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EP1347959A1 - Derives de l'indole utilises comme ligands de recepteurs de la thyroide - Google Patents

Derives de l'indole utilises comme ligands de recepteurs de la thyroide

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Publication number
EP1347959A1
EP1347959A1 EP01272011A EP01272011A EP1347959A1 EP 1347959 A1 EP1347959 A1 EP 1347959A1 EP 01272011 A EP01272011 A EP 01272011A EP 01272011 A EP01272011 A EP 01272011A EP 1347959 A1 EP1347959 A1 EP 1347959A1
Authority
EP
European Patent Office
Prior art keywords
indol
oxy
phenyl
group
acetic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01272011A
Other languages
German (de)
English (en)
Inventor
Helmut Haning
Michael Woltering
Gunter Schmidt
Hilmar Bischoff
Axel Kretschmer
Verena Vöhringer
Christiane Faeste
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Bayer Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10130830A external-priority patent/DE10130830A1/de
Application filed by Bayer AG, Bayer Healthcare AG filed Critical Bayer AG
Publication of EP1347959A1 publication Critical patent/EP1347959A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new indole derivatives, processes for their preparation and their use in medicaments.
  • EP-A-580 550 describes oxamic acid derivatives which have cholesterol-lowering properties in mammals.
  • the reduction in plasma cholesterol, in particular LDL cholesterol, is emphasized as a pharmacological property.
  • Cholesterol-lowering effects are also described in EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects which clearly differ in chemical structure from the compounds according to the invention.
  • WO 00/51971 discloses oxamic acid derivatives with an --ndol partial structure as thyroid receptor ligands for the treatment of various explanations.
  • WO 99/50268 discloses substituted indolalkane carboxylic acids which are suitable for the treatment of chronic complications caused by diabetes mellitus.
  • WO 95/20588 discloses indole derivatives which act as 5-HT r agonists.
  • WO 98/11895 discloses the use of 5-HT ⁇ agonists for the treatment of migraines; Indole derivatives are also indicated as suitable active ingredients.
  • WO 98/06402 describes the use of the same structures for the treatment of colds or rhinitis.
  • EP-A-639 573 discloses benzo-fused 5-ring heterocycles and their use in medicines and diagnostics. The compounds disclosed are inhibitors of the cellular sodium proton antiporter (Na + / H + exchanger).
  • US-A-5 468 899 relates to bicyclic aryl compounds with selective properties as LTB4 antagonists.
  • EP-A-377 450 discloses substituted indole, benzofuran and benzothiophene derivatives which act as 5-lipoxygenase inhibitors.
  • JP-A-07145 147 discloses testosterone-5-alpha-reductase inhibitors derived from benzoic acid, which can be used for the treatment of prostate cancer and certain hair loss conditions.
  • GB-A-2 253 848 describes di-ortho-substituted phenyl-indole in the phenyl part
  • Described ethers with herbicidal activity which can be used as crop protection agents. Thyromimetic effects have so far not been known for these ortho-substituted indoles.
  • the object of the invention is to provide new compounds with improved, in particular pharmaceutical, effects.
