WO2001074782A1 - Agonistes de recepteur adrenergique, compositions agonistes et procedes permettant de les preparer et de les utiliser - Google Patents

Agonistes de recepteur adrenergique, compositions agonistes et procedes permettant de les preparer et de les utiliser Download PDF

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Publication number
WO2001074782A1
WO2001074782A1 PCT/US2001/010376 US0110376W WO0174782A1 WO 2001074782 A1 WO2001074782 A1 WO 2001074782A1 US 0110376 W US0110376 W US 0110376W WO 0174782 A1 WO0174782 A1 WO 0174782A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
adrenoreceptor
compounds
members selected
Prior art date
Application number
PCT/US2001/010376
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English (en)
Inventor
Dennis R. Feller
Duane D. Miller
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Molecular Design International, Inc.
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 Molecular Design International, Inc. filed Critical Molecular Design International, Inc.
Priority to US10/149,953 priority Critical patent/US6593341B2/en
Priority to AU87298/01A priority patent/AU782148B2/en
Priority to EP01964673A priority patent/EP1373212A4/fr
Priority to PCT/US2001/010376 priority patent/WO2001074782A1/fr
Publication of WO2001074782A1 publication Critical patent/WO2001074782A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

  • the present invention relates to the field of ⁇ 3-Adrenoreceptor agonists and to methods of their preparation, formulation and use to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals. More particularly, the present invention relates to the field of treating obesity and overweight conditions in animals, particularly humans and other mammals and associated effects of conditions associated with obesity and overweight, including Type II diabetes mellitus (non-insulin dependent diabetes), insulin resistance, glucose intolerance, hypothyroidism, morbid obesity, and the like.
  • Type II diabetes mellitus non-insulin dependent diabetes
  • insulin resistance glucose intolerance
  • hypothyroidism morbid obesity, and the like.
  • ⁇ -Adrenoreceptor sub-type ⁇ 3- Adrenoreceptors.
  • the specific structure of the ⁇ 3-Adrenoreceptor has not been characterized, but it has been demonstrated to be a distinct cellular structure, distinguishable from the ⁇ i-Adrenoreceptor and the ⁇ 2-Adrenoreceptor sites previously identified.
  • Another object of the present invention is the provision of safe and effective ⁇ 3 Adrenoreceptor formulations for administration to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • Still another object of the present invention is to provide safe and effective administration of ⁇ 3-Adrenoreceptor agonists for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • Yet another object of the present invention is to provide a safe and effective regimen for causing and promoting weight loss in humans, and for the maintenance of healthy and personally desired body fat levels.
  • Still another object of the present invention is to provide safe and effective adjuncts to the husbandry of domesticated animals for the production of low fat dietary meats for human consumption.
  • the primary objective of the present invention is to provide for weight and body fat regulation through modalities which are effective and safe.
  • the present invention provides a clear path to safe and effective regulation of body weight and body fat which is safe and effective, which can provide significant and long lasting relief from the health consequences of overweight and obesity and the conditions associated therewith, and from the disease conditions which are aggravated by overweight and obesity.
  • Compounds which are highly potent and highly specific ⁇ 3-Adrenoreceptor agonists are provided.
  • the compounds are formulated into pharmaceutical preparations and administered for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • the compounds of the invention have the structure:
  • Ri and R_ are each independently members selected from the group consisting of H, OH, Cl, NO2, CH3SO2NH, NH2, CH3O and weak acids of the structure R7-NH, where R7 is an acyl group, wherein at least one of Ri and R2 is OH. It is generally preferred that R2 be OH.
  • R3, R4 and Rs are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
  • R4 and R5 are each a halogen, the same or different.
  • R- is an acid moiety which forms an acid salt with the NH group.
  • Re is desirably HCl or (COOH) 2 .
  • racemic mixtures are active, selective, and bioavailable, we have found that the isolated isomers are ordinarily of more particular interest.
  • the S(-) isomers are preferred, as they will be found to have the highest selectivity and the highest bioavailability.
  • the R(+) isomers are also of interest, as the R-isomers are in some cases easier to isolate.
