TREATMENT AND PREVENTION OF CARDIAC INSULIN RESISTANCE ASSOCIATED CONDITIONS

Abstract: A method for the treatment or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance, in humans or non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of PPARy agonist, such as Compound (I), or a pharmaceutically acceptable derivative thereof. Conditions associated with cardiac insulin resistance are: microvascular angina, atherosclerosis and congestive heart failure. Compounds include rosiglitazone, troglitazone, englitazone and pioglitazone.

Description: TREATMENT AND PREVENTION OF CARDIAC INSULIN RESISTANCE ASSOCIATED CONDITIONS This invention relates to a novel treatment and in particular to a method for the treatment and/or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance. Increases in insulin resistance represent an impairment in the normal biological response to insulin. It is usually associated with conditions such as Type 2 diabetes mellitus where the resistance is primarily manifest in skeletal muscle, adipose tissue and the liver. In certain circumstances however, insulin resistance presents in tissues and organs other than in skeletal muscle and liver and in particular can be present selectively in the heart as cardiac- insulin resistance. In diseases such as cardiac syndrome-X [a form of microvascular angina], or in patients with accelerated atherosclerosis or chronic heart-failure, the increased insulin resistance in the myocardium impairs the ability of the myocardium to rapidly and effectively utilise glucose for metabolism, and may further exacerbate the delicate metabolic balance in this critical tissue. Treatment of cardiac-insulin resistance would be expected to alleviate this metabolic stress and improve the efficiency of glucose uptake, and hence oxidative metabolism of cardiac muscle. Where cardiac muscle is ischaemic and susceptible to hypoxic damage, it is believed that improving the metabolic stress of insulin resistance, will help prevent ischaemic damage to the myocardium. European Patent Application, Publication Number 0306228 discloses certain thiazolidinedione derivatives which are disclosed inter alia as having hypoglycaemic and hypolipidaemic activity and activity in treating certain eating disorders. The compound of example 30 of EP 0306228 is 5-(4-[2-(N-methyl-N-(2-ρyridyl)amino)ethoxy]benzyl)-2,4- thiazolidinedione (or 'Compound (1)0. European Patent Applications, Publication Numbers: 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione derivatives which are stated to have hypoglycaemic and hypolipidaemic activity. It is known that the γ-isoform of peroxisome proliferator-activated receptor (herein after PPARγ) is member of a nuclear receptor superfamily that includes receptors for the steroid, thyroid and retinoid hormones( Evans, Science 240, 889-895, (1 ' 988)). It is also known from Chawla et al that PPARγ is expressed early during the differentiation of adipocytes (Endocrinology 135,798-800, 1994). It is known from J. Biol. Chem., 270,12963-12966 that thiazolidinediones such as Compound (I) are PPARγ agonists. USP 5521201 discloses that Compound (I) is useful in the treatment of cardiac disease especially athereosclerosis. Also WO 00/04889 discloses that Compound (I) is useful for reducing post-ischaemic injury of the heart and/or improving the functional recovery of the heart following myocardial ischaemia. It is now considered that Compound (I) has activity in the treatment or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance. It is therefore of potential use in the treatment or prophylaxis of microvascular angina, atherosclerosis associated with insulin resistance and in the treatment of congestive heart failure, especially in delaying the progression of congestive heart failure, ameliorating or reversing reductions in cardiac muscular endurance and strength associated with congestive heart failure and ameliorating and/or reversing the cachexic phase of congestive heart failure. Accordingly, the invention provides a method for the treatment or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance, in humans or non-human mammals, which method comprises the administration of an effective, non- toxic and pharmaceutically acceptable amount of a PPARγ agonist, such as Compound (I), or a pharmaceutically acceptable derivative thereof. Particular conditions associated with cardiac insulin resistance include microvascular angina and congestive heart failure. A further condition associated with cardiac insulin resistance is atherosclerosis associated with insulin resistance. A suitable condition associated with cardiac insulin resistance is microvascular angina. A suitable condition associated with cardiac insulin resistance is congestive heart failure. In the treatment or prophylaxis of congestive heart failure, the present treatment is particularly indicated to delay the progression of congestive heart failure, ameliorate and/or reverse reductions in cardiac muscular endurance and/or strength associated with congestive heart failure and ameliorate and/or