  • Z stands for O, S, SO, SO 2 , CH 2 , CHF, CF 2 or for NR 9 , in which R 9 denotes hydrogen or (dC) -alkyl,
  • R 1 and R 2 are identical or different and represent hydrogen, halogen, cyano, (C j - C 6 ) alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 7 ) cycloalkyl, where at least one of the two substituents is not hydrogen and is in the ortho position to the bridge bond,
  • R 12 and R 13 are the same or different and are hydrogen, cyano, (dC 4 ) alkyl or (dC 4 ) alkoxy,
  • D stands for a straight-chain (dC 3 ) alkylene group which, one or more times, identically or differently, by (C 1 -C 4 ) alkyl, hydroxy, (dC 4 ) alkoxy, halogen, amino, mono- (C ⁇ - C 4 ) -alkylamino, mono- (dC) -acylamino or (-C-C 4 ) -alkoxycarbonylamino may be substituted,
  • E and L independently of one another represent a C (O) or SO 2 group
  • G is NR 14 , in which R 14 is hydrogen or (dC) -alkyl, or represents a straight-chain (C 1 -C 3 ) -alkylene group which is mono- or polysilicon, the same or different, by (dC) -alkyl , Hydroxy, (CC) - Alkoxy, halogen, amino, mono- or di- (dC 4 ) -alkylamino or mono- (dC 4 ) -acylamino can be substituted,
  • n, o and p each independently represent the number 0 or 1, with the proviso that
  • Phenyl, benzyl, (dC 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (d- C 4 ) - Alkoxy, (dC 4 ) -alkoxy carbonyl, (C - C) -alkoxy-carbonylamino, (dC 5 ) -alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,
  • -LR 10 represents a group of the formula wherein
  • R 29 denotes hydrogen or (dC 4 ) -alkyl
  • r represents the number 0, 1 or 2
  • R and R 5 are the same or different and each represents hydrogen, hydroxy, halogen, cyano, nitro, (C 1 -C 4 ) alkyl or the rest of the formula NR 30 R 31 , where R 30 and R 31 are those for R 15 have the meaning given and, independently of one another, may be the same or different with this substituent,
  • R 6 represents hydrogen, halogen or a group of the formula
  • M represents a carbonyl group, a sulfonyl group or a methylene group
  • a represents the number 0 or 1
  • R 32 has the meaning of R 10 given above and can be identical or different with this substituent
  • R 7 represents hydrogen or an acyl group which can be split off under physiological conditions to form an NH function, preferably represents hydrogen or acetyl,
  • R 8 has the meaning of R 6 given above and can be identical or different with this substituent
  • R 6 , R 8 or R 10 The following may preferably be mentioned as heterocycles in the definition of R 6 , R 8 or R 10 :
  • heterocycle which can contain one or more double bonds and which is linked via a ring carbon atom or a ring nitrogen atom.
  • Examples include: Tefr-d ydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl,
  • pyridyl pyrimidinyl
  • pyridazinyl pyrimidinonyl
  • pyridazinonyl pyridazinonyl
  • alkyl represents a straight-chain or branched alkyl radical having preferably 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 3 carbon atoms is preferred. Examples and preferably are:
  • aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Cycloalkyl in the context of the invention represents a cycloalkyl group with preferably 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • alkoxy preferably represents a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
  • Alkoxycarbonyl in the context of the invention preferably represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
  • Alkanoyloxy in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 3 carbon atoms, which bears a double-bonded oxygen atom in the 1 position and which is linked via a further oxygen atom in the 1 position is.
  • a straight-chain or branched alkanoyloxy radical having 1 to 3 carbon atoms is preferred. Examples and preferably mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
  • monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, ethyl ⁇ uriino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.
  • dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • Straight-chain or branched dialkylamino radicals each with 1 to 4 are preferred
  • Carbon atoms Examples and preferably mentioned are: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-memyl- ⁇ mino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-memyl-i-tnino.
  • monoacylamino represents an amino group having a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group.
  • a monoacylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent which preferably has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
  • the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds according to the invention can also be present as salts.
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalene disulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid,
  • Physiologically acceptable salts can also be salts of the invention
  • Be compounds with bases such as metal or ammonium salts.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmopholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
  • prodrugs refer to those derivatives of the compounds of the general formula (I) which themselves may be less biologically active or also inactive but which, after application under physiological conditions, are converted into the corresponding biologically active form (for example metabolically, solvolytically or on other way).
