WO2006117076A1

WO2006117076A1 - Use of indolin-phenylsulfonamide derivatives

Info

Publication number: WO2006117076A1
Application number: PCT/EP2006/003572
Authority: WO
Inventors: Elke Dittrich-Wengenroth; Helmut Haning
Original assignee: Bayer Healthcare Ag
Priority date: 2005-04-30
Filing date: 2006-04-19
Publication date: 2006-11-09
Also published as: DE102005020229A1

Abstract

The present application relates to new uses of substituted indolin-phenylsulfonamide derivatives for the prevention and/or treatment of diseases.

Description

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Use of indoline-phenylsulfonamide derivatives

The present application relates to novel uses of substituted indoline-phenylsulfonamide derivatives as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of diseases.

PPAR delta activating compounds and their use are known and are described in WO 04/005253.

WO 00/23407 discloses PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes. In WO 93/15051 and EP 636 608-A1, 1-benzenesulfonyl-l, 3-dihydroindol-2-one derivatives are described as vasopressin and / or oxytocin antagonists for the treatment of various diseases.

The object of the present invention was to provide new uses of, in particular, known compounds which can be used as PPAR delta modulators.

It has now been found that PPAR-delta modulators, in particular compounds of the general formula (I)

in which

A is the group CR ¹ 'or N,

wherein

R ¹ 'is hydrogen or (C _r C ₄₎ -alkyl,

X is O, S or CH ₂ ,

R ^{1 is} (C ₆ -C 10) -aryl or 5- to 10-membered heteroaryl having up to three heteroatoms from the series N, O and / or S, which in turn are each one to three times, the same or different, by substituents selected from the group halogen, cyano, nitro, (Ci-C ₆₎ - alkyl, which may in turn be substituted by hydroxyl, (C] -Ce) -alkoxy, phenoxy, - -

Benzyloxy, trifluoromethyl, trifluoromethoxy, (C ₂ -C ₆₎ alkenyl, phenyl, benzyl, (Ci-Ce) - alkylthio, (C _r _C6) alkylsulfonyl, (C _r C ₆₎ alkanoyl, (Ci-C ₆ ) -alkoxycarbonyf, carboxyl, amino, (Ci-C ₆ ) -acylamino, mono- and di- (C iC ₆ ) -alkylamino and 5- to 6-membered heterocyclyl having up to two heteroatoms from the series N, O and / or S can be substituted,

or represents a group of the formula,

R ² and R ^{3 are the} same or different and are independently hydrogen or (C _r C ₆ ) - alkyl or together with the carbon atom to which they are attached, a 3- to 7-membered, spiro-linked cycloalkyl ring form,

R ⁴ is (C ₆ _r C) alkyl or hydrogen,

R ⁵ is (C ₆ _r C) alkyl or hydrogen,

R ^{6 is} hydrogen or (C 1 -C ₆ ) -alkyl,

R ⁷ is hydrogen, (C, -C ₆₎ alkyl, (C _r _C6) -alkoxy or is halogen,

R ⁸ and R ^{9 are} identical or different and independently of one another represent hydrogen or (C 1 -C ₄ ) -alkyl,

and

R ^{10 is} hydrogen or a hydrolyzable group which can be degraded to the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, solvates and solvates of the salts,

Particularly suitable for the treatment and prevention of coronary heart disease, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or stenting. The compounds of the formula (I) according to the invention are preferably suitable for the treatment of stroke, CNS disorders, Alzheimer's disease, osteoporosis, arteriosclerosis and hypercholesterolemia, for increasing pathologically low HDL levels and for lowering elevated triglyceride and LDL levels. In addition, they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinaemia, dyslipidemia and high blood pressure), liver fibrosis and cancer. In addition, the compounds of formula (I) can be used to treat elevated levels of postprandial plasma triglycerides, combined hyperlipidemias, insulin-dependent diabetes, non-insulin-dependent diabetes, hyperinsulinemia, insulin resistance, and diabetic sequelae such as retinopathy, nephropathy, and neuropathy. especially for the treatment of obesity in (suckle) animals, and can be used as medicaments or for the preparation of pharmaceutical formulations for the treatment of these diseases.

