KR20030019434A - Treatment and Prevention of Cardiac Insulin Resistance Associated Conditions - Google Patents

Abstract

A method of treating or preventing symptoms associated with cardiac insulin resistance or cardiac insulin resistance in a human or non-human mammal, comprising administering a non-toxic and pharmaceutically acceptable effective amount of a PPARγ agonist or a pharmaceutically acceptable derivative thereof. Symptoms related to cardiac insulin resistance are microvascular angina, atherosclerosis and congestive heart failure. Compounds include rosiclitazone, troglitazone, englitazone and pyroglitazone.

Description

Treatment and prevention of cardiac insulin resistance-related symptoms {Treatment and Prevention of Cardiac Insulin Resistance Associated Conditions}

The present invention relates to novel methods of treatment, in particular the treatment and / or prophylaxis of cardiac insulin resistance or cardiac insulin resistance related symptoms.

Increasing insulin resistance indicates impairment of normal physiological responses to insulin. It is commonly associated with diseases such as type 2 diabetes, which are highly resistant in skeletal muscle, adipose tissue and liver. In certain circumstances, however, insulin resistance is present in tissues and organs other than skeletal muscle and liver, and may optionally be present in the heart, particularly cardiac insulin resistance. In patients with diseases such as cardiac syndrome-X (a form of microvascular angina) or accelerated atherosclerosis or chronic heart failure, increased insulin resistance in the myocardium impairs the myocardium's ability to use glucose quickly and effectively for metabolism. In addition, the delicate metabolic balance in these major tissues can be worsened. Treatment of cardiac insulin resistance is thought to alleviate this metabolic stress and improve glucose absorption efficiency, thereby improving the oxidative metabolic efficiency of the myocardium. If the myocardium is ischemic and sensitive to hypoxic damage, it is believed that improvement of metabolic stress on insulin resistance helps prevent ischemic damage of the heart muscle layer.

European patent application, publication 0306228 describes certain thiazolidinedione derivatives which have been described as having particularly hypoglycemic and hypolipidemic activity and having activity in treating certain eating disorders. The compound of Example 30 of this 0306228 is 5- (4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl) -2,4-thiazolidinedione (or compound I)

In addition, European Patent Application Publication No. 0006228, No. 0008203, No. 039421, No. 032128, No. 0428312, No. 0489663, No. 0155845, No. 0778778, No. 0206020 No. 0177353, No. 0319189, No. 032331, No. 0332332, No. 0528734, No. 0,050,4; International Patent Application, Publication Nos. 92/18501, 93/02079, 93/22445, and US Pat. Nos. 5,104,888 and 56,547,52 describe certain thiazoli as described as having hypoglycemic and hypolipidemic activity. Dindione derivatives are described.

It is known that the γ-isoform (hereinafter referred to herein as PPARγ) of a receptor activated with a peroxysome proliferative agent is a member of the nuclear receptor superfamily including receptors for steroids, tyroids and retinoid hormones (Evans, Science 240, 889-895, (1988). It is also known by Chawla et al. That PPARγ is expressed early in the division of adipocytes (see Endocrinology 135, 798-800, 1994). Thiazolidinediones, such as compound I, are described as PPARγ agonistra [J. Biol. Chem., 270, 12963-12966.

U.S. Pat.No.5521201 describes that Compound I is useful for the treatment of heart disease, especially atherosclerosis. In addition, WO 00/04889 describes that Compound I is useful for reducing post-ischemic injury of the heart and / or improving the recovery of the heart function following myocardial ischemia.

In the present invention, Compound I is believed to be active in the treatment or prevention of cardiac insulin resistance or symptoms related to cardiac insulin resistance. Therefore, Compound I of the present invention potentially reduces microvascular angina, the treatment or prevention of insulin resistance related atherosclerosis and the treatment of congestive heart failure, in particular the delay of progression of congestive heart failure, myocardial endurance associated with congestive heart failure and May be used to improve or decrease reversal of ameliorative symptoms of amelioration of muscle strength or reversal and congestive heart failure.

Accordingly, the present invention includes the administration of a non-toxic and pharmaceutically acceptable effective amount of a PPARγ agonist, such as Compound I, or a pharmaceutically acceptable derivative thereof, in human or non-human mammals with symptoms related to cardiac insulin resistance or cardiac insulin resistance. Provides a method of treatment or prevention.

Certain symptoms associated with cardiac insulin resistance include microvascular angina and congestive heart failure. Another symptom associated with cardiac insulin resistance is atherosclerosis associated with insulin resistance.

A suitable symptom associated with cardiac insulin resistance is microvascular angina. A suitable symptom associated with cardiac insulin resistance is congestive heart failure.

In the treatment or prophylaxis of congestive heart failure, the treatment of the present invention in particular delays the progression of congestive heart failure, improves and / or reverses the reduction of myocardial endurance and / or muscle strength associated with congestive heart failure, and congestion. It has been shown to improve and / or reverse cachexia symptoms of sacred heart failure.

Suitably, the treatment of the present invention delays the progression of congestive heart failure. Suitably, the treatment of the present invention ameliorates and / or reverses the reduction of muscle endurance and / or muscle strength of the myocardium associated with congestive heart failure. Suitably, the treatment of the present invention ameliorates and / or reverses cachexia symptoms of congestive heart failure.

Suitable PPARγ agonists include thiazolidinediones, in particular thiazolidine-2,4-dione, which is a compound comprising the residue of formula (A).

Suitable compounds comprising residues of formula (a) include the compounds of formula (I) or tautomeric forms thereof and / or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable solvates thereof.

Where

T represents an aryl or heterocyclyl group optionally substituted with one or more alkyl, aralkyl or heterocyclylalkyl groups which may itself be optionally substituted.

Suitably, the carbon atom denoted by an asterisk (*) in formula (I) is chiral carbon.

In particular, T represents a residue selected from the group consisting of compounds of the formulas (a), (b), (c), (d), (e), (f), (g), (h) and (i) Indicates.

In particular, mention is made of the residues of the formulas (a), (b), (c), (d) and (e).

Further, the treatment of the present invention includes European Patent Application, Publication No. 0306228, No. 0008203, No. 039421, No. 0032128, No. 0428312, No. 0489663, No. 055845, No. 0257781. No. 0,020,20,0 177353,0 319189,0 032331,0 0332332,0 0528734,0 08740; PPARγ agonists described in International Patent Applications, Publication Nos. 92/18501, 93/02079, 93/22445, and US Pat. Nos. 5,104,888 and 55,547,52, in particular their specific examples. Included. The contents of these publications are incorporated herein by reference.

Thiazolidinedione PPARγ agonists may exist in one of several tautomeric forms, all of which are included in the present invention as individual tautomeric forms or as mixtures thereof. When the PPARγ agonist contains chiral carbons and is present in one or more stereoisomeric forms, or when one or more geometric isomers are present, the method of the present invention provides a method for the preparation of isomers wherein the PPARγ agonist comprises individual isomers or racemates. It will be understood to include all such forms in the form of mixtures.

Specific examples of thiazolidinediones are described in European Patent Nos. 0306228 and WO 94/05659. A further particular embodiment is thiazolidinediones described in European Patent No. 0139421 and U.S. Patent No. 5478852.

Preferred thiazolidinedione is compound I. Another specific thiazolidinedione is (+)-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-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2,4- Dione (or cyglitazone), 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).

As used herein, an agonist called “PPARγ agonist” relates to agonists such as low molecular weight agonists of receptors activated with a gamma subtype peroxysomal proliferative agent, which nuclear receptors are steroids, retinoids and thyroid receptors. It is a member of a ligand activated transcription factor family including.

PPARγ agonist activity can be assessed using the method disclosed in Lehmann et al: Journal of Biological Chem., 270, 12953-12956 (1995).

As used herein, the term "aryl" is optionally 5 or less, preferably 3 or less halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycar Phenyl and naphthyl substituted with a group selected from a carbonylalkyl, alkylcarbonyloxy or alkylcarbonyl group.

Suitable heterocyclyl groups are aromatic and non-aromatic heterocyclic groups.

Suitable non-aromatic heterocyclic groups are groups comprising a single or fused ring heterocyclic group comprising up to four hetero atoms selected from oxygen, sulfur or nitrogen in each ring, optionally fused to one or more aryl groups. .

Suitable aromatic heterocyclyl groups are substituted or unsubstituted, singly or fused ring aromatic heterocyclyl groups comprising up to four hetero atoms selected from oxygen, sulfur or nitrogen in each ring.