  • Z represents O, S or CH 2
  • R 1 and R 2 are the same or different and represent hydrogen, fluorine, chlorine, bromine,
  • D stands for a straight-chain (C 1 -C 3 ) alkylene group which is mono- or divalent, identical or different, by (dC) - alkyl, hydroxy, methoxy, ethoxy, fluorine, chlorine, amino, mono- (C 1 - C 4 ) -alkylamino or mono- (-C-C 4 ) -acylamino may be substituted,
  • E represents a C (O) group
  • L represents a C (O) or SO 2 group
  • G represents an NH group or a straight-chain (dC 3 ) alkylene group which can be substituted once or twice, identically or differently, by methyl, ethyl, hydroxy, methoxy, fluorine, chlorine, amino, methylamino or acetylamino,
  • n, o and p each independently represent the number 0 or 1 with which
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen,
  • Phenyl, benzyl, (dC 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (d-C 4 ) - Alkoxy, (dC 4 ) alkoxycarbonyl, (dC 4 ) alkoxy-carbonylamino, (d-C5) alkanoyloxy ,. a heterocycle or optionally substituted by halogen or hydroxy substituted phenyl,
  • R 4 and R 5 are the same or different and each represents hydrogen, halogen or (C r C 4 ) alkyl,
  • R 6 represents hydrogen, halogen or a group of the formula
  • M represents a carbonyl group, a sulfonyl group or a methylene group
  • a represents the number 0 or 1
  • R 32 represents (dC 10 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 4 ) alkenyl, naphthyl, phenyl, benzyl, pyridyl, pyridazinyl or pyridazinonyl, where the abovementioned radicals may be replaced by a , two or three identical or different substituents selected from the group
  • R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen, phenyl, benzyl, (dC 6 ) - alkyl or ( C 3 -C 6 ) cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (C) -C) alkoxy, (dC 4 ) alkoxycarbonyl, (C ⁇ - C) -alkoxycarbonylamino, (d- C 5 ) -alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,
  • R 7 represents hydrogen
  • R 8 has the meaning of R 6 given above and can be identical or different with this substituent
  • Z represents O or CH 2 .
  • R 1 and R 2 are the same or different and represent hydrogen, fluorine, chlorine, bromine,
  • A represents O, S or NH
  • D represents a straight-chain (C 1 -C 3 ) alkylene group which can be substituted once or twice, identically or differently, by methyl, ethyl, hydroxy, methoxy, fluorine, amino or acetylamino,
  • E represents a C (O) group
  • L represents a C (O) or SO 2 group
  • G represents an NH group or a methylene group, and p independently of one another each represent the number 0 or 1, with the proviso that
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen, Phenyl, benzyl, (-C-C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl, which in turn are optionally one to two times, identical or different, by fluorine, chlorine, hydroxy, amino, carboxyl, (dC 4th ) -Alkoxy, (dC 4 ) -alkoxycarbonyl, (dC 4 ) -alkoxy-carbonylamino, (-C-C 5 ) -alkanoyloxy, a heterocycle or phenyl optionally substituted by fluorine, chlorine or hydroxy,
  • R 4 and R 5 are the same or different and each represents hydrogen, fluorine, chlorine or methyl,
  • R represents hydrogen, halogen or a group of the formula
  • M represents a sulfonyl group or a methylene group
  • a represents the number 0 or 1
  • R 32 stands for (dd ⁇ -alkyl, (C 3 -C 7 ) cycloalkyl, phenyl, benzyl, pyridyl, pyridazinyl or pyridazinonyl, the aforementioned radicals optionally being selected from the group fluorine, chlorine by one or two identical or different substituents , Bromine, hydroxy, cyano, nitro, amino, NR 18 R 19 , trifluoromethyl, (dC) alkyl, (d- C 4 ) alkoxy, (C 3 -C 7 ) cycloalkyl, -OC (O) -R 21 , -C (O) -OR 22 , -C (O) -NR 23 R 24 , -SO 2 -NR 25 R 26 , -NH-C (O) -R 27 and -NH-C (O) - OR 28 are substituted, wherein
  • R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen, phenyl, benzyl,
  • R 7 represents hydrogen
  • R 8 represents hydrogen, carboxyl, (dC 4 ) alkoxycarbonyl, (CC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl, benzyl, pyridyl, phenylsulfonyl or benzylsulfonyl, the above-mentioned radicals optionally being substituted by one or two identical or different substituents selected from the group fluorine, chlorine, bromine, hydroxy, cyano, nitro, amino, NR 18 R 19 , trifluoromethyl, (d- C 4 ) -alkyl, (dC 4 ) -alkoxy, (C 3 - C 6 ) -cycloalkyl, -OC (O) -R 21 , -C (O) -OR 22 , -C (O) -NR 23 R 24 , -SO 2 -NR 25 R 26 , -NH-C (O ) -R 27 and