It has also been found that other independent risk factors for cardiovascular diseases, such as ischemia, myocardial infarction, angina pectoris, heart failure, increased levels of fibrinogen and low density LDL and increased levels of plasminogen activator inhibitor 1 (PAI-I), by the PPAR-delta modulators, in particular compounds of the general formula (I), can be treated.

In addition, the PPAR-delta modulators, in particular compounds of the general formula (I), can also be used for the treatment and / or prevention of microvascular and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thromboses, edemas, cancers (skin cancer, Liposarcoma, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract), neurodegenerative disorders (stroke, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), inflammatory diseases, immune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), kidney diseases (glomerulonephritis), thyroid diseases, diseases of the pancreas (pancreatitis), skin diseases (psoriasis, acne, eczema, neurodermatitis, dermatitis, keratitis, scarring, Wart formation, chilblains), viral diseases (HPV, HCMV, HTV, HAV, HBV, HCV), cachexia, gout, incontinence as well as wound healing and angiogenesis.

Further therapeutic fields for the PPAR-delta modulators, in particular compounds of the general formula (I), are also the edema treatment (fluid retention) and the improvement of endurance performance.

In the context of the invention, in the definition of R ^10, a hydrolyzable group means a group which, in particular in the body, leads to a conversion of the -C (O) OR ^{10 group} into the corresponding carboxylic acid (R ¹⁰ = hydrogen). Such groups are exemplary and preferably: benzyl, (C _r C ₆ ) alkyl or (C ₃ -C ₈ ) -cycloalkyl, each optionally mono- or polysubstituted, identical or different, by halogen, hydroxy, amino, (C _r C ₆₎ alkoxy, carboxyl, (Ci-C ₆₎ -alkoxycarbonyl, (C _r C6) alkoxycarbonylamino or (C _r C ₆₎ alkanoyloxy substituted - -

are, or in particular (C 1 -C ₄ ) -alkyl, which is optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, amino, (C 1 -C ₄ ) -alkoxy, carboxyl, (C 1 -C ₄ ) -alkoxycarbonyl , (C 1 -C ₄ ) -alkoxycarbonylamino or (C 1 -C ₄ ) -alkanoyloxy.

(C ₁ -Cg) -AlkVl and (C ₁ -Q) -AlkVl in the context of the invention are a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. By way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl and t-butyl.

(C 1 -C 5 -alkenyl in the context of the invention represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms, a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms being preferred. but-2-en-l-yl.

(CyCgVcycloalkyl in the context of the invention is a monocyclic cycloalkyl group having 3 to 8 carbon atoms, by way of example and by preference: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(Cfi-Cιn) -aryl is in the context of the invention an aromatic radical having preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C ₁ -Cg) -AlkoxyV and (C ₁ -Cd) -alkoxy in the context of the invention are a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

In the context of the invention, (C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkoxycarbonyl represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group Examples which may be mentioned by preference include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

(Ci-Cfi) -Alkoxycarbonylamino and (-CC) alkoxycarbonylamino in the context of the invention represent an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and via which Carbonyl group is linked. Preference is given to an alkoxycarbonylamino radical having 1 to 4 carbon atoms. By way of example and preferably mention may be made of: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.

in the context of the invention is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position. Preference is given to a straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.

(C _j -CfiVAlkanoyloxy and (CVCaVAlkanoyloxy are in the context of the invention a straight-chain or branched alkyl radical having from 1 to 6 or 1 to 4 carbon atoms which carries a doubly attached oxygen atom in the 1-position and in the 1-position Preference is given to an alkanoyloxy radical having 1 to 4 carbon atoms and by way of example and by way of example: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

Mono- (CV (_V) -alkylamino and mono- (CV (-V) -alkylamino in the context of the invention represent an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms is a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms and may be mentioned by way of example and preferably: methylamino, ethylamino, n-propylamino, isopropylamino and t-butylamino.

Di- (Ci-Cfi) -Alkylamino and di (-C-CV) alkylamino are in the context of the invention for an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms exhibit. Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred. Examples which may be mentioned by way of example and with preference: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N- Ethyln-pentylamino and Nn-hexyl-N-methylamino.

