WO2006117076A1 - Verwendung von indolin-phenylsulfonamid-derivaten - Google Patents

Verwendung von indolin-phenylsulfonamid-derivaten Download PDF

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Publication number
WO2006117076A1
WO2006117076A1 PCT/EP2006/003572 EP2006003572W WO2006117076A1 WO 2006117076 A1 WO2006117076 A1 WO 2006117076A1 EP 2006003572 W EP2006003572 W EP 2006003572W WO 2006117076 A1 WO2006117076 A1 WO 2006117076A1
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diseases
hydrogen
alkyl
ppar
compounds
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PCT/EP2006/003572
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German (de)
English (en)
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Elke Dittrich-Wengenroth
Helmut Haning
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Bayer Healthcare Ag
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Publication of WO2006117076A1 publication Critical patent/WO2006117076A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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.
  • A is the group CR 1 'or N
  • 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, - -
  • 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
  • R 10 is hydrogen or a hydrolyzable group which can be degraded to the corresponding carboxylic acid
  • 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.
  • they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinaemia, dyslipidemia and high blood pressure), liver fibrosis and cancer.
  • 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.
  • 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
  • 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 - -
  • 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.
  • (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-C ⁇ n) -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.
  • (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.
  • (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
  • 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.
  • 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.
  • (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.
  • 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.
  • heteroaromatic mono- or optionally bicyclic aromatic heterocycle
  • 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.
  • a saturated heterocycle which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heterocycle.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • 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.
  • the compounds used according to the invention can also be present as salts.
  • 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.
  • bases for example metal or ammonium salts.
  • alkali metal salts eg sodium or potassium salts
  • alkaline earth salts eg magnesium or calcium salts
  • 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.
  • A is the group CR 11 or N
  • R 1 ' is hydrogen or methyl
  • 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,
  • 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
  • R 10 is hydrogen
  • A is CH or N
  • 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
  • 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
  • R 10 is hydrogen
  • 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.
  • R 2 is hydrogen
  • R 3 is methyl, isopropyl or tert-butyl
  • 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,
  • R 1 , R 4 , R 5 and R 6 are each as defined above.
  • 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 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.
  • they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and high blood pressure), liver fibrosis and cancer.
  • 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.
  • ischemia myocardial infarction
  • angina pectoris heart failure
  • increased levels of fibrinogen and low density LDL heart failure
  • increased levels of fibrinogen activator inhibitor 1 (PAI-I) PAI-I
  • 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 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.
  • 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 / ⁇ , 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.
  • said compounds are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.
  • 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.
  • 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.
  • 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.
  • 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 ,
  • the compounds mentioned are administered in combination with an antagonist of the alpha 1 receptors such as by way of example and preferably prazosin.
  • the compounds mentioned are used in combination with a beta-receptor blocker, such as, by way of example and by way of preference, timolol,
  • 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.
  • RXR modulators 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.
  • 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.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melamine, pactimibe, eflucimibe or SMP-797.
  • said compounds are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • said compounds in combination with a PPAR alpha agonists such.
  • a PPAR alpha agonists such as the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate, gemfibrozil or as exemplified and preferably GW 590735, GW 641597, DRF-10945verabreicht.
  • 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).
  • a CETP inhibitor such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • said compounds are administered in combination with an antagonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Anatin or Radecol.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 SC-435
  • SC-635 SC-635
  • 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.
  • an antioxidant / radical catalyst such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
  • said compounds are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.
  • a cannabinoid receptor 1 antagonist such as by way of example and preferably rimonabant or SR-147778.
  • parenteral administration 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.
  • parenteral administration intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, should be mentioned in particular.
  • Very particular preference is given to oral administration.
  • the active ingredients can be administered alone or in the form of preparations.
  • preparations u.a. Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • the active ingredient must be present in such an amount that a therapeutic effect is achieved.
  • 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.
  • 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.
  • 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.
  • 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).
  • non-toxic organic solvents such as 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).
  • tablets may also contain additives such as sodium citrate together with adjuvants such as starch, gelatin and the like.
  • adjuvants such as starch, gelatin and the like.
  • Aqueous preparations for oral administration may also be treated with flavor enhancers or colorants.
  • 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.
  • 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.

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Abstract

Die vorliegende Anmeldung betrifft neue Verwendungen von substituierte Indolin-Phenylsulfon-amid-Derivaten zur Prophylaxe und/oder Behandlung von Erkrankungen.
PCT/EP2006/003572 2005-04-30 2006-04-19 Verwendung von indolin-phenylsulfonamid-derivaten WO2006117076A1 (fr)

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DE102005020229.2 2005-04-30
DE102005020229A DE102005020229A1 (de) 2005-04-30 2005-04-30 Verwendung von Indolin-Phenylsulfonamid-Derivaten

