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WO2005037284A1 - Inhibiteur de la sorbitol-deshydrogenase et associations d'agents antihypertenseurs - Google Patents

Inhibiteur de la sorbitol-deshydrogenase et associations d'agents antihypertenseurs Download PDF

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Publication number
WO2005037284A1
WO2005037284A1 PCT/IB2004/003252 IB2004003252W WO2005037284A1 WO 2005037284 A1 WO2005037284 A1 WO 2005037284A1 IB 2004003252 W IB2004003252 W IB 2004003252W WO 2005037284 A1 WO2005037284 A1 WO 2005037284A1
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Prior art keywords
alkyl
optionally substituted
alkoxy
fluoro
hydroxy
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PCT/IB2004/003252
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English (en)
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Banavara Lakshman Mylari
Peter Joseph Oates
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Pfizer Products Inc.
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Publication of WO2005037284A1 publication Critical patent/WO2005037284A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • This invention relates to pharmaceutical compositions comprising a sorbitol dehydrogenase inhibitor (SDI), or a pharmaceutically acceptable salt thereof, and an antihypertensive agent, or a pharmaceutically acceptable salt thereof.
  • SDI sorbitol dehydrogenase inhibitor
  • the invention further relates to methods of using such compositions for the treatment of diabetic complications such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • inhibitors of SDH are of therapeutic value for controlling diabetic complicatbns such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • diabetic complicatbns such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • the present invention is directed to pharmaceutical compositions comprising a sorbitol dehydrogenase inhibitor (SDI), or a pharmaceutically acceptable salt thereof, and an antihypertensive agent, or a pharmaceutically acceptable salt thereof.
  • SDI sorbitol dehydrogenase inhibitor
  • the invention further relates to methods of using such compositions for treating diabetic complications such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • diabetic complications such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • the present invention provides pharmaceutical compositions comprising a sorbitol dehydrogenase inhibitor (SDI), or a pharmaceutically acceptable salt thereof, and an antihypertensive agent, or a pharmaceutically acceptable salt thereof.
  • SDI sorbitol dehydrogenase inhibitor
  • the invention further provides methods of using such compositions for treating diabetic complications such as diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • treating refers to retarding, arresting, or reversing the progress of, or alleviating or preventing either the disorder or condition to which the term “treating” applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom, or condition, as the term “treating” is defined above.
  • Any SDI may be used in the combinations and methods of the present invention.
  • the following commonly-assigned patents and published applications exemplify SDIs useful in the compositions and methods of the present invention, including methods for the preparation and use thereof: U.S. Pat. No. 5,932,581; U.S. Pat. No 6,294,538; U.S. Pat. No.
  • the SDI comprises a compound of formula (I) disclosed in U.S. Pat. Nos. 6,414,149 and 6,602,875 hereinabove, or a pharmaceutically acceptable salt thereof,
  • R 1 is formyl, acetyl, propionyl, carbamoyl or -C(OH)R 4 R 5 ;
  • R 4 and R 5 are each independently hydrogen, methyl, ethyl or hydroxy-(C 1
  • R is hydrogen, (C C 4 )alkyl or (C r C 4 )alkoxy;
  • R 3 is a radical of the formula
  • radical of formula R 3a is additionally substituted on the ring by R 6 , R 7 and R 8 ; said radical of formula R 3b is additionally substituted on the ring by R 18 , R 19 and R 20 ;
  • G, G 1 and G 2 are taken separately and are each hydrogen and R 6 is hydrogen, (C C 4 )alkyl, (C C 4 )alkoxycarbonyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, hydroxy- (C C 4 )alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C C 4 )alkyl or (C r C 4 )alkoxy, wherein said (d-C 4 )alkyl in the definition of R 6 and said (C r C 4 )alkoxy in