reverse the cachexic phase of congestive heart failure. Suitably, the present treatment delays the progression of congestive heart failure. Suitably, the present treatment ameliorates and or reverses reductions in cardiac muscular endurance and/or strength associated with congestive heart failure. Suitably, the present treatment ameliorates and/or reverses the cachexic phase of congestive heart failure. Suitable PPARγ agonists include thiazolidinediones, especially thiazolidine-2,4- diones, that is a compound comprising a moiety of formula (A): Suitable compounds comprising a moiety of formula (a) include compounds of formula (I): (i) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein T represents an aryl or heterocyclyl group optionally substituted with one or more alkyl groups, aralkyl groups or heterocyclylalkyl groups, the said alkyl, aralkyl and heterocyclylalkyl groups themselves being optionally substituted. Suitably, the carbon atom marked with an asterisk (*) in formula (I) is a chiral carbon. In particular T represents a moiety selected from the list consisting of (a), (b), (c), (d), (e), (f), (g), (h) and (i): (a) (b) (C) ( (e) (f) (g) (h), and In particular should be mentioned the moieties of formula (a), (b), (c), (d) and (e). Also included in the treatment of the invention are the PPARγ agonists disclosed in European Patent Applications, Publication Numbers: 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734 and 0508740, International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, especially the specific example thereof. The contents of these publications are included herein by reference. Thiazolidinedione PPARγ agonists may exist in one of several tautomeric forms, all of which are encompassed by the present invention as individual tautomeric forms or as mixtures thereof. Where a PPARγ agonist contains a chiral carbon, and hence exists in one or more stereoisomeric forms or where one or more geometric isomers exist, it will be appreciated that the method of the present invention encompasses all of the said forms of the PPARγ agonists whether as individual isomers or as mixtures of isomers, including racemates. Particular examples of thiazolidinediones are those disclosed in EP 0306228 and WO94/05659. Further particular examples are the thiazolidinediones disclosed in EP0139421 and USP 5478852. A preferred thiazolidinedione is Compound (I). Further particular thiazolidinediones are, (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H- 1 -benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone) When used herein the term PPARγ agonist' relates to an agonist, such as a small molecular weight agonist, of the peroxisomal proliferator-activated receptor of the gamma subtype, this nuclear receptor is a member of the ligand activated transcription factor family that include the steroid, retinoid and thyroid receptors. PPARγ agonist activity may be assessed by use of the methodology disclosed by Lehmann et al : Journal of Biological Chem., 270, 12953-12956 (1995). When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups. Suitable heterocyclyl groups are aromatic and non-aromatic heterocylic groups. Suitable non-aromatic heterocylic groups include groups comprising single or fused ring heterocyclic groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen, optionally fused to one or more aryl groups. Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen. Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms. In particular, the aromatic heterocyclyl groups comprise 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen. Suitable substituents for the heterocyclyl include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted. It will be appreciated that where the above mentioned definitions of 'aryl', 'heterocyclyl' and the substituents thereof differ from those in the above mentioned patent publications with respect to the particular compounds disclosed therein, that the definitions in the said publications prevail. When used herein the term Tialogen' refers to fluorine, chlorine, bromine and iodine; preferably chlorine. When used herein the terms 'alkyl' and 'alkoxy' relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms. When used herein the term 'acyl' includes alkylcarbonyl groups. Suitable alkyl groups are Cj-^ alkyl groups, especially C\- alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups. Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl". Suitable derivatives of a PPARγ agonist are pharmaceutically acceptable derivatives, for example salts and solvates. Suitable derivatives of any particular PPARγ agonist include those disclosed in the above mentioned publications. Suitable pharmaceutically acceptable salts include salts of salts derived from appropriate acids, such as acid addition salts, or bases. Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate and a- glycerophosphate, especially the maleate salt. Suitable pharmaceutically acceptable salts of Compound (I) are as disclosed in EP 0306228 and WO94/05659 and include maleate salts. . Suitable pharmaceutically acceptable solvates include hydrates. Suitable pharmaceutically acceptable solvates of Compound (I) are as disclosed in EP 0306228 and WO94/05659 and include hydrates. The PPARγ agonists, such as the thiazolidinediones, referred to herein are conveniently prepared according to the methods disclosed in the above mentioned patent publications in which they are disclosed: Thus Compound (I), or the tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, may be prepared using the processes described in EP 0306228 and WO94/05659. The salts and/or solvates of the thiazolidinediones may be prepared and isolated according to conventional procedures for example those disclosed in the, above mentioned, patent publications. The present invention also provides a PPARγ agonist or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance. The present invention also provides a PPARγ agonist or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance. In the above mentioned method the PPARγ agonist, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. In the treatment of the invention, the PPARγ agonist mentioned herein is formulated and administered in accordance with the methods disclosed in the above mentioned publications, patent applications and patents. Accordingly, the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance, which composition comprises a PPARγ agonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor. As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt. The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used. In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant. Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose. Suitable dosages of the PPARγ agonist include the known doses for these compounds as described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Complete Drug Reference (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications or doses which can be determined by standard procedures. Suitable dosages of the Compound (I) include those disclosed in EP 0306228 and WO94/05659 and 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I). . Particular dosages of Compound (I) are 2mg, 4mg and 8mg. Particular dosages of troglitazone include from 100 to 800mg such as 200, 400, 600 or 800mg. Particular dosages of pioglitazone include from 5 to 50mg, including 10 to 40mg, such as 15, 20, 30 or 40 mg of pioglitazone. The composition of the invention may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day. The composition of the invention may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day. The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use. The compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Complete Drug Reference (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books). The activity of compounds in the treatment of the present invention can be determined using known methodology, for example by use of procedures disclosed by Eckel J, Asskamp,B, Reinauer, H (1991) Endocrinology 129, 345-352 Induction of insulin resistance in primary cultured adult cardiomyocytes. No adverse toxicological effects are expected for the compositions or methods of the invention in the above mentioned dosage ranges.

Claims: Claims: 1. A method for the treatment or prophylaxis of cardiac insulin resistance or conditions associated with cardiac insulin resistance, in humans or non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of a PPARγ agonist, such as Compound (I), or a pharmaceutically acceptable derivative thereof. 2. A method according to claim 1, wherein a condition associated with cardiac insulin resistance is selected from: microvascular angina, atherosclerosis associated with insulin resistance and congestive heart failure. 3. A method according to claim 1, wherein in the treatment of congestive heart failure there is provided: a delay in the progression of congestive heart failure; an amelioration and/or reversal of reductions in cardiac muscular endurance and/or strength associated with congestive heart failure; or an amelioration and/or reversal of the cachexic phase of congestive heart failure. 4. A method according to claim 1, wherein the PPAR agonist is a thiazolidinedione. 5. A method according to claim 4, wherein the PPAR agonist is selected from the list consisting of: Compound (I), (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l- benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(l- methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[(2-benzyl-2,3- dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone), and 5-[4-[2-(5- ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone). 6. A method according to claim 4, wherein the PPAR agonist is Compound (I). 7. A method according to claim 4, wherein the PPAR agonist is 5-[4-[2-(5-ethylpyridin- 2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone).

Inventors: NATHWANI AMEET, NATHWANI, AMEET
Applicants: NATHWANI AMEET, SMITHKLINE BEECHAM PLC, NATHWANI, AMEET, SMITHKLINE BEECHAM P.L.C.
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P3, A61P9, A61P43