  • R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each is hydrogen, phenyl, benzyl, (-C-C 6 ) alkyl or (C 3 -
  • R 1 and R 2 are the same or different and represent hydrogen, fluorine, chlorine, bromine, (C r C 4 ) alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 5 ) cycloalkyl , wherein at least one of the two substituents is not hydrogen and is in the ortho position to the bridge bond, in particular both substituents are not hydrogen and both are in the ortho position,
  • A represents O, S or NH
  • D represents a methylene or ethylene group which can be substituted one to two times, identically or differently, by methyl, ethyl, fluorine, amino or acetylamino,
  • E represents a C (O) group
  • L represents a C (O) or SO 2 group
  • G represents an NH group or a methylene group
  • n, o and p each independently represent the number 0 or 1, with the proviso that
  • R 10 is OR 15, NR 16 R 17 or (C, -C 4) -alkyl, where R 15, R 16 and R 17 are the same or different and each is hydrogen, phenyl,
  • Benzyl, (-C-C 6 ) - alkyl or (C 3 -C 6 ) -cycloalkyl which in turn are optionally one to two times, the same or different, by fluorine, chlorine, hydroxy, amino, carboxyl, (-C-C 4 ) - alkoxy, (dC) - alkoxycarbonyl, (dC 4 ) -alkoxycarbonylamino, (C 1 -C 5 ) -alkanoyloxy, a heterocycle or phenyl,
  • R 4 and R 5 are the same or different and each represents hydrogen, fluorine, chlorine or methyl,
  • R 6 represents hydrogen, halogen, (dC 10 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) cycloalkylmethyl, phenyl, benzyl, pyridazinonylmethyl, phenylsulfonyl or pyridylsulfonyl, the aforementioned aromatic radicals are optionally substituted by one or two identical or different substituents selected from the group consisting of fluorine, chlorine, cyano, nitro, trifluoromethyl, methyl, methoxy, carboxyl or methoxycarbonyl,
  • R 7 represents hydrogen
  • R 8 represents hydrogen, (dC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl, benzyl, phenylsulfonyl or benzylsulfonyl, the aforementioned aromatic
  • Residues optionally by one or two identical or different substituents selected from the group fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy are substituted,
  • Z represents CH or in particular oxygen
  • R 1 and R 2 are the same or different and represent methyl, ethyl, propyl, isopropyl, chlorine, bromine, CF, vinyl or cyclopropyl, where both substituents are in the ortho-position to the bridge bond,
  • R 4 and R 5 independently of one another represent methyl, fluorine or chlorine or in particular hydrogen
  • R 7 represents hydrogen
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the respectively specified combinations of the radicals.
  • Compounds of the formula (I) in which Z represents oxygen are particularly preferred.
  • R which is in the para position to the bridge bond and in which R is hydroxy or the radical -C (O) -R 10 has the meanings given for R for a group which, in the sense of a prodrug to the carboxylic acid -C (O) -OH or their salts can be broken down.
  • R 3 represents a group of the formula -CH 2 -C (O) -OH, -CHF-C (O) -OH or -CF 2 -C (O) -OH,
  • R for straight-chain or branched (dC 8 ) alkyl
  • R 1 and R 2 are identical or different and represent bromine, trifluoromethyl, ethyl, cyclopropyl and in particular methyl or chlorine,
  • R J stands for a group of the formula -NH-C (O) -CH 2 -C (O) -R 1 ⁇ 0 ⁇ , in which
  • R 10 represents hydroxy or the radical -C (O) -R 10 has the meanings given above of R 10 for a group which can be degraded as a prodrug to the carboxylic acid -C (O) -OH or its salts, and
  • R for straight-chain or branched (-CC 8 ) - alkyl
  • the compounds of the general formula (I) according to the invention can be prepared by reacting reactive indole derivatives of the general formula (II) with reactive phenyl derivatives of the general formula (III)
  • R 3 has the meaning given for R 3 or for ⁇ O 2 , NH 2 , NH-PG, OH, O-PG, SH, S-PG, or for an aldehyde, cyano, carboxyl or (dC- - Alkoxycarbonyl group,
  • Coupling catalysts such as Pd, Rh and / or Cu compounds may be mentioned as examples of catalysts.
  • reactive groups X and Y halogen, hydroxy, CH 2 Br, mercapto, amino, CHO, Li, magnesium, tin or boron derivatives.