  • C 4 )alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C C 4 )alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C r C 4 )alkyl, benzyl or Ar; and said carbonyl(C 0 - C 4 )alkylenylcarbonyl in the definition of X is optionally substituted indepedently with up to three (C ⁇ C ⁇ alkyl, benzyl or Ar;
  • R 10 is hydrogen or (C C 4 )alkyl;
  • R 9 is (C 3 -C 7 )cycloalkyl, Ar 1 -(C 0 -C 3 )alkylenyl or (d-C 6 )alkyl optionally substituted with up to five fluoro; provided that when
  • R 19 and R 20 are each independently hydrogen or (C 1 -C 4 )alkyl; or G 3 and G 4 are taken together and are (CrC 3 )alkylene; r is 0 or 1; and R 18 , R 19 , R 2Q and G 5 are hydrogen; or G 4 and G 5 are taken together and are (d-C 3 )alkylene; r is 0 or 1; and R 18 , R 19 , R 20 and G 3 are hydrogen; R 17 is SO 2 NR 21 R 22 , CONR ⁇ R 22 , (C ⁇ -C 6 )alkoxycarbonyl, (C C 6 )alkylcarbonyl,
  • R 21 and R 22 are taken separately and are each independently selected from hydrogen, (C r C 6 )alkyl, (C 3 -C 7 )cycloalkyl and Ar 2 -(C 0 -C 4 )alkylenyl; or R 21 and R 22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1 ]heptyl, 6,7-dihydro-5H- dibenzo[c,e]azepinyl, 1 ,2,3,4-tetrahydro-isoquinolyl or 5,6,7,
  • R 21 and R 22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(d- C 4 )alkyl, (C ⁇ -C 4 )alkoxy-(d-C 4 )alkyl, (C C 4 )alkyl optionally substituted with up to five fluoro and (C C 4 )alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R 21 and R 22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C 1 -C 4 )alkyl, (C C 4 )alkoxy-(C ⁇ -C 4 )alkyl, (C C 4 )alkyl optionally substituted with up to five fluoro and (C C 4 )alkoxy optionally substituted with up to five fluoro; Ar 2 is independently defined
  • t is 1 , 2 or 3;
  • Y is (C 2 -C 6 )alkylene;
  • R 44 , R 45 and R 46 are each independently hydrogen or (C C 4 )alkyl;
  • m and n are each independently 1 , 2 or 3, provided that the sum of m and n is
  • Y 1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
  • R 43 is (C 3 -C 7 )cycloalkyl, Ar 5 -(C 0 -C 4 )alkylenyl, NR 47 R 48 or (C r C 6 )alkyl optionally substituted with one to five fluoro; provided that when Y 1 is a covalent bond or oxycarbonyl, then R 43 is not NR 47 R 48 ;
  • R 47 and R 48 are taken separately and are each independently selected from hydrogen, Ar 5 , (C C 6 )alkyI and Ar 5 -(C 0 -C 4 )alkylenyl; or R 47 and R 48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aze
  • An especially preferred compound of formula (I) is (R)- ⁇ 4-[4-(4,6-dimethyl- [1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl ⁇ -ethanol, or a pharmaceutically acceptable salt thereof.
  • any antihypertensive agent may be employed in the compositions and methods of the invention, however, it is generally preferred that the antihypertensive agent comprise a calcium channel blocker, a renin-angiotensin system (RAS) inhibitor, a diuretic, a neutral endopeptidase inhibitor, a ⁇ -adrenergic receptor blocker, a vasodilator, or an ⁇ -adrenergic receptor blocker.
  • RAS renin-angiotensin system
  • Ca +2 channel blockers evoke a lowering of systemic blood pressure.
  • preferred calcium channel blockers useful in the compositions and methods of the invention include verapamil (U.S. Pat. No. 3,261 ,859), diltiazem (U.S. Pat. No. 3,562,257), mibefradil (U.S. Pat. No. 4,808,605), isradipine (U.S. Pat. No.
  • renin-angiotensin system (RAS) inhibitor refers to a compound having the ability to inhibit the conversion of the naturally-occurring plasma glycoprotein angiotensinogen into the N-terminal decapeptide angiotensin I, or the subsequent conversion of angiotensin I to the octapeptide angiotensin II.
  • angiotensin II is a potent vasoconstrictor, which mediates increased systemic vascular resistance with concomitant deleterious impact on various hemodynamic parameters in dysfunctional states.
  • Angiotensin II further promotes N retention of sodium and water through its role in the regulation of renal hemodynamics arid release from the adrenal cortex of aldosterone.