(dVCO-acylamino in the context of the invention stands for an amino group having a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and is linked via the carbonyl group, preference is given to an acylamino radical having 1 to 2 carbon atoms Preferred are: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

(C 1 -C 4 -alkylthio in the context of the invention represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms, preferably a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Propylthio, isopropylthio, t-butylthio, n-pentylthio and n-hexylthio. - -

(Cr-CV) -alkylsulfonyl in the context of the invention represents a straight-chain or branched alkylsulfonyl radical having 1 to 6 carbon atoms. Preferred is a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms. By way of example and by way of preference: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

5- to 10-membered or 5- to 6-membered heteroaryl having up to 3 or up to 2 identical or different heteroatoms from the series N, O and / or S is in the context of the invention for a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic), which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heteroaromatic. Examples which may be mentioned are: furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridyl nyl, quinazolinyl, quinoxalinyl. Preference is given to 5- to 6-membered heteroaryl radicals having up to two nitrogen atoms, for example imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

5- to 6-membered heterocyclyl having up to 2 heteroatoms from the series N, O and / or S is in the context of the invention a saturated heterocycle which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heterocycle. By way of example and by way of preference: tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

Depending on the substitution pattern, the compounds used according to the invention may exist in stereoisomeric forms which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers as well as their respective mixtures. The racemic forms can be separated as well as the diastereomers in a known manner in the stereoisomerically uniform components.

Furthermore, certain compounds may exist in tautomeric forms. This is known to those skilled in the art, and such compounds are also included within the scope of the invention.

The compounds used according to the invention can also be present as salts. In the context of the invention, physiologically acceptable salts are preferred. Physiologically acceptable salts may be salts of the compounds used according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be salts of the compounds according to the invention with bases, for example metal or ammonium salts. Preferred examples are alkali metal salts (eg sodium or potassium salts), alkaline earth salts (eg magnesium or calcium salts), and ammonium salts derived from ammonia or organic amines such as ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds used according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.

Preference is given to compounds of the general formula (I) in which

A is the group CR ¹¹ or N,

wherein

R ¹ 'is hydrogen or methyl,

X stands for O or S,

R ^{1 is} phenyl or 5- to 6-membered heteroaryl having up to two heteroatoms from the series N, O and / or S, which in turn each one to two times, the same or different, by substituents selected from the group Fluorine, chlorine, cyano,

(C 1 -C ₄ ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, vinyl, phenyl, benzyl, methylthio, methylsulfonyl, acetyl, propionyl, (C 1 -C ₄ ) -alkoxycarbonyl, amino, acetylamino, mono- and di- ( C 1 -C ₄ ) -alkylamino may be substituted, R ² and R ^{3 are the} same or different and are independently hydrogen or (Ci-C ₄ ) - alkyl or together with the carbon atom to which they are attached, a 5- to 6-gigen, spiro-linked cycloalkyl ring form,

R ^{4 is} hydrogen or methyl,

R ^{5 is} hydrogen, methyl or ethyl,

R ^{6 is} hydrogen or methyl,

R ^{7 is} hydrogen, (C 1 -C ₄ ) -alkyl, (C 1 -C ₄ ) -alkoxy, fluorine or chlorine,

R ⁸ and R ^{9 are the} same or different and independently of one another represent hydrogen or methyl,

and

R ^{10 is} hydrogen.

Particular preference is given to compounds of the general formula (I) in which

A is CH or N,

X stands for O,

R ^{1 is} phenyl or pyridyl, which in turn each one to two times, same or different, substituted by substituents selected from the group fluorine, chlorine, methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, methylthio, amino and dimethylamino substituted could be,

R ^{2 is} hydrogen or methyl,

R ^{3 is} methyl, isopropyl or tert-butyl,

or

R ² and R ³ together with the carbon atom to which they are attached form a spiro-linked cyclohexane ring,

R ^{4 is} hydrogen or methyl,

R ^{5 is} hydrogen, methyl or ethyl, R ^{6 is} hydrogen or methyl,

R ^{7 is} methyl,

R ⁸ and R ^{9 are} each hydrogen,

and

R ^{10 is} hydrogen.

The radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the particular combinations of the radicals indicated.

