E.U.A. No. 2,769,015; trimetazidine, which can be prepared as described in the patent of E.U.A. No. 3,262,852; trolnitrate phosphate, which can be prepared by nitration of triethanolamine followed by phosphoric acid precipitation according to method well known to those skilled in the art; visnadine, which can be prepared as described in the US patents. Nos. 2,816,118 and 2,980,699. The descriptions thereof are incorporated herein by reference. Peripheral vasodilators within the scope of this invention include, but are not limited to: aluminum nicotinate, which can be prepared as described in the US patent. No. 2,970,082; bamethan, which can be prepared as described in Corrigan, Journal of the American Chemical Society, 1945. 67. 1894; benciclane, which can be prepared as previously revealed; betahistine, which can be prepared as revealed in Walter, Journal of the American Chemical Society, 1941, 63. 2771; bradykinin, which can be prepared as disclosed in Hamburg, Arch. Biophys., 1958. 76. 252; brovincamine, which can be prepared as described in the patent of E.U.A. No. 4,146,643; bufeniode, which can be prepared as described in the patent of E.U.A. No. 3,542,870; buflomedil, which can be prepared as described in the patent of E.U.A. No. 3,895,030; butalamine, which can be prepared as described in the patent of E.U.A. No. 3,338,899; Cetiedil, which can be prepared as described in French Patent 1, 460,571; cycloncate, which can be prepared as described in German Patent No. 1, 910,481; cinepazide, which can be prepared as described in Belgian Patent No. 730,345; cinnarizine, which can be prepared as previously disclosed; cycladelate, which can be prepared as previously disclosed; diisopropylamine dichloroacetate, which can be prepared as disclosed above; eledolsin, which can be prepared as described in British Patent No. 984,810; phenoxymedil, which can be prepared as disclosed above; flunarizine, which can be prepared as previously revealed; hepronicato, which can be prepared as described in the patent of E.U.A. No. 3,384,642; Fenprodil, which can be prepared as disclosed above; iloprost, which can be prepared as described in the patent of E.U.A. No. 4,692,464; inositol niacinate, which can be prepared as described in Badgett, Journal of the American Chemical Society, 1947. 69. 2907; isoxsuprine, which can be prepared as described in the patent of E.U.A. No. 3,056,836; Calidin, which can be prepared as described in Biochem. Biophys. Res. Commun., 1961, 6, 210; kallikrein, which can be prepared as described in German Patent No. 1, 102,973; moxysilite, which can be prepared as described in German Patent No. 905,738; naphronil, which can be prepared as previously disclosed; nicamethate, which can be prepared as previously disclosed; nicergoline, which can be prepared as previously disclosed; nicofuranose, which can be prepared as described in Swiss Patent No. 366,523; nilidrine, which can be prepared as described in the patents of E.U.A. Nos. 2,661, 372 and 2,661, 373; pentiphylline, which can be prepared as disclosed above; pentoxifylline, which can be prepared as described in the patent of E.U.A. No. 3,422,107; piribedil, which can be prepared as described in the patent of E.U.A. No. 3,299,067; prostaglandin E1, which can be prepared by any of the methods referenced in the Merck index. Twelfth Edition, Budavari, Ed., New Jersey, 1996, p. 1353; Soloctidyl, which can be prepared as described in German Patent No. 2,334,404; tolazoline, which can be prepared as described in the patent of E.U.A. No. 2,161, 938; and xanthiol niacinate, which can be prepared as described in German Patent No. 1, 102,750 or Korbonits, Acta Pharm. Hung., 1968. 38 98. Descriptions of them are incorporated herein by reference. The term "diuretic", within the scope of this invention, includes diuretic benzothiadiazine derivatives, diuretic organomercutaries, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils and other diuretics such as amanozine, which can be prepared as described in Australian Patent No. 168,063; amiloride, which can be prepared as described in Belgian Patent No. 639,386; arbutin, which can be prepared as described in Tschitschibabin, Annalen, 1930. 479. 303; Chlorazanil, which can be prepared as described in Australian Patent No. 168,063; Ethacrynic acid, which can be prepared as described in the patent of E.U.A. No. 3,255,241; etozolin, which can be prepared as described in the patent of E.U.A. No. 3,072,653; Hydracarbazine, which can be prepared as described in British Patent No. 856,409; isosorbide, which can be prepared as described in the US patent. No. 3,160,641; mannitol; metachalcone, which can be prepared as described in Freudenberg, Ber., 1975. 90. 