  • the indoles of the general formula (II) which can be used according to the invention are known or can be prepared by known methods [compare e.g. Ozaki et al., Heterocycles 51, 727-731 (1999); Harvey et al., J. Chem. Soc, 473 (1959); Quadbeck et al., Hoppe-Seyler's Z. Physiolog. Chem. 297, 229 (1954); Chen et al., J. Org. Chem. 59, 3738 (1994); Synthesis, 480 (1988); J. Prakt. Chem. 340, 608 (1998)].
  • the phenyl derivatives of the general formula (III) are also known or can be prepared by known methods [compare e.g. van de Bunt, Recl. Trav. Chim. Pays-Bas 48, 131 (1929); Valkanas, J. Chem. Soc, 5554 (1963)].
  • Normal pressure However, it can also be carried out under increased or reduced pressure.
  • the reaction can be carried out in a temperature range from -100 ° C to 200 ° C, preferably between -78 ° C and 150 ° C in the presence of inert solvents become.
  • inert solvents dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-methyl-2-pyrrolidinone ( ⁇ MP), tetrahydrofuran (THF), diethyl ether, dichloromethane etc.
  • intermediates of the formula (IV) can also be formed in the reaction of (II) and (III), in which, for example, the substituent R 3 'for a ⁇ itro, aldehyde, cyano, carboxyl or alkoxycarbonyl group represents or Z 'represents a CHOH or C (O) group, which are then reacted with or without isolation of these intermediates by conventional methods to give compounds of formula (I).
  • Protective groups (PG) in the present application are understood to mean groups in starting, intermediate and / or end products which contain functional groups such as e.g. Protect carboxyl, amino, mercapto or hydroxy groups and which are common in preparative organic chemistry. The groups protected in this way can then be converted into free functional groups in a simple manner under known conditions.
  • the compounds of the formula (I) according to the invention have a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments for the treatment of humans and mammals, such as dogs and cats in particular. In particular, they can be used for all indications that can be treated with natural thyroid hormones, such as, for example and preferably, depression, goiter or thyroid cancer.
  • Arteriosclerosis, hypercholesterolemia and dyslipidemia can preferably be treated with the compounds of formula (I) according to the invention.
  • obesity and heart failure can be treated and a postprandial reduction in triglycerides can be achieved.
  • the compounds are also suitable for the treatment of certain respiratory diseases, in particular pulmonary emphysema and for the medicinal promotion of pulmonary maturation.
  • the compounds are also suitable for the treatment of pain and migraines, for neuronal repair (remyelination) and for the treatment of Alzheimer's disease.
  • the compounds are also suitable for the treatment of osteoporosis, cardiac arrhythmias, hypothyroidisms and skin diseases.
  • the compounds can also be used to promote and regenerate hair growth and to treat diabetes.
  • the active compounds according to the invention open up a further treatment alternative and are an enrichment for the pharmaceutical industry.
  • the compounds according to the invention show an improved spectrum of action. They are preferably characterized by great specificity, good tolerance and fewer side effects, especially in the cardiovascular area.
  • the activity of the compounds according to the invention can e.g. Test in vitro using the T3 promoter assay cell test described below:
  • the test is carried out with a stably transfected human HepG2 hepatocarcinoma cell which expresses a luciferase gene under the control of a thyroid hormone-regulated promoter.
  • the vector used for transfection carries a minimal thymidine kinase promoter with one in front of the luciferase gene
  • Thyroid hormone - responsive element which consists of two inverted palindromes of 12 bp each and an 8 bp spacer.
  • the cell cultures are sown in 96-well plates in Eagle's Minimal Essential Medium with the following additives: glutamine, tricine [N- (tris (hydroxymethyl) methyl) glycine], sodium pyruvate, non-essential amino acids (L- Ala, L-Asn, L-Asp, L-Pro, L-Ser, L-Glu, Gly), insulin, selenium and transfenin.
  • glutamine glutamine
  • sodium pyruvate sodium pyruvate
  • non-essential amino acids L- Ala, L-Asn, L-Asp, L-Pro, L-Ser, L-Glu, Gly
  • insulin selenium and transfenin.
  • T3, T4 serial dilutions of test substance or reference compound
  • costimulator retinoic acid costimulator retinoic acid
  • the substances that are to be examined for their serum cholesterol-lowering effect in vivo are administered orally to male mice with a body weight between 25 and 35 g.
  • the substances are administered orally once a day for 7 days.