  • the renin-angiotensin system is a known causative factor in hypertension.
  • RAS inhibitor may be employed. However, it is generally preferred that the RAS inhibitor comprise a renin inhibitor, an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II receptor antagonist.
  • ACE angiotensin-converting enzyme
  • renin inhibitor refers to a compound having the ability to inhibit the proteolytic conversion of angiotensinogen into angiotensin I, the penultimate precursor to angiotensin II.
  • renin inhibitors see, for example, Pharm. Res., 4, 364 (1987).
  • a variety of renin inhibitors will be known to one of ordinary skill in the ⁇ art, including those disclosed in U.S. Pat. Nos. 4,814,342, 4,855,303, and 4,895,834.
  • angiotensin-converting enzyme (ACE) inhibitor refers to a compound having the ability to inhibit the cleavage of angiotensin I to angiotensin II.
  • ACE angiotensin-converting enzyme
  • ACE inhibitors useful in the practice of the compositions and methods of the invention include benazeprilat (U.S. Pat. No. 4,410,520); captopril (U.S. Pat. No. 4,105,776); and enalapril and lisinopril (U.S. Pat. No. 4,374,829).
  • angiotensin II (A-ll) receptor antagonist refers to a compound having the ability to inhibit the vasoactive effects of endogenous angiotensin II by competitive blockade at the angiotensin receptor sites located in vascular smooth muscle and within the adrenal gland.
  • A-ll receptor antagonists or A-ll receptor blockers (ARB's) useful in the compositions and methods of the invention include candesartan (U.S. Patent No. 5,196,444); eprosartan (U.S. Patent No. 5,185,351); irbesartan (U.S. Patent Nos. 5,270,317 and 5,352,788); losartan (U.S. Patent No. 5,138,069); tasosartan (U.S. Pat. No. 5,149,699); telmisartan (European Patent Application Publication No. EP 502314); and valsartan (U.S. Patent No. 5,399,578).
  • candesartan U.S. Patent No. 5,196,444
  • eprosartan U.S. Patent No. 5,185,351
  • irbesartan U.S. Patent Nos. 5,270,317 and 5,352,788
  • losartan U.S. Patent No
  • diuretic agent embraces three main classes of compounds: 1) thiazides and derivatives thereof, which inhibit sodium and chloride reabsorption in the distal convoluted tubule of the nephron; 2) "loop" diuretics, which block Na + , K + , and Cl " reabsorption by the Na + , K + , and Cl " symporter in the thick ascending limb of the nephron; and 3) potassium-sparing diuretics, which block epithelial sodium channels in late distal tubules and collecting ducts of the nephron.
  • Diuretic agents useful in the practice of the compositions and methods of the present invention include benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils, and other diuretics such as amanozine (Austrian Patent No. 168,063); amiloride (Belgian Patent No. 639,386); arbutin (Tschitschibabin, Annalen, 479, 303 (1930)); chlorazanil (Austrian Patent No. 168,063); ethacrynic acid (U.S. Patent No. 3,255,241); etozolin (U.S. Patent No.
  • Diuretic benzothiadiazine derivatives include althiazide (British Patent No. 902,658); bendroflumethiazide (U.S.
  • Patent No. 3,265,573 benzthiazide (McManus et al., 136th Am. Soc. Meeting, Atlantic City, September 1959, Abstract of papers, p. 13-O); benzylhydrochlorothiazide (U.S. Patent No. 3,108,097); buthiazide (British Patent Nos. 861 ,367 and 885,078); chlorothiazide (U.S. Patent Nos. 2,809,194 and 2,937,169); chlorthalidone (U.S. Patent No. 3,055,904); cyclopenthiazide (Belgian Patent No. 587,225); cyclothiazide (Whitehead et al., J.
  • Diuretic sulfonamide derivatives useful in the compositions and methods of the invention include acetazolamide (Patent No.
  • Endopeptidase inhibitors belong to a class of compounds that inhibit enzymes that metabolize vasoactive peptides.
  • Neutral endopeptidase metabolizes various natriuretic peptides, including bradykinin. Because the secretion of natriuretic peptides is elevated by volume expansion, inhibition of NEP increases levels of natriuretic peptides during volume expansion. Thus, inhibition of NEP causes tends to cause natriuresis and lowering of blood pressure in volume-expanded hypertension.