957; muzolimine, which can be prepared as described in the patent of E.U.A. No. 4,018,890; perhexilin which can be prepared as disclosed above; ticrinafen, which can be prepared as described in the patent of E.U.A. No. 3,758,506; triamterene, which can be prepared as described in the patent of E.U.A. No. 3,081, 230; and urea. The descriptions thereof are incorporated herein by reference. The diuretic benzothiadiazine derivatives within the scope of this invention include, but are not limited to: altiazide, which may be prepared as described in British Patent No. 902,658; bendroflumetiazide, which can be prepared as described in the patent of E.U.A. No. 3,265,573; benzthiazide, McManus, 136th Am. Soc. Meeting (Atlantic City, September 1959), Summary of Documents, pp 13-0; benzylhydrochlorothiazide, which can be prepared as described in the patent of E.U.A. No. 3,108,097; butiazide, which can be prepared as described in British patents Nos. 861, 367 and 885,078; chlorothiazide, which can be prepared as described in the patents of E.U.A. No. 2,809,194 and 2,937,167; Chlorthalidone, which can be prepared as described in the patent of E.U.A. No. 3,055,904; Cyclopentiazide, which can be prepared as described in Belgian Patent No. 587,225; cyclothiazide, which can be prepared as described in Whitehead, Journal of Organic Chemistry, 1961. 26. 2814; epitiazide, which is prepared as described in the patent of E.U.A. No. 3,009,911; etiazide, which can be prepared as described in British Patent No. 861, 367; fenquizone, which can be prepared as described in the patent of E.U.A. No. 3,870,720; indapamide, which can be prepared as described in the US patent. No. 3,565,911; hydrochlorothiazide, which can be prepared as described in the patent of E.U.A. No. 3,164,588; hydrochlorothiazide, which can be prepared as described in the patent of E.U.A. No. 3,74,076; methicylthiazide, which can be prepared as described in Cióse, Journal of the American Chemical Society, 1960. 82. 1132; meticrane, which can be prepared as described in French patent No. M2790 and 1, 365,504; metolazone, which can be prepared as described in the patent of E.U.A. No. 3,360,518; paraflutizide, which may be prepared as described in Belgian Patent No. 620,829; polythiazide, which can be prepared as described in the patent of E.U.A. No. 3,009,911; Quinetazone, which can be prepared as described in the patent of E.U.A. No. 2,976,289; teclothiazide, which can be prepared as described in Cióse, Journal of the American Chemical Society, 1960, 82 1132; and trichloromethiazide, which can be prepared as described in deStevens, Experientia, 1960, 16, 113. Descriptions thereof are incorporated herein by reference. Diuretic sulphonamide derivatives within the scope of this invention include, but are not limited to: acetazolamide, which can be prepared as described in the U.S.A. No. 2,980,679; ambuside, to which it can be prepared as described in the patent of E.U.A. No. 3,188,329; azosemide, which can be prepared as described in the US patent. No. 3,665,002; bumetanide, which can be prepared as described in the patent of E.U.A. No. 3,634,583; butazolamide, which can be prepared as described in British Patent No. 769,757; chloraminophenamide, which can be prepared as described in the patents of E.U.A. Nos. 2,809,194, 2,965,650 and 2,965,656; clofenamide, which can be prepared as described in Oliver, Rec. Trav. Chim., 1918. 37, 307; clopamide, which can be prepared as described in the patent of E.U.A. No. 3,459,756; chlorexolone, which can be prepared as described in the patent of E.U.A. No. 3,183,243Bm. ; disulfamide, which can be prepared as described in British Patent No. 851, 287; etoxolamide, which can be prepared as described in British Patent No. 795,174; furosemide, which can be prepared as described in the US patent. No. 3,058,882; mefruside, which can be prepared as described in the US patent. No. 3,356,692; metazolamide, which can be prepared as described in the patent of E.U.A. No. 2,783,241; pyretinide, which can be prepared as described in the patent of E.U.A. No. 4,010,273; torasemide, which can be prepared as described in the US patent. No. 4,018,929; tripamide, which can be prepared as described in Japanese Patent No. 7305,585; and xipamide, which can be prepared as described in the US patent. No. 3,567,777. The descriptions thereof are incorporated herein by reference. The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cation salts, where appropriate. The term "pharmaceutically acceptable cationic salts" is intended to define but is not limited to salts such as alkali metal salts, (eg, sodium and potassium), alkaline earth metal salts (eg, calcium and magnesium), salts of aluminum, and salts with organic amines such as benzathine (N, N'-dibenzylethylendlamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino- 2-hydroxymethyl-1,3-propanediol) and procaine. The term "pharmaceutically acceptable acid addition salts" is intended to define, but is not limited to, salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate salts, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate).