  • the test substances are, for example, in a solution of Solutol HS 15 + ethanol + saline (0.9%) in a ratio of 1 + 1 + 8 or in a solution of Solutol HS 15 + saline (0.9%) in a ratio of 2 + 8 solved.
  • the application The dissolved substances are carried out in a volume of 10 ml / kg body weight with a pharyngeal tube. Animals that are treated in the same way but only receive the solvent (10 ml / kg body weight) without test substance serve as a control group.
  • the effect of the test substances on the serum cholesterol concentration is determined by subtracting the cholesterol value of the 1st blood sample (previous value) from the cholesterol value of the 2nd blood sample (after treatment). The differences of all cholesterol values in a group are averaged and compared with the mean value of the differences in the control group.
  • Control groups statistically significant (p ⁇ 0.05) lower by at least 10%, are considered to be pharmacologically active.
  • the animals are weighed and killed after the blood is drawn.
  • the hearts are removed and weighed.
  • An effect on the heart Circulatory system can be determined by a significant increase in heart weight.
  • a change in body weight can be used as a further parameter for the substance effect.
  • the cholesterol-lowering action of the compounds according to the invention can also be exerted on normocholesterolemic dogs by oral administration of the test substances for 5-7 days.
  • mRNA of the "hype ⁇ olarization-activated cyclic nucleotide-gated" cation channel (HCN2) in rat hearts was carried out by real-time PCR (TaqMan-PCR; Heid et al, Genome Res. 6 (10), 986-994).
  • TaqMan-PCR Real-time PCR
  • the total RNA is isolated using RNaesy columns (Qiagen), digested with DNase and then rewritten into cDNA
  • Quencher 6-carboxytetramethylrhodamine Quencher 6-carboxytetramethylrhodamine.
  • the 5'-exonuclease activity of the Taq polymerase cleaves the fluorescent dye FAM and thereby the previously quenched fluorescence signal is obtained.
  • the number of cycles at which the fluorescence intensity was 10 standard deviations above the background fluorescence is recorded as the so-called “threshold cyle” (Ct value).
  • the relative expression of the HCN2 mRNA calculated in this way is then normalized to the expression of the ribosomal protein L32.
  • all customary application forms come into consideration, i.e. i.e. oral, parenteral, inhalative, nasal, sublingual, buccal, rectal or external, e.g. transdermally, particularly preferably orally or parenterally.
  • parenteral administration intravenous, intramuscular, subcutaneous administration should be mentioned in particular, e.g. as a subcutaneous depot.
  • Oral application is very particularly preferred.
  • Compounds of the general formulas (Ia) and (Ib) in particular have surprisingly advantageous pharmacokinetic properties after oral administration, for example with regard to the bioavailability, the active substance concentration in the blood, the half-life and / or the excretion rate.
  • the active ingredients can be administered alone or in the form of preparations. Preparations suitable for oral administration include 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 ingredient can 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 0.5-90% by weight, ie the active ingredient should be present in amounts which are sufficient to achieve the dosage range indicated.
  • the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
  • auxiliary substances are: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), sugar (e.g.
  • non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), sugar (e.g.
  • Milk sugar emulsifiers
  • dispersants e.g. polyvinylpyrrolidone
  • lubricants e.g. magnesium sulfate
  • tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.
  • dosages of 0.001 to 5 mg / kg, preferably 0.001 to 3 mg / kg body weight are applied per 24 hours.
  • the new active substances can be used alone and, if necessary, also in combination with other active substances, preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase Gene expression, squalene synthesis J inhibitors, ACAT-J inhibitors, blood flow-promoting agents, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, inhibitors, aldose reductibrase Anorectics, lipase inhibitors and PPAR agonists are administered.
  • Example I 500 mg of 5- (2,6-dichloro-4-nitrophenoxy) -3-isopropyl-1H-indole (Example I) are mixed with 6.18 g of tin (II) chloride dihydrate in 5 ml of NMP at 50 ° C. for 17 hours touched. The solvent is removed in vacuo and the residue is taken up in ethyl acetate. It is washed with saturated ammonium chloride solution and saturated sodium chloride solution, the organic phase is dried and the solvent is removed in vacuo. The product is precipitated with diethyl ether.
