WO2007132475A1 - Agoniste sélectif de la tr-bêta 1 - Google Patents

Agoniste sélectif de la tr-bêta 1 Download PDF

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Publication number
WO2007132475A1
WO2007132475A1 PCT/IN2007/000159 IN2007000159W WO2007132475A1 WO 2007132475 A1 WO2007132475 A1 WO 2007132475A1 IN 2007000159 W IN2007000159 W IN 2007000159W WO 2007132475 A1 WO2007132475 A1 WO 2007132475A1
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WO
WIPO (PCT)
Prior art keywords
phenoxy
dichloro
phenyl
dione
hydroxy
Prior art date
Application number
PCT/IN2007/000159
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English (en)
Inventor
Saurin Raval
Preeti Raval
Braj Bhushan Lohray
Vidya Bhushan Lohray
Pankaj Ramanbhai Patel
Original Assignee
Cadila Healthcare Limited
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
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2007132475A1 publication Critical patent/WO2007132475A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds of general formula (I) which are thyroid receptor ligands and are preferably selective for the thyroid ho ⁇ none receptor beta. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.
  • Thyroid hormone Triiodothyronine (T3) is an important endocrine signaling hormone and it is essential for normal development, differentiation and maintenance of metabolic balance in mammals. Natural thyroid hormone, T3 exhibit its physiological effect by acting on a Thyroid Hormone Receptor (THR), which belongs to the nuclear hormone receptor super family. There are two different isoforms of Thyroid Hormone
  • THR- ⁇ and THR- ⁇ are sub-classified as ⁇ l; ⁇ 2 and ⁇ l; ⁇ 2 subtypes.
  • THR ⁇ l is prevalent in liver (85%), while THR ⁇ l is mainly present in cardiac tissue (Yen P. M., Physiol. Rev; 81 (2001) 1097-1142).
  • T3 maintains body weight, metabolic rate, body temperature, mood and regulate serum cholesterol.
  • Hypothyroidism is associated with weight gain, high levels of low-density lipoproteins (LDL) cholesterol and depression.
  • LDL low-density lipoproteins
  • Hyperthyroidism leads to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, bone loss and anxiety.
  • T3 The natural thyroid hormone T3 does not show any selectivity in binding to both of the THR isoforms (THR ⁇ l and THR ⁇ l). Thus, administration of T3 lowers plasma cholesterol, low-density lipoprotein (LDL) and triglyceride levels in animal models and humans.
  • LDL low-density lipoprotein
  • T3 cannot be used therapeutically to treat hypercholesterolemia and obesity due to its cardiac side effects.
  • knockout l animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the TEDR. ⁇ l isoform.
  • some effects of T3 may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation (Cheng S., Steroids; 70 (2005); 450-454).
  • THR ⁇ l agonist could lead to specific therapies for disorders such as obesity and hyperlipidemia, while avoiding the cardiovascular and other toxicities of native thyroid hormones.
  • compounds mimicking only the beneficial effects of the thyroid hormone and lacking their cardiac side effects potentially could be used to treat a number of conditions such as obesity and dyslipidemia.
  • THR agonists that interact selectively with the ⁇ l isoform of the THR offer an especially attractive method for avoiding cardio-toxicity (J. D. Baxter; Trends Endocrinol. Metab., 15 (2004); 154-157).
  • the present invention describes novel compounds that are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor beta I 9 which are useful for the treatment of a number of conditions such as obesity and dyslipidemia.
  • the novel compounds are defined by the general formula (I) as given below.
  • the compounds of the present invention are useful in the treatment of the human or animal body, by regulation of selective thyroid hormone receptor gene expression.
  • the compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of obesity and dyslipidemia.
  • novel compounds of the present invention as antidiabetic agents, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
  • R OR 15 NHR 1 wherein Ri may be selected from H, optionally substituted groups selected from (Ci- C6)alkyl, (C 3 -C 7 )cycloalkyl, acyl, aryl, aralkyl groups; in a preferred embodiment the alkyl groups is selected from (Ci-C 3 )alkyl and the aryl group represents optionally substituted phenyl group;
  • R 2 represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (Ci-C 6 )alkyl, acyl, oxo, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives such as (Ci-C 3 )alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing -CONRsR 6 , -SO 2 NRSR O , wherein
  • R 5 and R 6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-C6)alkyl, (C3-C 7 )cycloalkyl, bicycloalkyl, aryl or the groups R 5 and R 6 together with the nitrogen atom to which they are attached, form a six to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
  • R 2 may be selected from hydroxy, halo, optionally substituted groups selected from (Ci-C 6 )alkyl, phenyl, heteroaryl groups;
  • the various groups representing R 2 may be selected from - optionally substituted (Ci-C ⁇ )alkyl, acyl, oxo, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives such as (Ci-C 3 )alkyl esters and amides, or the groups representing -CONR 5 R 6 , -SO 2 NR 5 R 6 , wherein
  • R 5 and R 6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-Ce)alkyl, (C 3 -C 7 )cycloalkyl, bicycloalkyl, phenyl or the groups R 5 & R 6 together with the nitrogen atom to which they are attached, form a six to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
  • R 3 , R 4 may be same or different and independently selected from H, halogen, optionally substituted (Q-C ⁇ alkyl groups;
  • X is selected from O, -CH 2 -, CO;