  • Generally preferred NEP inhibitors include candoxatril and candoxatrilat (European Patent
  • Preferred dual ACE inhibitor/NEP inhibitors include sampatrilat (European Patent Application Publication No. EP 358398) and omapatrilat (U.S. Patent No. 5,508,272), prodrugs thereof and pharmaceutically acceptable salts thereof and of said prodrugs.
  • Sampatrilat and omapatrilat are dual ACE inhibitor/NEP inhibitors.
  • Antagonism of ⁇ -adrenergic receptors affects the regulation of circulation through a number of mechanisms, including reduction in myocardial contractility and cardiac output.
  • ⁇ -adrenergic receptor blockers useful in the compositions and methods of the invention include acebutolol (U.S. Patent No.
  • vasodilator includes cerebral vasodilators, coronary vasodilators, and peripheral vasodilators.
  • cerebral vasodilators useful in the compositions and methods of the invention include citicoline (Kennedy et al., J. Am. Chem. Soc, 77, 250 (1955) or J. Biol. Chem., 222, 185 (1956)); cyclandelate (U.S. Patent No. 3,663,597); ciclonicate (German Patent No. 1 ,910,481); diisopropylamine dichloroacetate (British Patent No.
  • nitroglycerin pentaerythritol tetranitrate, which may be prepared by the nitration of pentaerythritol according to known methods; pentrinitrol (German Patent No. 638,422-3); pimefylline (U.S. Patent No. 3,350,400); prenylamine (U.S. Patent No. 3,152,173); propatyl nitrate (French Patent No. 1 ,103,113); trapidil (East German Patent No. 55,956); tricromyl (U.S. Patent No. 2,769,015); (U.S. Patent No. 3,262,852); visnadine (U.S.
  • peripheral vasodilators include aluminum nicotinate (U.S. Patent No. 2,970,082); bamethan (Corrigan et al., J. Am. Chem. Soc, 67, 1894 (1945)); betahistine (Walter et al.; J. Am. Chem. Soc,_63, 2771 (1941)); bradykinin (Hamburg et al., Arch. Biochem. Biophys., 76, 252 (1958)); brovincamine (U.S.
  • Patent No. 4,146,643 bufeniode (U.S. Patent No. 3,542,870); buflomedil (U.S. Patent No. 3,895,030); butalamine (U.S. Patent No. 3,338,899); cetiedil (French Patent Nos. 1 ,460,571); ciclonicate (German Patent No. 1 ,910,481); cinepazide (Belgian Patent No. 730,345); eledoisin (British Patent No. 984,810); heoronicate (U.S. Patent No. 3,384,642); iloprost (U.S. Patent No.
  • Patent No. 3,422,107 discloses piribedil (U.S. Patent No. 3,299,067); prostaglandin E-, (prepared by any of the methods referenced in the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1353 (1996)); suloctidil (German Patent No. 2,334,404); tolazoline (U.S. Patent No. 2,161,938); and xanthinol niacinate (German Patent No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung., 38, 98 (1968)).
  • ⁇ -Adrenergic receptors mediate many salient actions of endogenous catecholamines, including r receptor-mediated contraction of arterial and venous smooth muscle.
  • blockade of ⁇ r adrenergic receptors inhibits vas ⁇ constriction induced by both endogenous catecholamines and sympathomirnetic amines, resulting in a fall in blood pressure because of decreased peripheral resistance.
  • ⁇ -blockers useful in the compositions and methods of the invention include amosulalol (U.S. Patent No.
  • Pharmaceutically acceptable aid addition salts of basic compounds include hydrochloride, hydrobromide, sulfate, hydrogen . sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, benzenesulfonate (besylate), methanesulfonate (mesylate), and p- toluenesulfonate (tosylate) salts.
  • the pharmaceutically acceptable basic addition salts of acidic groups, such as carboxyl groups may be formed by contacting the acid form of a compound with an appropriate organic or inorganic conjugate base.
  • Pharmaceutically acceptable basic addition salts of acidic groups include sodium, potassium, lithium, calcium, and magnesium salts.