  • Example VII Analogously to the instructions of Example VII, 4.8 g (12.66 mmol) of benzyl alcohol derivative from Example XVII are mixed with 6.95 g (16.46 mmol) of dibromotriphenylphosphorane and 1.6 g (20.26 mmol) of pyridine in 80 ml Acetonitrile implemented. Yield: 2.03 g (35.5%)
  • Example VIII Analogously to the procedure of Example VIII, 1.0 g (2.42 mmol) of benzyl bromide from Example XVIII is mixed with 0.15 g (3.03 mmol) of sodium cyanide in DMF / H 2 O (10: 1) at 50 ° C. in 60 Min. Implemented. After isolation of the crude product (distilling DMF and quenching with ethyl acetate / water), chromatography on silica gel 60 is carried out using toluene.
  • Example VII The preparation is carried out in analogy to the procedure of Example VII from 2.0 g (4.18 mmol) of benzyl alcohol derivative from Example XXI and 2.82 g (6.69 mmol) of dibromotriphenylphosphorane in 40 ml of acetonitrile. After 3 hours of stirring at room temperature, another 0.3 equivalents of dibromotriphenylphosphorane are added. The mixture is stirred for 5 hours at 70 ° C and then overnight at room temperature. The product is purified on silica gel using toluene as the eluent. Yield: 0.96 g (40.2%)
  • Example VIII The preparation is carried out in analogy to the procedure of Example VIII from 0.85 g (1.59 mmol) of benzyl bromide from Example XXII with 0.1 g (1.99 mmol) of sodium cyanide in 5 ml of dimethylformamide and 0.5 ml of water at 50 ° C in 1.5 hours.
  • the crude product is chromatographed on silica gel 60 using toluene.
  • Example XV 4 - [(3-isopropyl-lH-indol-5-yl) oxy] -3,5-dimethylaniline (Example XV) are dissolved in 2 ml of acetone with 76 mg (0 , 75 mmol) of triethylamine and 102 mg (0.75 mmol) of methyl malonate were added at 0 ° C. The mixture is stirred for 1 h, diluted with dichloromethane and extracted with sodium chloride solution and with NaHCO 3 solution. The organic phase is dried and the solvent is removed in vacuo.
  • Example 1 50 mg of methyl 3 - ( ⁇ 4 - [(3-sopropyl-lH-indol-5-yl) oxy] -3,5-dimethyl-phenyl ⁇ amino) - 3-oxo-propanoate (Example 1) are added in 2 ml Ethanol stirred with 30 mg sodium hydroxide for 30 minutes. The solvent is removed in vacuo. It is taken up in ether / water, the organic phase is dried and the solvent is removed in vacuo.
  • Example XV 210 mg of 4 - [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylaniline (Example XV) are mixed with 119 mg of ethyl bromoacetate and 117 mg of sodium acetate in 10 ml Ethanol refluxed for 24 h. After adding water, the mixture is extracted with ether, the organic phase is dried and evaporated.
  • Example 4a Analogously to Example 4a, starting from 2.50 g (7.94 mmol) of 3-chloro-4- [(3-isopropyl-1H-indol-5-yl) oxy] -5-methylaniline (Example III) and 1.26 g (7.94 mmol) ethyl malonate 3.65 g (99% of theory) ethyl 3 - ( ⁇ 3-chloro-4- [(3-isopropyl-1H-indol-5-yl) oxy ] -5-methylphenyl ⁇ amino) -3-oxo-propanoate.
  • This compound can be prepared starting from 3-chloro-4 - [(3-isopropyl-1H-indol-5-yl) oxy] - 5-methylaniline (Example HI) in analogy to Example 4a.
  • Example 4d
  • Example 6 This compound is obtained in a manner analogous to Example 6a, starting from 3 - ( ⁇ 3-chloro-4 - [(3-isopropyl-1 H-indole-5-yl) oxy] -5-methylphenyl ⁇ amino) -3-oxopropion - Acid (Example 6) and sodium hydroxide.
  • Example 6 This compound is obtained analogously to Example 6a starting from 3 - ( ⁇ 3-chloro-4 - [(3-isopropyl-1H-indol-5-yl) oxy] -5-methylphenyl ⁇ amino) -3-oxopropion- acid (Example 6) and magnesium methanolate
  • Example 7 This compound is obtained analogously to Example 6a starting from 3 - ( ⁇ 3-chloro-4 - [(3-isopropyl-1H-indol-5-yl) oxy] -5-methylphenyl ⁇ amino) -3-oxopropion- acid (Example 6) and calcium hydroxide.