Aromatic heterocyclyl groups of interest include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.

In particular, aromatic heterocyclyl groups comprise one, two or three heteroatoms, in particular one or two, selected from oxygen, sulfur or nitrogen.

Suitable substituents for heterocyclyl are on up to four substituents selected from the group consisting of alkyl, alkoxy, aryl and halogen or on adjacent carbon atoms which may form an aryl group, preferably a benzene ring, with the carbon atoms to which they are attached And any two substituents, wherein the carbon atom of the aryl group represented by the two substituents can be substituted or unsubstituted.

It will be appreciated that where the above-mentioned definitions of 'aryl', 'heterocyclyl' and substituents thereof differ from the definitions relating to certain compounds disclosed in the above-mentioned patent publications, the definitions of such publications prevail.

As used herein, the term 'halogen' refers to fluorine, chlorine, bromine and iodine, preferably chlorine.

As used herein, the terms 'alkyl' and 'alkoxy' refer to groups having straight or branched carbon chains containing up to 12 carbon atoms.

As used herein, the term 'acyl' includes alkylcarbonyl groups.

Suitable alkyl groups are C _1-12 alkyl groups, in particular C _1-6 alkyl groups, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.

Suitable substituents for any alkyl group include those substituents indicated above, denoted by the term "aryl".

Suitable derivatives of PPARγ agonists are pharmaceutically acceptable derivatives such as salts and solvates.

Suitable derivatives of any particular PPARγ agonist include derivatives disclosed in the publications mentioned above.

Suitable pharmaceutically acceptable salts include salts of salts derived from suitable acids and salts derived from bases, such as acid addition salts.

Suitable pharmaceutically acceptable salts include metal salts such as aluminum; Alkali metal salts such as lithium, sodium or potassium; Alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts such as lower alkylamines such as triethylamine, hydroxy alkylamines (eg 2-hydroxyethylamine, bis- Ammonium salt or procaine, dibenzylpiperidine substituted with (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine), cycloalkylamine (eg, bicyclohexylamine) , N-benzyl-b-phenethylamine, dihydroabiethylamine, N, N'-bisdehydrobiethylamine, glucamine, N-methylglucamine or pyridine type (e.g. pyridine, collidine, quinine or Ammonium salts substituted with a base of quinoline).

Suitable acid addition salts are pharmaceutically acceptable inorganic salts such as sulfates, nitrates, phosphates, borates, hydrochlorides and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetates, tartrates, maleates, sheets Latex, succinate, benzoate, ascorbate, methane-sulfonate, α-keto glutarate and α-glycerophosphate, in particular maleate salts.

Pharmaceutically acceptable salts of compound I are as disclosed in European Patent Nos. 0206228 and WO 94/05659 and include maleate salts.

Suitable pharmaceutically acceptable solvates include hydrates.

Suitable pharmaceutically acceptable solvates of compound I are as disclosed in European Patent Nos. 0306228 and WO 94/05659 and include hydrates.

PPARγ agonists, such as thiazolidinediones, shown herein are readily prepared according to the methods disclosed in the aforementioned patent publications. Thus, Compound I or tautomeric forms thereof and / or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable solvates thereof are prepared using the methods described in EP 0306228 and WO 00/05659. I can do it.

Salts and / or solvates of thiazolidinediones can be prepared and isolated, for example, according to conventional methods disclosed in the aforementioned patent publications.

The present invention also provides a PPARγ agonist or a pharmaceutically acceptable derivative thereof for use in the treatment and / or prevention of cardiac insulin resistance or symptoms related to 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 prevention of cardiac insulin resistance or symptoms associated with cardiac insulin resistance.

In the above-mentioned methods, the PPARγ agonist can be administered by itself or preferably as a pharmaceutical composition which also comprises a pharmaceutically acceptable carrier.

In the treatment of the present invention, the PPARγ agonist referred to herein is formulated and administered according to the methods disclosed in the publications, patent applications and patents mentioned above.

Accordingly, the present invention also provides pharmaceutical compositions for the treatment and / or prevention of cardiac insulin resistance or cardiac insulin resistance related symptoms comprising a PPARγ agonist or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier thereof.

As used herein, the term 'pharmaceutically acceptable' includes compounds, compositions and components for human and veterinary use, for example the term 'pharmaceutically acceptable salts' includes veterinary acceptable salts. do.