Of particular importance are compounds of the formula (I-A)

in which

R ^{2 is} hydrogen,

R ^{3 is} methyl, isopropyl or tert-butyl,

or

R ² and R ^{3 are} both methyl or together with the carbon atom to which they are attached form a spiro-linked cyclohexane ring,

and

A, R ¹ , R ⁴ , R ⁵ and R ^{6 are} each as defined above.

Very particular preference is given to the compounds listed below: Examples:

example 1

[4 - ({3-Isopropyl-7-methyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) -2-methylphenoxy-acetic acid

Example 2

[2-Methyl-4 - ({2,3,7-trimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -sulfonyl) -phenoxy] -acetic acid

Example 3

[4 - ({3,7-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) -2-methylphenoxy] acetic acid

Example 4

[4 - ({3-Isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyo [3,2-b] pyridin-1-yl} sulfonyl) -2-methylphenoxy] acetic acid

Example 5

(4 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-3-spiro-r-cyclohexyl-1H-indol-1-yl] sulfonyl} -2-methylphenoxy) -acetic acid

Example 6

(4- {[5- (4-Methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] sulfony1} -2-methylphenoxy) -acetic acid

Example 7

(4 - {[5- (4-trifluoromethylphenyl) -3,3-dimethyl-2,3-dihydro-1H-indol-1-yl] -sulfonyl} -2-methylphenoxy) -acetic acid

as well as the exemplary embodiments 8-96 listed in the following table: Insert Excel table Example 8-96 (Page 70-95) Le A 35987 a

-13-

-14-

-15-

- -

-17-

-18-

- -

- -

- -

-22-

-23-

-24-

-25-

-26-

-27-

-28-

-29-

-30-

-31-

-32-

-33-

- -

-35-

-36-

- -

-38-

- 39 -

The compounds of the general formula (I), (I-A) and the compounds listed individually are known and can be prepared by the processes described in WO-04/005253.

In particular, the compounds of formula (I) show a surprising and valuable pharmacological spectrum of action and can therefore be used in the indications mentioned in humans and animals.

Compounds which activate PPAR delta, in particular the compounds of the formula (I), are particularly suitable for the treatment of coronary heart disease, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or stenting. The compounds of the formula (I) according to the invention are preferably suitable for the treatment of stroke, CNS disorders, Alzheimer's disease, osteoporosis, arteriosclerosis and hypercholesterolemia, for increasing pathologically low HDL levels and for lowering elevated triglyceride and LDL levels. In addition, they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and high blood pressure), liver fibrosis and cancer.

Moreover, the compounds of formula (I) can be used to treat elevated levels of postprandial plasma triglycerides, combined hyperlipidemias, insulin-dependent diabetes, non-insulin-dependent diabetes, hyperinsulinemia, insulin resistance and diabetic sequelae such as retinopathy, nephropathy and neuropathy. Particularly noteworthy here is the treatment of obesity in (mammals) animals.

Other independent risk factors for cardiovascular disease that can be treated by the compounds mentioned are ischemia, myocardial infarction, angina pectoris, heart failure, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator inhibitor 1 (PAI-I).

In addition, the compounds mentioned can also for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thrombosis, edema, cancer (skin cancer, liposarcoma, carcinomas of the gastrointestinal tract, liver, pancreas , Lung, kidney, ureter, prostate and genital tract), neurodegenerative disorders (stroke, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), inflammatory diseases, immune disorders (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), kidney disease (glomerulonephritis), thyroid disease, diseases of the pancreas (pancreatitis), skin diseases (psoriasis, acne, eczema, atopic dermatitis, dermatitis, keratitis, scarring, wart formation, chilblains), viral diseases (HPV, - 40 -

HCMV, HIV, HAV, HBV, HCV), cachexia, gout, incontinence as well as wound healing and angiogenesis. Further therapeutic fields for the compounds mentioned are edema treatment (fluid retention) and the improvement of endurance performance.

The compounds mentioned can be used alone or as required in combination with other active substances, preferably from the group of chemokine receptor antagonists, P38 kinase inhibitors, NPY agonists, orexin agonists, PAF-AH inhibitors, CCK-I receptor antagonists , Leptin receptor agonists, LTB4 receptor antagonists, analgesics, anti-depressants and other psychotropic drugs.