The pharmaceutically acceptable salts of the aldose reductase inhibitors of this invention can be readily prepared by reacting the free acid form of said aldose reductase inhibitor with an appropriate base, usually an equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by the addition of a non-solvent. In many cases, the salts are preferably prepared by mixing a solution of the acid with a solution of a salt other than the cation (sodium or potassium ethylhexanoate, magnesium oleate), and using a solvent (example, ethyl acetate) from which the desired cationic salt is precipitated, or it can be isolated by concentration and / or addition of a non-solvent. The acid addition salts of the aldose reductase inhibitors of this invention can be easily prepared by reacting the free base form of said aldose reductase inhibitor with the appropriate acid. When the salt is a monobasic acid (eg, hydrochloride, hydrobromide, p-toluenesulfonate, acetate), the hydrogen form of a dibasic acid (eg, hydrogen sulfate, succinate) or the form of dihydrogen of a tribasic acid (eg, dihydrogen phosphate, citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However, when salts such as sulfate, hemisuccinate, hydrogen phosphate or phosphate are desired, appropriate chemical equivalents and acid extracts will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired salt is precipitated, or may otherwise be isolated by concentration and / or addition of a non-solvent. The pharmaceutically acceptable acid addition and cationic salts of the antihypertensive agents used in combination of this invention can be prepared in a manner analogous to that described for the preparation of the pharmaceutically acceptable cationic and addition salts of said reductive aldose inhibitors, but replacing a desired antihypertensive agent with said aldose reductose inhibitor. In addition, aldose reductase inhibitors and antihypertensive agents that can be used according to this invention, prodrugs thereof and pharmaceutically acceptable salts thereof, can occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention. This invention relates to methods of treating diabetic complications in which the reductive aldose inhibitor and antihypertensive agent are administered together, as part of the same pharmaceutical composition, and with methods in which these two active agents are administered separately , as part of an appropriate dosage regimen designed to obtain the benefits of combination therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the active agents will depend on the inhibitor of aldose reductase and the antihypertensive agent used, the type of pharmaceutical formulations used, the characteristics of the subject being treated and the severity of the the complications Generally, to carry out the methods of this invention, an effective dose for the aldose reductase inhibitors of this invention is on the scale between about 0.01 and 100 mg / kg / day in single or divided doses, preferably between 0.1 and 20. mg / kg / day approximately in single or divided doses and the antihypertensive agent will be administered in single or divided doses. Antihypertensive agents will generally be administered in amounts ranging from 0.01 to 500 mg / kg / day approximately in single or divided doses, preferably between 10 mg and approximately 300 mg per day for an average subject, depending on the antihypertensive agent and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the treated subject. The doctor at any event will determine the appropriate dose for the individual subject. The administration of the pharmaceutical compositions of this invention can be through any method that releases a composition of this invention preferentially toward the desired tissue (eg, nerve, kidney, retina and / or cardiac tissues). These methods include oral, parenteral, intratraudermal routes, and so on. Generally, the compositions of the present invention are administered in single (eg, once a day) or multiple doses or through constant infusion.