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EP2114396A2 (fr) * 2006-12-29 2009-11-11 The Salk Institute for Biological Studies Procédés permettant une amélioration des performances d'exercice
WO2013063526A1 (fr) 2011-10-28 2013-05-02 Lumena Pharmaceuticals, Inc. Inhibiteurs du recyclage de l'acide biliaire pour traitement de l'hypercholémie et de la maladie cholestatique hépatique
WO2014144650A2 (fr) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Inhibiteurs du recyclage de l'acide biliaire pour le traitement de l'angiocholite sclérosante primaire et de la maladie inflammatoire de l'intestin
WO2014144485A1 (fr) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Inhibiteurs de recyclage d'acide biliaire pour le traitement de l'œsophage de barrett et du reflux gastroœsophagien pathologique
EP2995317A1 (fr) 2010-05-26 2016-03-16 Satiogen Pharmaceuticals, Inc. Inhibiteurs de recyclage d'acide biliaire et satiogènes pour le traitement du diabète, de l'obésité et des conditions gastro-intestinales inflammatoires
EP3266457A1 (fr) 2011-10-28 2018-01-10 Lumena Pharmaceuticals LLC Inhibiteurs du recyclage de l'acide biliaire pour le traitement de maladies cholestatiques hépatiques pédiatriques
EP4241840A2 (fr) 2019-02-12 2023-09-13 Mirum Pharmaceuticals, Inc. Procédés de traitement de la cholestase

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WO2002100351A2 (fr) * 2001-06-11 2002-12-19 Merck & Co., Inc. Procede de traitement de maladies inflammatoires par administration d'un agoniste ppar-delta
WO2003024395A2 (fr) * 2001-09-14 2003-03-27 Tularik Inc. Composes biaryles lies
WO2004005253A1 (fr) * 2002-07-03 2004-01-15 Bayer Healthcare Ag Derives d'indoline-phenylsulfonamide

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WO2002100351A2 (fr) * 2001-06-11 2002-12-19 Merck & Co., Inc. Procede de traitement de maladies inflammatoires par administration d'un agoniste ppar-delta
WO2003024395A2 (fr) * 2001-09-14 2003-03-27 Tularik Inc. Composes biaryles lies
WO2004005253A1 (fr) * 2002-07-03 2004-01-15 Bayer Healthcare Ag Derives d'indoline-phenylsulfonamide

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2114396A4 (fr) * 2006-12-29 2010-03-10 Salk Inst For Biological Studi Procédés permettant une amélioration des performances d'exercice
EP2114396A2 (fr) * 2006-12-29 2009-11-11 The Salk Institute for Biological Studies Procédés permettant une amélioration des performances d'exercice
EP2995317A1 (fr) 2010-05-26 2016-03-16 Satiogen Pharmaceuticals, Inc. Inhibiteurs de recyclage d'acide biliaire et satiogènes pour le traitement du diabète, de l'obésité et des conditions gastro-intestinales inflammatoires
EP4137137A1 (fr) 2010-05-26 2023-02-22 Satiogen Pharmaceuticals, Inc. Inhibiteurs et satiogènes de recyclage d'acide biliaire pour le traitement du diabète, de l'obésité et d'états gastro-intestinaux inflammatoires
EP3593802A2 (fr) 2010-05-26 2020-01-15 Satiogen Pharmaceuticals, Inc. Inhibiteurs de recyclage d'acide biliaire et satiogènes pour le traitement du diabète, de l'obésité et des conditions gastro-intestinales inflammatoires
EP3266457A1 (fr) 2011-10-28 2018-01-10 Lumena Pharmaceuticals LLC Inhibiteurs du recyclage de l'acide biliaire pour le traitement de maladies cholestatiques hépatiques pédiatriques
EP3278796A1 (fr) 2011-10-28 2018-02-07 Lumena Pharmaceuticals LLC Inhibiteurs du recyclage de l'acide biliaire pour traitement de l'hypercholémie et de la maladie cholestatique hépatique
US10512657B2 (en) 2011-10-28 2019-12-24 Lumena Pharmaceutials Llc Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
US11229661B2 (en) 2011-10-28 2022-01-25 Shire Human Genetic Therapies, Inc. Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
US11376251B2 (en) 2011-10-28 2022-07-05 Shire Human Genetic Therapies, Inc. Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
WO2013063526A1 (fr) 2011-10-28 2013-05-02 Lumena Pharmaceuticals, Inc. Inhibiteurs du recyclage de l'acide biliaire pour traitement de l'hypercholémie et de la maladie cholestatique hépatique
WO2014144485A1 (fr) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Inhibiteurs de recyclage d'acide biliaire pour le traitement de l'œsophage de barrett et du reflux gastroœsophagien pathologique
WO2014144650A2 (fr) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Inhibiteurs du recyclage de l'acide biliaire pour le traitement de l'angiocholite sclérosante primaire et de la maladie inflammatoire de l'intestin
EP4241840A2 (fr) 2019-02-12 2023-09-13 Mirum Pharmaceuticals, Inc. Procédés de traitement de la cholestase
EP4245367A2 (fr) 2019-02-12 2023-09-20 Mirum Pharmaceuticals, Inc. Procédés de traitement de la cholestase

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