The compounds mentioned are preferably each with an antidiabetic agent or several antidiabetics, which are mentioned in the Red List 2002 / π, Chapter 12, and by way of example and preferably those from the group glucosidase inhibitors, the CCK-1 receptor agonists and Leptin receptor agonists combined.

In a preferred embodiment of the invention, said compounds are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.

Antithrombotic agents are preferably understood as meaning compounds from the group of anticoagulants.

In a preferred embodiment of the invention, the compounds mentioned are used in combination with a factor Xa inhibitor, such as by way of example and preferably BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-31 12, YM-150, KFA - 1982, EMD-503982, MCM-17, MLN-1021, SSR-126512 or SSR-128428.

By blood pressure lowering agents are meant, by way of example and by way of preference, compounds from the group of alpha-blockers blockers, beta-receptor blockers, phosphodiesterase inhibitors, sGC stimulators / activators, enhancers of cGMP levels and the aldosterone antagonists / mineralocorticoid receptor antagonists ,

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with an antagonist of the alpha 1 receptors such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds mentioned are used in combination with a beta-receptor blocker, such as, by way of example and by way of preference, timolol,

Pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, - -

Carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

Among the lipid metabolizing agents are exemplified and preferably compounds from the group of RXR modulators, FXR modulators, LXR modulators, ATP citrate lyase inhibitors, leptin receptor agonists, cannabinoid receptor 1 antagonists, bombesin receptor antagonists. Agonists, bile acid reabsorption inhibitors, agonists of the niacin receptor and histamine receptor agonists and radical scavengers understood.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melamine, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, said compounds are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, said compounds in combination with a PPAR alpha agonists such. For example, the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate, gemfibrozil or as exemplified and preferably GW 590735, GW 641597, DRF-10945verabreicht.

In a preferred embodiment of the invention, said compounds are administered in combination with a CETP inhibitor such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, said compounds are administered in combination with an antagonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Acifran or Radecol.

In a preferred embodiment of the invention, said compounds are used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, said compounds are administered in combination with an antioxidant / radical catalyst, such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150. - -

In a preferred embodiment of the invention, said compounds are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.

For the application of the compounds mentioned all the usual forms of administration are possible, i. oral, parenteral, inhalative, nasal, sublingual, rectal, external, e.g. transdermally, or locally as e.g. for implants or stents. In parenteral administration, intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, should be mentioned in particular. Preference is given to oral or parenteral administration. Very particular preference is given to oral administration.

Here, the active ingredients can be administered alone or in the form of preparations. For oral administration are useful as preparations u.a. Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. In this case, the active ingredient must be present in such an amount that a therapeutic effect is achieved. In general, the active compound may be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight. In particular, the concentration of the active ingredient should be 0.5 to 90% by weight, i. the active substance should be present in sufficient quantities to reach the stated dose latitude.

For this purpose, the active compounds can be converted in a conventional manner into the usual preparations. This is done using inert, non-toxic, pharmaceutically suitable excipients, adjuvants, solvents, vehicles, emulsifiers and / or dispersants.

As adjuvants may be mentioned, for example: water, non-toxic organic solvents such. Paraffins, vegetable oils (eg sesame oil), alcohols (eg ethanol, glycerine), glycols (eg polyethylene glycol), solid carriers such as natural or synthetic minerals (eg talc or silicates), sugars (eg lactose), emulsifiers, dispersants (eg polyols) vinylpyrrolidone) and lubricants (eg, magnesium sulfate).

Of course, in the case of oral administration, tablets may also contain additives such as sodium citrate together with adjuvants such as starch, gelatin and the like. Aqueous preparations for oral administration may also be treated with flavor enhancers or colorants.

In the case of oral administration, dosages of 0.001 to 5 mg / kg, preferably of 0.005 to 3 mg / kg of body weight, per 24 hours are preferably applied. - 43 -

The following exemplary embodiments illustrate the invention. The invention is not limited to the examples.

Claims

- Patent claims

1. Use of PPAR-delta modulators for the preparation of pharmaceutical formulations for the treatment and prevention of elevated levels of postprandial plasma triglycerides, combined hyperlipidemias, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, obesity ( Obesity) and diabetic sequelae such as retinopathy, nephropathy and neuropathy.