Pharmaceutical compositions comprising an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug and an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug are hereinafter collectively referred to as "the active compositions of this invention". The active compositions of this invention can be administered to a subject in need of treatment by a variety of conventional routes of administration including oral, topical, parenteral, such as, for example, intravenous, subcutaneous or intramedullary. In addition, the active compositions of this invention can be administered intranasally, as a rectal suppository or by using an "instant" formulation, i.e. allowing the medicament to dissolve in the mouth without the need to use water. The active compositions of this invention can be administered alone or in combination with pharmaceutically appropriate carriers, diluents or carriers, in single or multiple doses. Suitable pharmaceutically suitable carriers, diluents and carriers include inert solid fillers or diluents, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compositions of this invention and the pharmaceutically acceptable carriers, carriers or diluents, are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. Thus, for purposes of oral 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 acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be used as fillings in gelatin capsules with soft and hard filling. Preferred materials for this include lactose or lactin and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient may be by combining with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. For parenteral administration, the solutions of the active compositions of this invention can be used in sesame or peanut oil, propylene glycol or in sterile aqueous solutions. Such aqueous solutions should be appropriately buffered if necessary and the liquid diluent first rendered 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 standard techniques known to those skilled in the art. Generally, a composition of this invention is administered orally, or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, when the patient suffers from gastrointestinal disorders or whenever the medication is better applied to the surface of a tissue or organ as determined by the physician. For buccal administration the composition (two active agents administered together or separately) can take the form of tablets or lozenges formulated in a conventional manner. For intranasal administration or administration by inhalation, the active compounds of the invention (two active agents administered together or separately) are conveniently released in the form of a solution or suspension from an atomization container that is compressed or pumped by the patient or as an aerosol spray presentation. from a pressurized container or a nebulizer, with the use of an appropriate propellant, eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gas. In the case of a pressurized aerosol, the dosage unit can be determined by supplying a valve to release a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound or compounds of the invention and an appropriate powder base ta! like lactose or starch. For purposes of transdermal administration (eg, topical), dilute, aqueous or partially aqueous solutions are usually prepared in a concentration of about 0.1% to 5%), otherwise similar to the above parenteral solutions. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in the light of this disclosure, to those skilled in the art. For examples of methods of preparing pharmaceutical compositions, see Remington Pharmaceutical Sciences (Remington s Pharmaceutical Sciences), Mack Publishing Company, Easton, Pa., Issue 19 (1995). The active compositions of this invention containing an amount of both an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor and of an antihypertensive agent, a prodrug thereof, a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug. The amount of each of these ingredients can independently be, for example 0.0001% - 95% of the total amount of the composition, where the total amount can not, of course, exceed 100%. In any event, the composition or formulation to be administered will contain an amount of each of the components of the composition according to the invention in an amount effective to treat the disease / condition of the subject being treated. Since the present invention has an aspect that relates to the treatment of the disease / condition described herein with a combination of active ingredients that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: an aldose reductase inhibitor, a prodrug thereof or a salt of such an inhibitor of aldose reductase or prodrug; and an antihypertensive agent, a prodrug thereof and a salt of said antihypertensive agent or prodrug as described above. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided sheet pack. Typically the kit comprises instructions for the administration of the separate components. The form of the kit is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), are administered at different dosage intervals, or when the titration of the individual components of the combination is desired by the doctor who prescribed. An example of such a kit comprises the known blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally comprise a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packaging process, depressions form in the plastic sheet. The depressions generally conform to the size and shape of the tablets or capsules to be contained therein. Then, the tablets or capsules are placed in the depressions and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet that is opposite from the direction in which the depressions were formed. As a result, the tablets or capsules are sealed in the depressions between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying manual pressure on the depressions whereby an opening is formed in the sheet at the depression site. The tablet or capsule can then be removed through said opening. It may be desirable to provide a memory aid on the package, eg, in the form of numbers or similar indications adjacent to the tablets or capsules, such indications correspond to the days of the regime in which the dosage form so specified will be swallowed Another additional example of such memory aid is a calendar printed on the card, eg, as follows "first week, Monday tuesday, ... etc ... second week, Monday, Tuesday ...." etc. Other variations of memory aids will be readily apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of the aldose reductase inhibitor may consist of a tablet or capsule while a daily dose of the antihypertensive agent may consist of several tablets or capsules and vice versa. The memory aid should reflect this. In another specific embodiment of the invention, a dispenser designed to dispense daily doses one at a time in the order of their future use is provided. Preferably, the dispenser is equipped with a memory aid, to further facilitate compliance with the regime. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled with a liquid crystal read display, or a reminder auditory signal which, for example, reads the date on which the last daily dose has been taken and / or remind the patient when the next dose will be taken. The compositions of this invention will generally be administered in a convenient formulation.