  • Y is selected from O, S, -NH or the group representing -CR 7 Rs, wherein R 7 , R 8 may be same or different and independently selected from hydrogen, halogen optionally substituted groups selected from (Q-C ⁇ alkyl groups; Z may be selected from H, groups;
  • the substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxy 1, halo, cyano, optionally substituted groups selected from (Ci-C 6 )alkyl, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups. When any of these groups are further substituted, the substituents on these substitutes may be selected from those described above.
  • radicals described above may be selected from:
  • alkyl used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, /7-propyl, ⁇ o-propyl, «-butyl, sec-butyl, tert-butyl, amyl, t-am ⁇ l, «-pentyl, n- hexyl, w ⁇ -hexyl and the like;
  • cycloalkyl or "alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like;
  • alkoxy group used either alone or in combination with other radicals is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n- propoxy, /so-propoxy, R-butoxy, t-butoxy, ⁇ -butoxy, pentyloxy, hexyloxy, and the like;
  • haloalkyl is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(Ci-C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • perhaloalkyl more preferably, perfluoro(Ci-C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • aryl or aromatic group used either alone or in combination with other radicals is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
  • heteroaryl or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from
  • the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphth
  • acyl group used either alone or in combination with other radicals is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, wo-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
  • carboxylic acid used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides;
  • ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; - the "amide" group used alone or in combination
  • alkylthio denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted;
  • thioalkyl used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted;
  • sulfenyl group or “sulfenyl derivatives” used alone or in combination with other radicals, represents a bivalent group, -SO- or R x SO, where R x is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above;
  • the "sulfonyl” group or “sulfones derivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -SO 2 -, or R x SO 2 -, where R x is as defined above.
  • the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • Preferred compounds according to the present invention include but not limited to: l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; 1 - [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -[ 1 ,2,4]triazolidine-3 , 5 - dione;
  • This amine 2 was converted to it's corresponding hydrazine compound 3 by reacting the amine 2_with NaNO 2 and then reducing with SnCl 2 .2H 2 O.
  • Compound 3 may be reacted with Ethyl ailophanate to give a compound of formula (1).
  • Further compound of formula (V) may be prepared by suitably deprotecting the protecting group R.
  • Step 1 Preparation of 4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine To a solution of Stannous chloride dihydrate (3.46 g, O.Ol ⁇ mol) in concentrated
  • Step 2 Preparation of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
  • Step 3 Preparation of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
  • a solution of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione (180 mg, 0.42 mmol) in CH 2 Cl 2 (5 mL) was cooled to -60 0 C under nitrogen atmosphere. To that IM BBr 3 solution (0.85 mL) was added dropwise.
  • reaction mixture was allowed to warm up to 20-25 0 C over 3 h. Then diluted with more ethyl acetate (25 mL) and quenched with H 2 O(20 mL). After stirring at 20-25 0 C for 30-45 min organic phase was separated, washed with H 2 O & brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 100 mg of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione.
  • Step 1 Preparation of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
  • Stannous chloride dihydrate 10.97 g, 0.048 mol
  • concentrated HCl 3 mL
  • 3,5-dichloro-4-(4'-methoxy-3'-sec-butyl- phenoxy)nitrobenzene 4.5 g, 0.012 mol
  • EtOH 25 mL
  • the reaction mixture was refluxed for 2 h.
  • the resulting mixture was brought at 20-30 0 C and diluted with ethyl acetate (100 mL).
  • the mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite.
  • Step 2 Preparation of [4-(3-sec-Buty l-4-methoxy-phenoxy)-3, 5 -dichloro-phenyl] - hydrazine To a mixture of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
  • Step 4 Preparation of 1 -[4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3, 5 -dichloro-phenyl] - [l,2,4]triazolidine-3,5-dione
  • novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of formula (1) or pharmaceutical compositions containing them are useful as Thyroid hormone receptor ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc.
  • the pharmaceutical composition is provided by employing conventional techniques.
  • the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (1) according to this invention.
  • the quantity of active component that is, the compounds of formula (1) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouveaux composés de formule générale (I) ligands du récepteur de l'hormone thyroïdienne et spécialement de l'hormone thyroïdienne bêta. L'invention porte en outre sur le procédé de préparation de ces composés, sur leurs tautomères, sur de nouveaux intermédiaires servant à leur leur synthèse, sur leurs sels pharmacocompatibles, sur leurs méthodes d'utilisation et sur des préparations pharmaceutiques les contenant
PCT/IN2007/000159 2006-05-15 2007-04-23 Agoniste sélectif de la tr-bêta 1 WO2007132475A1 (fr)