  • the salt is of a monobasic acid (e.g., the hydrochoride, hydrobromide, p-toluenesulfonate, acetate, etc.)
  • at least one molar equivalent and usually a molar excess of the acid is employed.
  • salts such as the sulfate, hemisuccinate, hydrogen phosphate, or phosphate are desired
  • the appropriate and exact chemical equivalents of the conjugate acid will generally be used.
  • the free base and the acid are combined in a co-solvent from which the desired salt precipitates, or can be otherwise advantageously isolated by concentration or addition of a non-solvent.
  • compositions of the present invention comprise an amount of a sorbitol dehydrogenase inhibitor, or a pharmaceutically acceptable salt thereof, an amount of an antihypertensive agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the compositions may be readily administered in a variety of dosage forms, such as tablets, powders, lozenges, syrups, injectable solutions, and the like.
  • the compositions may,, if desired, further comprise ingredients such as flavorings, binders, excipients, and the like.
  • compositions with amounts of active ingredients are known, or will be apparent in light of the instant disclosure, to one skilled in the relevant art.
  • excipients such as sodium citrate, calcium carbonate, or calcium phosphate
  • disintegrants such as starch, alginic acid, and certain complex silicates
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin, or acacia.
  • lubricating agents such as magnesium stearate, sodum lauryl sulfate or talc are often useful for tableting purposes.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules.
  • Preferred materials for this purpose include lactose or milk sugar and high molecular weight polyethylene glycols. Tablets and pills may also be prepared with enteric coatings.
  • the essential active ingredients therein may be combined wirh 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, or combinations thereof, all of which are pharmaceutically acceptable.
  • solutions of the active agents in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution can be employed.
  • aqueous solutions should be suitable 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, or intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the relevant art. Such media may be sterilized by, for example, filtration through a bacteria- retaining filter, by incorporating sterilizing agents into the compositions, or by irradiating or heating the compositions. They can also be manufactured in the form of sterile solid compositions for extemporaneous preparation.
  • transdermal For purposes of transdermal, e.g., topical, administration, dilute, sterile, aqueous or partially aqueous solutions (normally in about 0.1% to about 0.5% concentration), otherwise similar to the above parenteral solutions, are employed.
  • aqueous or partially aqueous solutions normally in about 0.1% to about 0.5% concentration
  • Methods of preparing various pharmaceutical compositions with certain amounts of active ingredients are known, or will be apparent in light of this disclosure, to those skilled in this art.
  • methods of preparing pharmaceutical compositions see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
  • the invention further provides methods of treating diabetic complications with a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a sorbitol dehydrogenase inhibitor, or a pharmaceutically acceptable salt thereof, an effective amount of an antihypertensive agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the diabetic complication is diabetic macroangiopathy, diabetic microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot ulcers, myocardial infarction, or diabetic cardiomyopathy.
  • the ability to determine appropriate, effective dosages of the sorbitol dehydrogenase inhibitors, or the pharmaceutically acceptable salts thereof, and the antihypertensive agents, or the pharmaceutically acceptable salts thereof, necessary to achieve the desired therapeutic effect(s) according to the methods of the invention is within the ordinary skill of one who practices in the art having benefit of the disclosure herein.
  • the amounts of the sorbitol dehydrogenase inhibitors, or the pharmaceutically acceptable salts thereof, and the antihypertensive agents, or the pharmaceutically acceptable salts thereof may independently comprise, for example, from about 0.0001% to about 95% of the total amount of the composition, where the total amount may not exceed 100%.
  • the composition to be administered will contain an amount of each of the components of the composition of the invention effective to treat the diabetic complication(s) of the subject being treated therewith.
  • dosage ranges of sorbitol dehydrogenase inhibitors have been reported with representative dosages being from about 0.001 to about 100 mg/kg, preferably from about 0.01 to about 10 mg/kg body mass of the subject to be treated per day, in single or divided doses.
  • some variation in dosage may necessarily occur, depending upon the condition of the subject being treated.
  • the prescribing physician will, in any event, determine the appropriate dose for the individual subject.
  • dosage ranges for certain renin inhibitors have been reported with representative dosages being 0.25 mg/kg to about 1.4 mg/kg i.v. and 40 mg/kg to about 1 ,200 mg/kg/day orally.