Claims (43)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug; an antihypertensive agent, a prodrug thereof, or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent, provided said antihypertensive agent is not an ACE inhibitor.

2. The composition according to claim 1, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said inhibitor of aldose reductase or said prodigy.

3. The composition according to claim 2, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

4. The composition according to claim 1, wherein said antihypertensive agent is a calcium channel blocker, an A-II antagonist, a diuretic, a neutral endopeptidase inhibitor, a beta-adrenergic receptor blocker. or a blocker of the alpha-adrenergic receptors, a prodrug of said antihypertensive agent or a pharmaceutically acceptable salt of said antihypertensive agent or of said prodrug.

5. The composition according to claim 4, wherein said antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, miberafradil, isradipine, lacidipine, nicardipine, nifenipine, amlodipine, nimodipine, nisoldipine, nitrendipine or felodipine, a prodrug of said calcium channel blocker or a pharmaceutically acceptable salt of said calcium channel blocker or said prodrug.

6. The composition according to claim 5, wherein said calcium channel blocker is felodipine, amlodipine, nifenipine, a prodrug of said calcium channel blocker or a pharmaceutically acceptable salt of said calcium channel blocker. calcium or of said prodrug.

7. The composition according to claim 6, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

8. The composition according to claim 7, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

9. The composition according to claim 4, wherein said antihypertensive agent is an A-II antagonist, said A-II antagonist being losartan, irbesartan or valsartan, a prodrug of said antagonist or a pharmaceutically acceptable salt of said antagonist A -II or of said prodroga.

10. The composition according to claim 9, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarestat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

11. The composition according to claim 10, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

12. The pharmaceutical composition according to claim 4, wherein said antihypertensive agent is a diuretic, said diuretic being amiloride, bendroflumethiazide, a prodrug of said diuretic or a pharmaceutically acceptable salt of said diuretic or said prodrug.

13. The composition according to claim 12, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarestat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

14. The composition according to claim 13, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

15. - The pharmaceutical composition according to claim 4, wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blocker being carvedilol, a prodrug thereof or a pharmaceutically acceptable salt thereof or said prodigy.