The composition may, if desired, be in the form of a pack with written or printed instructions for use.

In general, the pharmaceutical compositions of the present invention will be applied by oral administration, although it is also envisaged as a composition for administration by other routes such as injection and transdermal absorption.

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

In accordance with conventional pharmaceutical practice the carrier may comprise diluents, fillers, disintegrants, wetting agents, lubricants, colorants, sweeteners or other conventional adjuvants.

Examples of typical carriers are microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulfate or sucrose.

Suitable dosages of PPARγ agonists are described in British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Complete Drug Reference (London, The Pharmaceutical Press) (see, e.g., 3131 341). Or a dose that can be measured by known or standard methods of the compounds described or indicated in references, such as the publications mentioned above.

Suitable dosages of compound I include the dosages disclosed in European Patent Nos. 0306228 and W0 94/05659 and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of the compound. Contains I

Particular dosages of compound I are 2 mg, 4 mg and 8 mg.

Specific dosages of troglitazone include 100 to 800 mg, for example 200, 400, 600 or 800 mg.

Specific dosages of pioglitazone include 10 to 40 mg, for example 5 to 50 mg, including 15, 20, 30 or 40 mg.

The composition of the present invention may be administered 1 to 6 times per day, but preferably 1 or 2 times per day.

Solid oral compositions can be prepared by conventional methods of blending, filling or tableting. Repeated blending operations can be used to dispense the active agent throughout the composition using a large amount of filler. This action is, of course, common in the art. Tablets may be coated according to methods well known in typical pharmaceutical practice, in particular with enteric coatings.

Oral liquid formulations may be, for example, in the form of emulsions, syrups or elixirs or may be present as dry products which liquefy with water or other suitable vehicle prior to use. Such liquid preparations include conventional additives, for example suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; Emulsifying agents such as lecithin, sorbitan monooleate or gum arabic; Non-water soluble vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; It may contain a preservative such as methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired, may contain conventional sweeteners or colorants.

In parenteral administration, liquid unit dosage forms can be prepared using the compound and sterile vehicle and suspended or dissolved in the vehicle depending on the concentration used. In the preparation of the solution, the compound may be dissolved in water for injection, sterile filtered and then filled into a suitable vial or ampoule and sealed. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. To increase the stability, the composition can be filled into a vial and the water removed under vacuum and then frozen. Parenteral suspensions are prepared in substantially the same manner as in parenteral solutions, except that the compounds are suspended in the vehicle instead of dissolving and sterilization is not performed by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

The composition may comprise 0.1% to 99% by weight, preferably 10 to 60% by weight of the active substance, depending on the method of administration.

If desired, the composition may be in the form of a pack with written or printed instructions for use.

Such compositions are described in standard references, such as 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) Formulated according to conventional methods disclosed herein.

The activity of a compound in the treatment of the present invention may be determined using known methods using methods disclosed in EckelJ, Asskamp, B, Reinauer, H (1991) Endocrinology 129, 345-352, Induction of insulin resistance in primary cultured adult cardiomyocytes. Can be measured.

No deleterious toxicological effects are expected in the compositions or methods of the present invention in the above-mentioned dosage ranges.

Claims (7)

A method of treating or preventing symptoms associated with cardiac insulin resistance or cardiac insulin resistance in a human or non-human mammal, comprising administering a non-toxic and pharmaceutically acceptable effective amount of a PPARγ agonist or a pharmaceutically acceptable derivative thereof. The method of claim 1, wherein the cardiac insulin resistance related symptoms are selected from microvascular angina, insulin resistance related atherosclerosis and congestive heart failure. The cachexia of claim 1, wherein the treatment of congestive heart failure comprises delaying the progression of congestive heart failure, ameliorating myocardial endurance and / or muscle strength reduction associated with congestive heart failure and / or reversing or congestive heart failure. Providing improvement and / or reversal of the phenomenon. The method of claim 1, wherein the PPAR agonist is thiazolidinedione. The compound of claim 4, wherein the PPAR agonist is Compound I, (+)-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-[(1-methylcyclohexyl) methoxy] benzyl] thiazoli Din-2,4-dione (or siglitazone), 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englita Zone) and 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone). The method of claim 4, wherein the PPAR agonist is Compound I. The method of claim 4, wherein the PPAR agonist is 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone). .