  • Dosage ranges for certain ACE inhibitors have been reported with representative dosages of about 50 mg/kg to about 450 mg/kg/day orally and about 20 mg/kg parenterally.
  • Dosage ranges for certain A-ll antagonists have been reported with representative dosages being about 0.5 mg/kg to about 500 mg/kg p.o., preferably about 2 mg/kg to about 80 mg/kg p.o., and about 3 mg/kg/day.
  • the dosages employed according to the methods of the invention may be varied depending upon the requirements of the subject being treated, the degree of severity of the condition being treated, and the compound(s) being administered.
  • the administration of the compositions of the invention may be sequential in time, or simultaneous, with the simultaneous method being generally preferred.
  • the sorbitol dehydrogenase inhibitor, or the pharmaceutically acceptable salt thereof, and the antihypertensive agent, or the pharmaceutically acceptable salt thereof may be administered in any order. It is generally preferred that such administration be oral. It is further preferred that administration be oral and simultaneous.
  • Diabetes is induced in male Sprague-Dawley rats (350-400 g) by a tail vein injection of 85 mg/kg streptozocin. Twenty-four hours later, four groups of diabetic rats are given a single dose of the test compound (0.001 to 100 mg/kg) by oral gavage. The animals are sacrificed four to six hours post-dose and blood and sciatic nerves are harvested. Tissues and cells are extracted with 6% perchloric acid. Sorbitol in erythrocytes and nerves is measured by a modification of the method of Clements, et al., Science, 166, 1007 (1969).
  • tissue extracts are added to an assay system which has final concentrations of 0.033 M glycine, pH 9.4, 800 ⁇ M ⁇ -nicotine adenine dinucleotide, and 4 units/mL of SDH. After incubation for 30 minutes at room temperature, sample fluorescence is determined on a fluorescence spectrophotometer with excitation at 366 nm and emission at 452 nm. After subtracting appropriate blanks, the amount of sorbitol in each sample is determined from a linear regression of sorbitol standards processed in the same manner as the tissue extracts. Fructose is determined by the method of T. W. Seigel, et al., Anal. Biochem.,

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Abstract

L'invention concerne des compositions pharmaceutiques contenant un inhibiteur de la sorbitol-déshydrogénase (SDI), ou un de ses sels pharmaceutiquement acceptables, et un agent antihypertenseur, ou un de ses sels pharmaceutiquement acceptables. L'invention concerne également des méthodes d'utilisation de ces compositions pour traiter les complications diabétiques telles que la macro-angiopathie diabétique, la micro-angiopathie diabétique, la neuropathie diabétique, la néphropathie diabétique, la rétinopathie diabétique, les ulcères au pied, l'infarctus du myocarde, ou bien la cardiomyopathie diabétique.
PCT/IB2004/003252 2003-10-15 2004-10-04 Inhibiteur de la sorbitol-deshydrogenase et associations d'agents antihypertenseurs WO2005037284A1 (fr)

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US51123403P 2003-10-15 2003-10-15
US60/511,234 2003-10-15

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US8476277B2 (en) 2007-04-27 2013-07-02 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US8575199B2 (en) 2007-04-27 2013-11-05 Purdue Pharma L.P. Formula (IA″) compounds comprising (piperidin-4-yl)pyridine or (1,2,3,6-tetrahydropyridin-4-4yl) as TRPV1 antagonists
US8889690B2 (en) 2007-04-27 2014-11-18 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9365563B2 (en) 2007-04-27 2016-06-14 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9878991B2 (en) 2007-04-27 2018-01-30 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10584110B2 (en) 2007-04-27 2020-03-10 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9630959B2 (en) 2011-06-22 2017-04-25 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10450308B2 (en) 2011-06-22 2019-10-22 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
CN107847548A (zh) * 2015-05-18 2018-03-27 贝思以色列女会吏医学中心公司 P物质、肥大细胞脱颗粒抑制剂和周围神经病
CN107847548B (zh) * 2015-05-18 2022-06-14 贝思以色列女会吏医学中心公司 P物质、肥大细胞脱颗粒抑制剂和周围神经病

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