Applications Claiming Priority (2)

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IN749MU2006 2006-05-15
IN749/MUM/2006 2006-05-15

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WO2007132475A1 true WO2007132475A1 (fr) 2007-11-22

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086878A2 (fr) 2009-01-09 2010-08-05 Cadila Healthcare Limited Modulateurs des récepteurs de la thyroïde
WO2010122980A1 (fr) 2009-04-20 2010-10-28 田辺三菱製薬株式会社 Nouvel agoniste du récepteur ss de l'hormone thyroïdienne
WO2012000896A2 (fr) 2010-06-28 2012-01-05 Bayer Cropscience Ag Composés hétérocycliques utilisés en tant qu'agents de lutte contre les parasites
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2019054514A1 (fr) 2017-09-14 2019-03-21 国立研究開発法人理化学研究所 Procédé de production de tissus rétiniens
WO2020184720A1 (fr) 2019-03-13 2020-09-17 大日本住友製薬株式会社 Procédé d'évaluation de la qualité d'une rétine neurale de transplantation, et feuille de rétine neurale de transplantation
WO2022054925A1 (fr) 2020-09-11 2022-03-17 国立研究開発法人理化学研究所 Complexe contenant des agrégats cellulaires contenant une rétine neuronale, matrice et procédé de fabrication
WO2022054924A1 (fr) 2020-09-11 2022-03-17 大日本住友製薬株式会社 Milieu pour tissu destiné à la transplantation
WO2023090427A1 (fr) 2021-11-19 2023-05-25 国立研究開発法人理化学研究所 Procédé de production de tissu rétinien en forme de feuille

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WO2000039077A2 (fr) * 1998-12-24 2000-07-06 Karo Bio Ab Nouveaux ligands de recepteurs thyroidiens et procede ii
EP1088819A2 (fr) * 1999-09-30 2001-04-04 Pfizer Products Inc. Dérivés de 6-azauracil utiles en tant que ligands du récepteur thyroid
EP1148054A1 (fr) * 2000-04-21 2001-10-24 Pfizer Products Inc. Ligands du recepteur de la thyroide
US6344481B1 (en) * 1999-03-01 2002-02-05 Pfizer Inc. Thyromimetic antiobesity agents
WO2004067482A2 (fr) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Ligands anilide substitues destines au recepteur thyroidien
WO2004093799A2 (fr) * 2003-04-18 2004-11-04 Bristol-Myers Squibb Company Ligands de recepteur des hormones thyroidiennes

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2000039077A2 (fr) * 1998-12-24 2000-07-06 Karo Bio Ab Nouveaux ligands de recepteurs thyroidiens et procede ii
US6344481B1 (en) * 1999-03-01 2002-02-05 Pfizer Inc. Thyromimetic antiobesity agents
EP1088819A2 (fr) * 1999-09-30 2001-04-04 Pfizer Products Inc. Dérivés de 6-azauracil utiles en tant que ligands du récepteur thyroid
EP1148054A1 (fr) * 2000-04-21 2001-10-24 Pfizer Products Inc. Ligands du recepteur de la thyroide
WO2004067482A2 (fr) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Ligands anilide substitues destines au recepteur thyroidien
WO2004093799A2 (fr) * 2003-04-18 2004-11-04 Bristol-Myers Squibb Company Ligands de recepteur des hormones thyroidiennes

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086878A2 (fr) 2009-01-09 2010-08-05 Cadila Healthcare Limited Modulateurs des récepteurs de la thyroïde
WO2010122980A1 (fr) 2009-04-20 2010-10-28 田辺三菱製薬株式会社 Nouvel agoniste du récepteur ss de l'hormone thyroïdienne
US8791266B2 (en) 2009-04-20 2014-07-29 Mitsubishi Tanabe Pharma Corporation Thyroid hormone β receptor agonist
US8686004B2 (en) 2010-06-28 2014-04-01 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2012000896A2 (fr) 2010-06-28 2012-01-05 Bayer Cropscience Ag Composés hétérocycliques utilisés en tant qu'agents de lutte contre les parasites
US9044015B2 (en) 2010-06-28 2015-06-02 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2019054514A1 (fr) 2017-09-14 2019-03-21 国立研究開発法人理化学研究所 Procédé de production de tissus rétiniens
WO2020184720A1 (fr) 2019-03-13 2020-09-17 大日本住友製薬株式会社 Procédé d'évaluation de la qualité d'une rétine neurale de transplantation, et feuille de rétine neurale de transplantation
WO2022054925A1 (fr) 2020-09-11 2022-03-17 国立研究開発法人理化学研究所 Complexe contenant des agrégats cellulaires contenant une rétine neuronale, matrice et procédé de fabrication
WO2022054924A1 (fr) 2020-09-11 2022-03-17 大日本住友製薬株式会社 Milieu pour tissu destiné à la transplantation
WO2023090427A1 (fr) 2021-11-19 2023-05-25 国立研究開発法人理化学研究所 Procédé de production de tissu rétinien en forme de feuille

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