CN1592620A - Treating and preventing method of disease relative to cardiac insulin resistance - Google Patents

Treating and preventing method of disease relative to cardiac insulin resistance Download PDF

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CN1592620A
CN1592620A CNA008197679A CN00819767A CN1592620A CN 1592620 A CN1592620 A CN 1592620A CN A008197679 A CNA008197679 A CN A008197679A CN 00819767 A CN00819767 A CN 00819767A CN 1592620 A CN1592620 A CN 1592620A
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ppar
analeptic
heart failure
insulin resistant
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阿米特·纳思瓦尼
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SmithKline Beecham Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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 of diseases and the prevention method relevant with the heart insulin resistant
The present invention relates to novel method of treatment and be particularly related to the method that is used for the treatment of and/or prevents heart insulin resistant or the disease relevant with the heart insulin resistant.
It is unusual to the normal biological respinse appearance of insulin that insulin resistant increases representative.It is usually with relevant such as the such disease of type 2 diabetes mellitus, and wherein said opposing mainly shows in skeletal muscle, fatty tissue and the liver.Yet in some cases, insulin resistant appears in the tissue of non-skeletal muscle and liver and the organ and particularly can optionally occur with the heart insulin resistant in heart.In form such as heart syndrome-X[blood capillary angor] in such disease or suffering among the patient of the atherosclerosis of acceleration or chronic heart failure, the insulin resistant increase in the cardiac muscle has damaged myocardiumly uses metabolism fast and effectively with the ability of glucose and the weak metabolic balance in this critical tissue is aggravated.Expectation can slow down this metabolic stress to the treatment of heart insulin resistant and improve glucose absorption and the effect of myocardium oxidative metabolism thus.If myocardial ischaemia and responsive to anoxia infringement thinks that then improvement to the metabolic stress reaction of insulin resistant can help to prevent the ischemic infringement to cardiac muscle.
Disclosing some in the European patent application publication No. 0306228 has blood sugar lowering especially and impels serum lipids to reduce active and have active thiazolidine diketone derivative in some eating disorder of treatment.The chemical compound of the embodiment 30 of EP 0306228 is 5-(4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl)-2, the 4-thiazolidinedione (or ' chemical compound (I) ').
Also disclose some in the following document and thought to have blood sugar lowering and impel serum lipids to reduce active thiazolidine diketone derivative: European patent application publication No.: 0306228,0008203,0139421,0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189,0332331,0332332,0528734,0508740; International Patent Application Publication No. 92/18501,93/02079,93/22445; With U.S. Pat 5104888 and US 5478852.
γ-the isotype of peroxide known enzyme body multiplication agent activated receptors (PPAR γ hereinafter) is the member (Evans, Science 240,889-895, (1988)) who comprises the nuclear receptor superfamily of steroid hormone, thyroxin and biostearin hormone.From the paper of Chawla etc., learn the early expression PAR γ (Endocrinology 135,798-800,1994) in the adipose cell atomization in addition.From J.Biol.Chem., 270, learn among the 12963-12966 that such as the such thiazolidinediones of chemical compound (I) be PPAR γ analeptic.
Disclose chemical compound (I) among the USP 5521201 and be used for the treatment of heart disease, especially atherosclerosis.In addition, disclose among the WO 00/04889 damage after the ischemia that chemical compound (I) is used to alleviate heart and/or improve myocardial ischaemia after the functional rehabilitation of heart.
Think that at present chemical compound (I) has the activity of treatment or prevention heart insulin resistant or the disease relevant with the heart insulin resistant.It is thus in treatment or prevention blood capillary angor, the atherosclerosis relevant with insulin resistant and treating congestive heart failure, especially going down or make its reverse and improve the congestive heart failure cachexia phase and/or make and have potential purposes aspect its reverse delaying myocardium toleration that congestive heart failure development, improvement and congestive heart failure be correlated with and intensity.