2. Use of PPAR-delta modulators for the preparation of pharmaceutical formulations for the treatment and prevention of cardiovascular diseases, from the group ischemia, myocardial infarction, angina pectoris, heart failure, cardiac insufficiency, restenosis, increased levels of fibrinogen and low-density LDL and increased concentrations of plasminogen activator inhibitor 1 (PAI-I.

3. Use of PPAR-delta modulators for the preparation of pharmaceutical formulations for the treatment and prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thrombosis, edema,

Cancers (skin cancer, liposarcoma, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract), neurodegenerative disorders (stroke, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis ), inflammatory diseases, immune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis,

Asthma), kidney diseases (glomerulonephritis), thyroid diseases, diseases of the pancreas (pancreatitis), skin diseases (psoriasis, acne, eczema, atopic dermatitis, dermatitis, keratitis, scarring, warts, chilblains), viral diseases (HPV, HCMV, HTV, HAV, HBV , HCV), cachexia, gout, incontinence as well as wound healing and angiogenesis.

4. Use of PPAR-delta modulators for the preparation of drug formulations for fluid retention and for improving endurance performance.

5. Use according to one of claims 1 to 4, characterized in that as PPAR delta modulators compounds of the formula (I) - 45 -

in which

A is the group CR ¹¹ or N,

wherein

R ^{11 is} hydrogen or (C 1 -C ₄ ) -alkyl,

X is O, S or CH ₂ ,

R ^{1 represents} (C 6 -C 10) -aryl or represents 5- to 10-membered heteroaryl having up to three heteroatoms from the series N, O and / or S, which in turn are each one to three times, identical or different, by substituents selected from the group consisting of halogen, cyano, nitro, (C 1 -C 6) -alkyl, which in turn may be substituted by hydroxyl, (C ₁ -C 6) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, (C ₂ - C ₆₎ alkenyl, phenyl, benzyl, (C ₁ -C ₆₎ alkylthio, (Ci-C ₆ onyl) -Alkylsulf-, (Ci-C ₆₎ alkanoyl, (C _r C6) alkoxycarbonyl, carboxyl, Amino, (C) -Co) -Acylamino, mono- and di (Ci-C ₆ ) -alkylamino and 5- to 6-gIiedriges heterocyclyl substituted with up to two heteroatoms from the series N, O and / or S. could be,

or is a group of the formula \ JU Λ,

R ² and R ^{3 are the} same or different and independently of one another represent hydrogen or (C 1 -C 6) -alkyl or together with the carbon atom to which they are attached form a 3 to 7-membered, spiro-linked cycloalkyl ring,

R ⁴ is (C ₆ _r C) alkyl or hydrogen,

R ^{5 is} hydrogen or (C ₁ -C 6) -alkyl,

R ⁶ is (C ₆ _r C) alkyl or hydrogen, - -

R ⁷ is hydrogen, (C _r _C6) alkyl, (C _r C _6> alkoxy or halogen,

R ⁸ and R ⁹ are identical or different and independently of one another are hydrogen or (C _r C ₄₎ alkyl,

and

R ^{10 is} hydrogen or a hydrolyzable group corresponding to the corresponding

Carboxylic acid can be broken down,

and their pharmaceutically acceptable salts, solvates and solvates of the salts used.

6. Use according to claim 5, characterized in that compounds of the formula (I-A)

in which

R ^{2 is} hydrogen,

R ^{3 is} methyl, isopropyl or tert-butyl,

or

R ² and R ^{3 are} both methyl or together with the carbon atom to which they are attached form a spiro-linked cyclohexane ring, and A, R ¹ , R ⁴ , R ⁵ and R ^{6 are} each as defined in claim 5 Have meanings.

7. Medicaments for the treatment of the diseases mentioned in claims 1 to 4, comprising at least one PPAR-delta modulator and inert, non-toxic, pharmaceutically suitable excipients, adjuvants, solvents, vehicles, emulsifiers and / or dispersants. - -

8. Medicaments for the treatment of the diseases mentioned in claims 1 to 4, comprising at least one PPAR-delta modulator and additionally at least one further active ingredient.

Method for the prevention and treatment of diseases as described in claims 1 to 4, characterized in that PPAR delta modulators such as the compounds of the formula (I) or (IA) as defined in claims 5 and 6 are obtained Let living beings act.