  • Example 7 This compound is obtained analogously to Example 6a starting from 3 - ( ⁇ 3-chloro-4 - [(3-isopropyl-1H-indol-5-yl) oxy] -5-methylphenyl ⁇ amino) -3-oxopropion- acid (Example 6) and calcium hydroxide.
  • Example 7 Example 7
  • Example IV 139 mg of 3,5-dichloro-4 - [(3-isopropyl-lH-indol-5-yl) oxy] aniline (Example IV) are dissolved in 46 ml of triethylamine in 3 ml of acetone and with 62 mg of methyl malonate at 0 ° C added dropwise. The mixture is stirred at room temperature for 1 hour, poured onto 20 ml of dichloromethane, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and rotated in.
  • Example IV 100 mg of 3,5-dichloro-4 - [(3-isopropyl-1H-indol-5-yl) oxy] aniline (Example IV) are refluxed with 49 mg of sodium acetate and 50 mg of ethyl bromoacetate in 5 ml of ethanol for 17 hours. A further 21 mg of ethyl bromoacetate are added and the mixture is refluxed for 2 hours. The solvent is removed in vacuo, the mixture is taken up in water and dichloromethane, the organic phase is washed with saturated sodium chloride solution, the organic phase is dried and the solvent is removed in vacuo.
  • reaction solution from Example 19 (approx. 2.06 mmol - 100%) is mixed with 50 ml of dioxane and at 0 ° C. with 0.899 g (4.12 mmol) of di-tert-butyl dicarbonate dissolved in 5 ml of dioxane dropwise implemented. The reaction solution is then left on
  • the pentanecarboxylic acid derivative is formed as a by-product in the catalytic hydrogenation of the 3-oxopentecarboxylic acid derivative in Example 27. Yield: 15 mg (6.2%)
  • the preparation is carried out in analogy to the procedure of Example 17 from 0.3 g (0.62 mmol) of phenylacetonitrile derivative from Example XXIII by dissolving the nitrile in 10 ml of dioxane and adding 4 ml of conc. Treated sulfuric acid and 4 ml of water at 100 ° C for 4 hours.
  • the crude product is chromatographed on silica gel 60 using toluene / ethyl acetate (1: 1) in the isocratic mode.
  • Example 116 (3-bromo-4 - ⁇ [3- (cyclohexylethyl) -lH-indol-5-yl] oxy ⁇ -5-methylphenoxy) acetic acid
  • Example 117 (3-bromo-4 - ⁇ [3- (cyclohexylethyl) -lH-indol-5-yl] oxy ⁇ -5-methylphenoxy) acetic acid
  • Example 183 ⁇ [4- [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) phenyl] sulfanyl ⁇ acetic acid
  • Example 184 ⁇ [4- [(3-isopropyl-1H-indol-5-yl) oxy] -3,5-bis (trifluoromethyl) phenyl] sulfanyl ⁇ acetic acid
  • Example 209 3 - ( ⁇ 4 - [(3-Isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylphenyl ⁇ amino) -3-oxopropionic acid
  • Example 210 3 - ( ⁇ 4 - [(3-Isopropyl-1H-indol-5-yl) oxy] -3,5-dimethylphenyl ⁇ amino) -3-oxopropionic acid
  • Example 234 [3-Chloro-4 - [(3-cyclohexyl-1H-indol-5-yl) oxy] -5- (trifluoromethyl) phenyl] acetic acid
  • Example 235 [3-Chloro-4 - [(3-cyclohexyl-1H-indol-5-yl) oxy] -5- (trifluoromethyl) phenyl] acetic acid

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Abstract

L'invention concerne de nouveaux dérivés de l'indole de formule (I), leur procédé de fabrication ainsi que leur utilisation dans des médicaments.
EP01272011A 2000-12-27 2001-12-14 Derives de l'indole utilises comme ligands de recepteurs de la thyroide Withdrawn EP1347959A1 (fr)

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US20050032874A1 (en) 2005-02-10

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