Therefore, the invention provides people or inhuman mammalian heart insulin resistant or treatment of diseases or the prevention method relevant with the heart insulin resistant, this method comprise administration effectively, avirulence and pharmaceutically acceptable consumption such as chemical compound (I) or the such PPAR γ analeptic of its pharmaceutically acceptable derivant.
The specified disease relevant with the heart insulin resistant comprises blood capillary angor and congestive heart failure.Other disease relevant with the heart insulin resistant is the atherosclerosis relevant with insulin resistant.
The suitable disease relevant with the heart insulin resistant is blood capillary angor.The suitable disease relevant with the heart insulin resistance is congestive heart failure.
In the process of treatment or prevention congestive heart failure, Therapeutic Method of the present invention is proved to be especially and can delays congestive heart failure development, the improvement myocardium toleration relevant with congestive heart failure and/or intensity and go down and/or make its reverse and improve the congestive heart failure cachexia phase and/or make its reverse.
Therapeutic Method of the present invention can delay the development of congestive heart failure aptly.Therapeutic Method of the present invention can improve the aptly myocardium toleration relevant with congestive heart failure and intensity go down and/or make its reverse.Therapeutic Method of the present invention can improve the congestive heart failure cachexia phase aptly and/or make its reverse.
Suitable PPAR γ analeptic comprises thiazolidinediones, thiazolidine-2 especially, and 4-two ketones, they are the chemical compounds that comprise general formula (A) part:
Figure A0081976700051
The suitable chemical compound that comprises general formula (a) part comprises chemical compound or its tautomer and/or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable solvate of general formula (I):
Wherein the T representative can be by one or more alkyl, aralkyl or the replacement of heterocyclic radical alkyl or the aryl or the heterocyclic radical that are not replaced by their, and described alkyl, aralkyl or heterocyclic radical alkyl can be substituted or not be substituted itself.
Be chiral carbon with asterisk (*) marked carbon atoms in suitable the is general formula (I).
The T special representative is selected from (a) and (b), (c), (d), (e), (f), (g), (h) and the group of the group (i) formed:
Figure A0081976700053
Figure A0081976700061
What be to be noted that is general formula (a) and (b), (c), (d) and group (e).
What also comprise in Therapeutic Method of the present invention is the PPAR γ analeptic that is disclosed in the following document: European patent application publication No.: 0306228,0008203,0139421,0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189,0332331,0332332,0528734 and 0508740; International Patent Application Publication No. 92/18501,93/02079,93/22445 and U.S. Pat 5104888 and US5478852, especially their specific embodiment.The content of these open source literatures is incorporated herein by reference.
Thiazolidinedione PPAR γ analeptic can exist with several tautomers, and the form of ownership with single tautomer or its mixture in them includes in the present invention.If if PPAR γ analeptic contains chiral carbon and has or exist one or more geometric isomers with one or more stereoisomer forms thus, think that then method of the present invention comprises the anti-depressant described form of all PPAR γ, no matter be, all comprise racemate as single isomer or as isomer mixture.
The particular instance of thiazolidinediones is that those are disclosed in the chemical compound among EP 0306228 and the W094/05659.Other particular instance is the thiazolidinediones that is disclosed among EP 0139421 and the USP 5478852.
Preferred thiazolidinedione is chemical compound (I).
Other specific thiazolidinediones is: (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone); The 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone); 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone); Or 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-the 5-ylmethyl) thiazolidine-2,4-diketone (or englitazone).
Term " PPAR γ analeptic " refers to the anti-depressant analeptic such as the peroxisome proliferator-activated such small-molecular weight of receptor of γ hypotype when using in this article, this nuclear receptor is the member of transcription factor family who comprises the ligand activation of steroid receptor, biostearin receptor and thryoid receptor.
Can be by using Lehmann etc. at Journal of Biological Chem., 270,12953-12956 (1995) disclosed method is estimated PPAR γ stimulant activity.
Term " aryl " comprises when using in this article and can be reached 5 groups, preferred nearly 3 phenyl and naphthyls that group replaces or do not replaced by them, described group is selected from halogen, alkyl, phenyl, alkoxyl, haloalkyl, hydroxyl, amino, nitro, carboxyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl oxygen base or alkyl-carbonyl.
Suitable heterocyclic radical is the heterocyclic radical of fragrance and non-fragrance.
Suitable nonaromatic heterocycles base comprises the group of the heterocyclic radical that contains monocycle or fused rings, wherein comprises nearly 4 hetero atoms that are selected from oxygen, sulfur or nitrogen in each ring, and these heterocyclic radicals can be with one or more aryl-condensed or not with aryl-condensed.
Suitable fragrant heterocyclic radical comprises the fragrant heterocyclic radical of replacement or not substituted monocycle or fused rings, wherein comprises nearly 4 hetero atoms that are selected from oxygen, sulfur or nitrogen in each ring.
Favourable fragrant heterocyclic radical comprises replacement or the not substituted 5-7 of containing annular atoms, the monocycle fragrant heterocyclic radical of preferred 5 or 6 annular atomses.
Described fragrant heterocyclic radical is particularly including 1,2 or 3 hetero atom, especially 1 or 2 hetero atoms, and it is selected from oxygen, sulfur or nitrogen.
The suitable substituents that is used for described heterocyclic radical comprises nearly 4 substituent groups that are selected from the group of following groups composition: alkyl, alkoxyl, aryl and halogen; Or any two substituent groups on the adjacent carbon atom can form aryl, preferred phenyl ring with the carbon atom that they connected and wherein can be substituted or not be substituted by the carbon atom itself in the aryl of described two substituent groups representative.
Be understandable that if above-mentioned " aryl ", " heterocyclic radical " and substituent definition thereof are different from the above-mentioned patent application corresponding to those substituent definition of disclosed specific compound wherein, then according to the definition in the described open source literature.
Term " halogen " refers to fluorine, chlorine, bromine and iodine when using in this article; Preferred chlorine.
Term " alkyl " and " alkoxyl " refer to the nearly group of 12 carbon atoms that contains that has the straight or branched carbochain when using in this article.
Term " acyl group " comprises alkyl-carbonyl when using in this article.
Suitable alkyl is C 1-12Alkyl, especially C 1-6Alkyl, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group or the tert-butyl group.
The suitable substituents that is used for any alkyl comprises that those above-mentionedly relate to the substituent group that term " aryl " illustrates.
Suitable PPAR γ analeptic derivant is pharmaceutically acceptable derivant, for example salt and solvate.
The anti-depressant suitable derivant of the PPAR γ of any specific comprises disclosed chemical compound in those above-mentioned open source literatures.
Suitable pharmaceutically acceptable salt comprises that the salt such as sour addition derives from the salt of suitable acid like this or derives from the salt of suitable alkali.
Suitable pharmaceutically acceptable salt comprises: slaine, such as, for example aluminum salt; Alkali metal salt is such as lithium, sodium or potassium salt; Alkali salt is such as calcium or magnesium salt; With the ammonium salt of ammonium salt or replacement, for example those with such as the such low alkyl group amine of triethylamine, the salt that forms such as the such hydroxyl amine of 2 hydroxy ethylamine, two-(2-ethoxy)-amine or three-(2-ethoxy)-amine, such as the such cycloalkyl amine of dicyclohexyl amine; Or with procaine, dibenzyl piperidines, N-benzyl-b-phenethyl amine, dehydroabietylamine, N, the salt that N '-two dehydroabietylamines, glycosamine, N-methylglucosamine form; Or with the salt that forms such as the such pyridine type alkali of pyridine, collidine, quinine or quinoline.
The salt of suitable sour addition comprises such as the pharmaceutically acceptable like this inorganic acid addition salt of sulfate, nitrate, phosphate, borate, hydrochlorate and hydrobromate with such as the salt of acetate, tartrate, maleate, citrate, succinate, benzoate, Ascorbate, mesylate, α-Tong Jiwuersuan salt and the pharmaceutically acceptable like this organic acid addition of glycerophosphate, especially maleate.
The suitable pharmaceutically acceptable salt of chemical compound (I) is as disclosed salt among EP 0306228 and the WO94/05659 and comprises maleate.