16. The composition according to claim 15, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarestat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

17. The composition according to claim 16, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

18. The pharmaceutical composition according to claim 4, wherein said antihypertensive agent is a blocker of the alpha-adrenergic receptors, said blocker of the alpha-adrenergic receptors being doxazosin, prazosin, trimazosin, a prodrug of said blocker of the alpha-adrenergic receptors or a pharmaceutically acceptable salt of said alpha-adrenergic receptor blocker or said prodrug.

19. The composition according to claim 18, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

20. The composition according to claim 19, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopoirestat or said prodrug.

21. The composition according to claim 4, wherein said antihypertensive agent is an inhibitor of the neutral endopeptidase, said inhibitor of the neutral endopeptidase being candoxatril, sampatrilat or omapatrilat, a prodrug thereof or a pharmaceutically acceptable salt of said inhibitor. of the neutral endopeptidase or of said prodrug.

22. The composition according to claim 21, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

23. The composition according to claim 22, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

24. The use of a pharmaceutical composition as claimed in claim 1 for the manufacture of a medicament for treating a diabetic complication in a mammal.

25. The use as claimed in claim 24, wherein said antihypertensive agent is a calcium channel blocker, an A-II antagonist, a diuretic, a beta-adrenergic receptor blocker or a beta blocker. alpha-adrenergic receptors, a pharmaceutically acceptable salt of any of said agents or a prodrug of any of said agents or said salts.

26 The use as claimed in claim 25, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodigal

27. The use as claimed in claim 26, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

28. The use as claimed in claim 27, wherein said diabetic complication is a diabetic neuropathy.

29. The use as claimed in claim 27, wherein said diabetic complication is a diabetic nephropathy.

30. The use as claimed in claim 27, wherein said diabetic complication is a diabetic cardiomyopathy.

31. The use as claimed in claim 27, wherein said diabetic complication is diabetic retinopathy.

32.- The use as claimed in claim 27, wherein said diabetic complication are cataracts.

33. The use as claimed in claim 27, wherein said diabetic complication is a myocardial infarction.

34. The use of an ARI, a prodrug thereof, or a pharmaceutically acceptable salt of said ARI or of said prodrug and an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said hypertensive agent or said prodrug, always and when said antihypertensive agent is not an ACE inhibitor for the manufacture of a medicament for treating a diabetic complication in a mammal.

35. The use as claimed in claim 34, wherein said antihypertensive agent is a calcium channel blocker, an A-II antagonist, a diuretic, a neutral endopeptidase inhibitor, a receptor blocker. beta-adrenergic or an alpha-adrenergic receptor blocker, or a pharmaceutically acceptable salt of any of said agents or a prodrug of any of said agents or said salts.

36. The use as claimed in claim 35, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodigal

37. The use as claimed in claim 36, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.

38.- The use as claimed in claim 35, wherein the ARI, the prodrug thereof or the pharmaceutically acceptable salt of said ARI or said prodrug and the antihypertensive agent, prodrug thereof or pharmaceutically acceptable salt of said Antihypertensive agent are administered separately.

39.- EF USE as claimed in claim 35, wherein the ARI, the prodrug thereof or the pharmaceutically acceptable salt of said ARI or said prodrug and antihypertensive agent, prodrug thereof or pharmaceutically acceptable salt of said agent antihypertensive drugs are administered together.

40. A kit comprising: a) a first unit dosage form comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a carrier, vehicle or diluent pharmaceutically acceptable; b) a second unit dosage form comprising an antihypertensive agent, a prodrug thereof or a pharmaceutically acceptable salt of said antihypertensive agent or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent, provided said antihypertensive agent is not an ACE inhibitor; and c) a container.

41. The kit according to claim 40, wherein said anti-hypertensive agent is a calcium channel blocker, an A-II antagonist, a diuretic, a neutral endopeptidase inhibitor, a beta-adrenergic receptor blocker or a blocker of the alpha-adrenergic receptors, a pharmaceutically acceptable salt of said agents or a prodrug of any of said agents or said salts.

42. The kit according to claim 41, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug.

43. The use as claimed in claim 42, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug.