OA12831A - Treatment and prevention of cardiac insulin resistance associated conditions. - Google Patents

Description

012831

TREATMENT AND PREVENTION OF CARDIAC INSULIN RESISTANCE ASSOCIATED CONDITIONS

This invention relates to a novel treatment and in particular to a method for thetreatment and/or prophylaxis of cardiac insulin résistance or conditions associated with 5 cardiac insulin résistance.

Increases in insulin résistance represent an impairment in the normal biologicalresponse to insulin. It is usually associated with conditions such as Type 2 diabètes mellituswhere the résistance is primarily manifest in skeletal muscle, adipose tissue and the liver. Incertain circumstances however, insulin résistance présents in tissues and organs other than in 10 skeletal muscle and liver and in particular csa be présent selectively in the heart as cardiac-insulin résistance. In diseases such as cardiac syndrome-X [a form of microvascular angina],or in patients with accelerated atherosclerosis or chronic heart-failure, the increased insulinrésistance in the myocardium impairs the ability of the myocardium to rapidly andeffectively utilise glucose for metabolism, and may further exacerbate the délicate metabolic 15 balance in this critical tissue. Treatment of cardiac-insulin résistance would be expected toalleviate this metabolic stress and improve the efficiency of glucose uptake, and henceoxidative metabolism of cardiac muscle. Where cardiac muscle is ischaemic and susceptibleto hypoxie damage, it is believed that improving the metabolic stress of insulin résistance,will help prevent ischaemic damage to the myocardium. 20 European Patent Application, Publication Number 0306228 discloses certain thiazolidinedione dérivatives which are disclosed inter alla as having hypoglycaemic and hypolipidaemic activity and activity in treating certain eating disorders. The compound ofexample 30 of EP 0306228 is 5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione (or ’Compound (1)0- 25 European Patent Applications, Publication Numbers: 0306228,0008203, 0139421, 0032128, 0428312, 0489663,0155845,0257781, 0208420,0177353, 0319189, 0332331,0332332,0528734,0508740; International Patent Application, Publication Numbers92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852,also disclose certain thiazolidinedione dérivatives which are stated to hâve hypoglycaemic 30 and hypolipidaemic activity.

It is known that the γ-isoform of peroxisome proliferator-activated receptor (hereinafter PPARy) is member of a nuclear receptor superfamily that includes receptors for thesteroid, thyroid and retinoid hormones( Evans, Science 240,889-895, (1988)). It is alsoknown from Chawla et al that PPARy is expressed early during the différentiation of 35 adipocytes (Endocrinology 135,798-800,1994). -1- 01283ί

It is known from J. Biol. Chem., 270,12963-12966 that thiazolidinediones such as

Compound (I) are PPARy agonists. , USP 5521201 discloses that Compound (I) is useful in the treatment of cardiacdisease especially athereosclerosis. Also WO 00/04889 discloses that Compound (I) isuseful for reducing post-ischaemic injury of the heart and/or improving the functionalrecovery of the heart following myocardial ischaemia.

It is now considered that Compound (I) has activity in the treatment or prophylaxis ofcardiac insulin résistance or conditions associated with cardiac insulin résistance. It istherefore of potential use in the treatment or prophylaxis of microvascular angina,atherosclerosis associated with insulin résistance and in the treatment of congestive heartfailure, especially in delaying the progression of congestive heart failure, ameliorating orreversing réductions in cardiac muscular endurance and strenglh associated with congestive .heart failure and ameliorating and/or reversing the cachexie phase of congestive heart failure.

Accordingly, the invention provides a method for the treatment or prophylaxis ofcardiac insulin résistance or conditions associated with cardiac insulin résistance, in humansor non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of a PPARy agonist, such as Compound (I), ora pharmaceutically acceptable dérivative thereof.

Particular conditions associated with cardiac insulin résistance include micro vascularangina and congestive heart failure. A further condition associated with cardiac insulinrésistance is atherosclerosis associated with insulin résistance. A suitable condition associated with cardiac insulin résistance is microvascularangina. A suitable condition associated with cardiac insulin résistance is congestive heartfailure.

In the treatment or prophylaxis of congestive heart failure, the présent treatment isparticularly indicated to delay the progression of congestive heart failure, ameliorate and/orreverse réductions in cardiac muscular endurance and/or strength associated with congestiveheart failure and ameliorate and/or reverse the cachexie phase of congestive heart failure.

Suitably, the présent treatment delays the progression of congestive heart failure.

Suitably, the présent treatment améliorâtes and/or reverses réductions in cardiac muscularendurance and/or strength associated with congestive heart failure. Suitably, the présenttreatment améliorâtes and/or reverses the cachexie phase of congestive heart failure.

Suitable PPARy agonists include thiazolidinediones, especially thiazolidine-2,4-diones, that is a compound comprising a moiety of formula (A): -2- 01283

ο (A).

Suitable compounds comprising a moiety of formula (a) include compounds offormula (I):

° O) or a tautomeric form thereof and/or a pharmaceutically acceptable sait thereof and/or apharmaceutically acceptable solvaté thereof, wherein T represents an aryl or heterocyclyl 10 group optionally substituted with one or more alkyl groups, aralkyl groups or heterocyclylalkyl groups, the said alkyl, aralkyl and heterocyclylalkyl groups themselvesbeing optionally substituted.

Suitably, the carbon atom marked with an asterisk (*) in formula (I) is a chiral carbon. 15 In particular T represents a moiety selected from the list consisting of (a), (b), (c), (d),(e),(f),(g),(h) and(i):

-3- 012831

ch3

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 PPARy agonists disclosed in

European Patent Applications, Publication Numbers: 0306228, 0008203,0139421,0032128,10 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 thespécifie example thereof. The contents of these publications are included herein byreference. -4-

Thiazolidinedione PPARy agonists may exist in one of several tautomeric forms, ailof which are encompassed by the présent invention as individual tautomeric forms or asmixtures thereof. Where a PPARy agonist contains a chiral carbon, and hence exists in one ormore stereoisomeric forms or where one or more géométrie isomers exist, it will beappreciated that the method of the présent invention encompasses ail of the said forms of thePPARy agonists whether as individual isomers or as mixtures of isomers, includingracemates.

Particular examples of thiazolidinediones are those disclosed in EP 0306228 andWO94/05659. Further particular examples are the thiazolidinediones disclosed inEP0139421 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-l-benzopyran-2-yl)methoxy]phenyl]methy]]-2,4-thiazo]idinedione (ortroglitazone), 5-[4-[(l-methylcyclohexyl)methoxy)benzyl] thiazolidine-2,4-dione (orciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (orpioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (orenglitazone)

When used herein the terni PPARy agonist’relates to an agonist, such as a smallmolecular weight agonist, of the peroxisomal proliferator-activated receptor of the gammasubtype, this nuclear receptor is a member of the ligand activated transcription factor familythat include the steroid, retinoid and thyroid receptors. PPARy agonist activity may be assessed by use of the methodology disclosed byLehmann et al : Journal of Biological Chem., 270,12953-12956 (1995).

When used herein the terni ’aryl’includes phenyl and naphthyl optionally substitutedwith 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 fusedring 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 ringselected from oxygen, sulphur or nitrogen. -5- 012831

Favoured aromatic heterocyclyl groups include substituted or unsubstituted singlering aïomatic 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 fromthe group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacentcarbon atoms, together with the carbon atoms to which they are attached, may form an arylgroup, preferably a benzene ring, and wherein the carbon atoms of the aryl group representedby the said two substituents may themselves be substituted or unsubstituted.

It will be appreciated that where the abové mentioned définitions of ’aryl’,heterocyclyr and the substituents thereof differ from those in the above mentioned patentpublications with respect to the particular compounds disclosed therein, that the définitionsin the said publications prevail.

When used herein the terni halogen’ refers to fluorine, chlorine, bromine and iodine;preferably chlorine.

When used herein the terras ’alkyl’ and ’alkoxy’relate to groups having straight orbranched carbon chains, containing up to 12 carbon atoms.

When used herein the term ’acyl’ includes alkylcarbonyl groups.

Suitable alkyl groups are Cpi2 alkyl groups, especially Cpg 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 tothe term ”aryl”.

Suitable dérivatives of a PPARy agonist are pharmaceutically acceptable dérivatives,for example salts and solvatés.

Suitable dérivatives of any particular PPARy agonist include those disclosed in theabove mentioned publications.

Suitable pharmaceutically acceptable salts include salts of salts derived fromappropriate acids, such as acid addition salts, or bases.

Suitable pharmaceutically acceptable salts include métal salts, such as for examplealuminium, alkali métal salts such as lithium, sodium or potassium, alkaline earth métal saltssuch as calcium or magnésium and ammonium or substituted ammonium salts, for examplethose with lower alkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,çyçloalkylamines such as bicyclohexylamine, or withprocaine, dibenzylpiperidine,N-benzyl-b-phenethylamine, dehydroabietylamine, Ν,Ν’-bisdehydroabietylamine, -6- 012831 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 suchas the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide andpharmaceutically 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 sait.

Suitable pharmaceutically acceptable salts of Compound (I) are as disclosed in EP0306228 and WO94/05659 and include maleate salts. . Suitable pharmaceutically acceptable solvatés include hydrates.

Suitable pharmaceutically acceptable solvatés of Compound (I) are as disclosed in EP0306228 and WO94/05659 and include hydrates.

The PPARy agonists, such as the thiazolidinediones, referred to herein areconveniently prepared according to the methods disclosed in the above mentioned patentpublications in which they are disclosed: Thus Compound (I), or the tautomeric formthereof, and/or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticallyacceptable solvaté thereof, may be prepared using the processes described in EP 0306228and WO94/05659.

The salts and/or solvatés of the thiazolidinediones may be prepared and isolatedaccording to conventional procedures for example those disclosed in the, above mentioned,patent publications.

The présent invention also provides a PPARy agonist or a pharmaceuticallyacceptable dérivative thereof, for use in the treatment and/or prophylaxis of cardiac insulinrésistance or conditions associated with cardiac insulin résistance.

The présent invention also provides a PPARy agonist or a pharmaceuticallyacceptable dérivative thereof, for use in the manufacture of a médicament for the treatment.and/or prophylaxis of cardiac insulin résistance or conditions associated with cardiac insulinrésistance.

In the above mentioned method the PPARy agonist, may be administered per se or,preferàbly, as a pharmaceutical composition also comprising a pharmaceutically acceptablecarrier.

In the treatment of the invention, the PPARy agonist mentioned herein is formulatedand administered in accordance with the methods disclosed in the above mentionedpublications, patent applications and patents. -7- 012831

Accordingly, the présent invention also provides a pharmaceuticai composition forthe treatment and/or prophylaxis of cardiac insulin résistance or conditions associated withcardiac insulin résistance, which composition comprises a PPARy agonist, or apharmaceutically acceptable dérivative thereof, and a pharmaceutically acceptable carriertherefor.

As used herein the terni 'pharmaceutically acceptable’ embraces compounds,compositions and ingrédients for both human and veterinary use: for example the tenu'pharmaceutically acceptable sait’embraces a veterinarily acceptable sait.

The composition may, if desired, be in the form of a pack accompanied by written orprinted instructions for use.

Usually the pharmaceuticai compositions of the présent invention will be adapted fororal administration, although compositions for administration by other routes, such as byinjection and percutaneous absorption are also envisaged.

Particularly suitable compositions for oral administration are unit dosage forms suchas tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets,may also be used.

In accordance with conventional pharmaceuticai practice the carrier may comprise adiluent, filler, désintégrant, wetting agent, lubricant, colourant, flavourant or otherconventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose, starch, sodiumstarch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnésium stéarate,sodium lauryl sulphate or sucrose.

Suitable dosages of the PPARy agonist include the known doses for thesecompounds as described or referred to in reference texts such as the British and USPharmacopoeias, Remington’s Pharmaceuticai Sciences (Mack Publishing Co.), MartindaleThe Complété Drug Reference (London, The Pharmaceuticai Press) (for example see the3 lst Edition page 341 and pages cited therein) or the above mentioned publications or doseswhich can be determined by standard procedures.

Suitable dosages of the Compound (I) include those disclosed in EP 0306228 andWO94/05659 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. -8-

Ü1283I

The composition of the invention may be administered from 1 to 6 times a day, butmost preferably 1 or 2 times per day.

The composition of the invention may be administered from 1 îo 6 times a day, butmost 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 agentthroughout those compositions employing large quantities of fillers. Such operations are ofcourse conventional in the art. The tablets may be coated according to methods well knownin normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid préparations may be in the form of, for example, émulsions, syrups, orélixirs, or may be presented as a dry product for reconstitution with water or other suitablevehicle before use. Such liquid préparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stéarate gel, hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueousvehicles (which may include edible oils), for example almond oil, fractionated coconut oil,oily esters such as esters of glycérine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventionalflavouring or colouring agents.

For parentéral administration, fluid unit dosage forms are prepared utilizing thecompound and a stérile vehicle, and, depending on the concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions the compound can be dissolvedin water for injection and filter sterilized before filling into a suitable vial or ampoule andsealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and bufferingagents can be dissolved in the vehicle. To enhance the stability, the composition can befrozen after filling into the vial and the water removed under vacuum. Parentéralsuspensions are prepared in substantially the same manner, except that the compound issuspended in the vehicle instead of being dissolved, and sterilization cannot be accomplishedby filtration. The compound can be sterilized by exposure to ethylene oxide beforesuspending in the stérile vehicle. Advantageously, a surfactant or wetting agent is includedin 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 orprinted instructions for use. -9- 012831

The compositions are formulated according to conventional methods, such as thosedisclosed in standard reference texts, for example the British and US Pharmacopoeias,Remington’s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The ComplétéDrug Reference (London, The Pharmaceutical Press) and Harry’s Cosmeticology (Leonard 5 Hill Books).

The activity of compounds in the treatment of the présent invention can bedetercnined using known methodology, for examplê by use of procedures disclosed by EckelJ, Asskamp,B, Reinauer, H (1991) Endocrinologv 129, 345-352

Induction of insulin résistance in primary cultured adult cardiomyocytes. 10 No adverse toxicological effects are expected for the compositions or methods of the invention in the above mentioned dosage ranges. -10-

Claims (7)

1. 012831 Claims:

   1. Use of a PPARy agonist, such. as Compound (I), or a pharmaceutically acceptabledérivative thereof in the manufacture of a médicament for the treatment or prophylaxis ofcardiac insulin résistance or conditions associated with cardiac insulin résistance, inhumans or non-human mammals.
2. 2. A use according to claim 1, wherein a condition associated with cardiac insulinrésistance is selected from: microvascular angina, atherosclerosis associated with insulinrésistance and congestive heart failure.
3. 3. A use according to claim 1, wherein. in the treatment of congestive heart failurethere is provided: a delay in the progression of congestive heart failure; an ameliorationand/or reversai of réductions in cardiac muscular endurance and/or strength associated withcongestive heart failure; or an amelioration and/or reversai of the cachexie phase ofcongestive heart failure.
4. 4. A use according to claim 1, wherein the PPAR agonist is a thiazoîidinedione.
5. 5. . A use 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. 6. A use according to claim 4, wherein the PPAR agonist is Compound (I).
7. 7. A use according to claim 4, wherein the PPAR agonist is 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazoEdine-2,4-dione (or pioglitazone). -11-