Suitable pharmaceutically acceptable solvate comprises hydrate.
The suitable pharmaceutically acceptable solvate of chemical compound (I) is as disclosed solvate among EP 0306228 and the WO94/05659 and comprises hydrate.
Prepare the PPAR γ analeptic that this paper relates to expediently according to disclosed method in the above-mentioned patent publication us such as thiazolidinediones, wherein open: as can to use that disclosed method prepares chemical compound (I) or its tautomer and/or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable solvate among EP 0306228 and the WO94/05659.
Can be according to disclosed conventional method preparation and salt that separates described thiazolidinediones and/or solvate in the above-mentioned patent publication us for example.
The present invention also provides PPAR γ analeptic or its pharmaceutically acceptable derivant, and it is used for the treatment of and/or prevents heart insulin resistant or the disease relevant with the heart insulin resistant.
The present invention also provides PPAR γ analeptic or its pharmaceutically acceptable derivant, and it is used to prepare the medicine that treats and/or prevents heart insulin resistant or the disease relevant with the heart insulin resistant.
In said method, can administration PPAR γ analeptic itself or preferred as the form administration PPAR γ analeptic that also contains the pharmaceutical composition that can accept carrier on the medicine.
In Therapeutic Method of the present invention, according to disclosed method preparation and administration PPAR γ as herein described analeptic in above-mentioned open source literature, patent application and the patent.
Therefore, the present invention also provides the pharmaceutical composition that is used for the treatment of and/or prevents heart insulin resistant or the disease relevant with the heart insulin resistant, and said composition comprises PPAR γ analeptic or its pharmaceutically acceptable derivant and pharmaceutically acceptable carrier.
Term used herein " pharmaceutically acceptable " comprises chemical compound, compositions and the component that is used for people and veterinary drug application: for example term " pharmaceutically acceptable salt " comprises acceptable salt on the veterinary drug.
If desired, compositions can be the form of the medicated bag of the subsidiary application specifications that writing is arranged or print.
Pharmaceutical composition of the present invention is generally suitable for oral administration, but, also can be by such as by such other administration compositions of injection, and Transdermal absorption also be pay close attention to.
Specially suitable oral administration compositions is such as tablet and the such unit dosage forms of capsule.Can also use such as other the so fixed unit dosage forms of powder that is present in the sachet.
According to the medicinal practice of routine, described carrier can comprise diluent, filler, disintegrating agent, wetting agent, lubricant, coloring agent, flavoring agent or other adjuvant commonly used.
Typical carrier comprises for example microcrystalline Cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, crospovidone, magnesium stearate, sodium lauryl sulphate or sucrose.
The anti-depressant suitable dose of PPAR γ comprises the known dosage of these chemical compounds described in handbook or with reference to these handbook: such as Britain and American Pharmacopeia; Remington ' s PharmaceuticalSciences (Mack Publishing Co.), Martindale The Complete Drug Reference (London, The Pharmaceutical Press) (for example, referring to the 31st edition the 341st page and the page or leaf wherein quoted) or above-mentioned list of references; Maybe can be by the dosage of standard method mensuration.
The optimal dose of chemical compound (1) comprises that those are disclosed in disclosed dosage and 1,2,3,4,5,6,7,8,9,10 among EP 0306228 and the WO94/05659,11 or the chemical compound (I) of 12mg.
The given dose of chemical compound (1) is 2mg, 4mg and 8mg.
The given dose of troglitazone comprises 100-800mg, such as 200,400,600 or 800mg.
The given dose of pioglitazone comprises 5-50mg, comprises 10-40mg, such as 15,20,30 or the pioglitazone of 40mg.
Can be with compositions of the present invention administration every day 1-6 time, but most preferably administration every day 1 time or 2 times.
Can be with compositions of the present invention administration every day 1-6 time, but most preferably administration every day 1 time or 2 times.
Can prepare solid oral composition by the conventional method of mixing, filling or tabletting.Multiple married operation can be used for described activating agent is well-dispersed in the compositions that those use a large amount of filleies.Commonly used in this generic operation yes this area.Can give tablet coating, particularly enteric coated according to well-known method in the medicinal practice commonly used.
Oral liquid can be that the such form of example emulsion, syrup or elixir maybe can be made oral liquid water or the dissolved again dry products of other appropriate carrier before use.This class I liquid I preparation can contain typical additives, such as: suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent, for example lecithin, dehydrating sorbitol monooleate, or arabic gum; Nonaqueous carrier (can comprise edible oil), for example Oleum Cocois of almond oil, fractionated, grease class are such as glycerol, propylene glycol or alcoholic acid esters; Antiseptic, for example methyl parahydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid; And can also contain flavoring agent commonly used or coloring agent if desired.
In order to carry out parenterai administration, use described chemical compound and sterile carrier to prepare liquid unit dosage forms and different along with used concentration, can be by described chemical compound being suspended in or being dissolved in and preparing described liquid unit dosage forms in the described carrier.In preparation solution process, described chemical compound can be dissolved in water for injection and before pack into suitable bottle or ampoule and sealing, carry out aseptic filtration.Favourable situation is will be dissolved in described carrier such as the such adjuvant of local anesthetic, antiseptic and buffer agent.In order to improve stability, can be behind bottle that said composition is packed into lyophilizing and under vacuum, remove and anhydrate.Prepare non-intestinal suspension according to substantially similar mode, but described reactive compound is not dissolved in described carrier but is suspended in described carrier and can not finishes sterilization by filtering.Can sterilize by described chemical compound is contacted with oxirane, after this it is suspended in sterile carrier.Advantageously in said composition, comprise surfactant or wetting agent so that help the uniform distribution of described chemical compound.
Compositions can contain the described active substance of 0.1%-99% weight, preferred 10-60% weight, and this depends on medication.
If desired, compositions can be the form of the medicated bag of the subsidiary application specifications that writing is arranged or print.
Prepare described compositions according to conventional method, be disclosed in method in the canonical reference book such as those, for example: Britain and American Pharmacopeia, Remington ' s Pharmaceutical Sciences (MackPublishing Co.), Martindale The Complete Drug Reference (London, ThePharmaceutical Press) and Harry ' s Cosmetiology (leonard Hill Books).
Can use known method, for example pass through to use Eckel J, Asskamp, B, Reinauer, H are at Endocrinology 129, and disclosed method is measured the activity of the chemical compound in the Therapeutic Method of the present invention among the 345-352 (1991).
With regard to the present composition or method in being in above-mentioned dosage range, do not predict bad toxicological effect.

Claims (7)

1. be used for people or inhuman mammalian heart insulin resistant or treatment of diseases or the prevention method relevant with the heart insulin resistant, this method comprise administration effectively, avirulence and pharmaceutically acceptable consumption such as chemical compound (I) or the such PPAR γ analeptic of its pharmaceutically acceptable derivant.
2. the process of claim 1 wherein that the disease relevant with the heart insulin resistant is selected from: blood capillary angor, the atherosclerosis and the congestive heart failure of being correlated with insulin resistant.
3. the process of claim 1 wherein provides in the process of treatment congestive heart failure: delay the congestive heart failure development; Improving myocardium toleration relevant with congestive heart failure and/or intensity goes down and/or makes its reverse; Or improve the congestive heart failure cachexia phase and/or make its reverse.
4. the process of claim 1 wherein that described PPAR analeptic is thiazolidinedione.
5. the method for claim 4, wherein said PPAR analeptic is selected from following compounds: chemical compound (I), (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone); The 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone); 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-the 5-ylmethyl) thiazolidine-2,4-diketone (or englitazone); Or 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone).
6. the method for claim 4, wherein said PPAR analeptic is chemical compound (I).
7. the method for claim 4, wherein said PPAR analeptic is 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone).
CNA008197679A 2000-06-16 2000-06-16 Treating and preventing method of disease relative to cardiac insulin resistance Pending CN1592620A (en)

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