  • the compounds are formulated into pharmaceutical carriers to serve as highly selective, effective and safe ⁇ 3-Adrenoreceptor agonists to provide long term weight control.
  • compositions are administered to control body fat levels, and to maintain acceptable body fat levels over time.
  • compositions are administered to attain desirably low fat content in carcass meats intended for human consumption.
  • the compounds of the present invention the method of their synthesis, their formulation into pharmaceutical compositions suitable for administration, and the method of their use for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals..
  • the highly desirable goals of stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals through the modality of administering a pharmaceutical formulation of one or more compounds which are ⁇ - Adrenoreceptor selective agonists is provided.
  • the regulatory and modulatory effect of the compounds of the present invention are dependent on continued administration over time, and the attainment of an equilibrium state which is believed to be dose dependent. In that fashion, the present invention affords the control of body fat in animals, particularly humans and other mammals, over sustained periods, at desirable levels of body fat and /or body mass indices, as defined in the medical literature.
  • the compounds of the present invention attain the high affinity for the ⁇ - Adrenoreceptor, the low affinity for the ⁇ i Adrenoreceptor and the ⁇ Adrenoreceptor required for effective selectivity and freedom from adverse side effects, and high levels of agonist activity to make the compounds effect in their required role in fat metabolism.
  • Adrenaline to exemplify the biochemical action of these catechol amine hormones, is a primary agonist for these receptors in the body, and activates metabolic processes within the cells to which it binds.
  • Adrenaline is associated with specific cellular processes which are dependent upon the nature of the cell to which it is bound.
  • the action of adrenaline on the cell is to activate an enzyme within the cell, adenylate cyclase.
  • the adenylate cyclase in turn catalyses further reactions within the target cell, typically beginning an enzyme cascade until the enzyme is broken down or deactivated by cellular regulatory mechanisms.
  • the primary action of adenylate cyclase is the conversion of ATP to cAMP (cyclic adenosine monophosphate or "cyclic adenylate").
  • the cAMP activates, in turn, an enzyme cascade which catalyses the conversion of glycogen into glucose and inhibits the conversion of glucose into glycogen, greatly increasing extra-cellular levels of blood glucose in the body.
  • cAMP triggers the breakdown of glycogen into lactate and ATP, providing high levels of ATP to support high levels of muscular activity.
  • the effect is hypertensive and is accompanied by vasodilation throughout the body, increasing blood flow and transport of blood glucose to the cells.
  • ⁇ -blockers are among the commonly prescribed drugs in the field of cardiology. For the hypertensive patient, competitive binding of the blocking agent to the ⁇ Adrenoreceptors modulates and limits the additional hypertensive action of adrenaline on the heart muscle.
  • the ⁇ -blockers may be employed in combination with vasodilators, decreasing the resistance to blood flow peripherally without increasing the heart rate and strength of contraction. A reduction in blood pressure and the work requirement on the heart muscle results.
  • cAMP acts to cause bronchodilation which, when combined with increased blood flow, supplies higher levels of oxygen transport.
  • epinephrine is widely employed to stimulate bronchodilation in the treatment of asthma and allergenic reactions which constrict the bronchia.
  • Adrenoreceptor agonists and blockers have been known for some time, and have proved to be a fruitful field for drug development.
  • Adrenoreceptor agonists and blockers are both competitive and non-competitive (non-equilibrium) binding agents. Some of such agents are ubiquitous in their action, while others exhibit varying degrees of selectivity for the two sub-types (and hence in the action response produced).
  • Trimetoquinol is a potent nonspecific ⁇ -adrenoceptor ( ⁇ -AR) agonist clinically used in Japan as a bronchorelaxant.
  • ⁇ -AR nonspecific ⁇ -adrenoceptor
  • catecholamine hormones such as epinephrine, norepinephrine, dopamine, and the ⁇ -adrenoceptor agonist isoproterenol
  • catecholamine hormones such as epinephrine, norepinephrine, dopamine, and the ⁇ -adrenoceptor agonist isoproterenol
  • isoproterenol is incorporated within the tetrahydroisoquinoline nucleus of trimetoquinol.
  • Aspll3 with Asnll3 abolished receptor binding of trimetoquinol and its analogs.
  • Fraundorfer, P. F. "Functional and biochemical Characterization of trimetoquinol (TMQ) analog interactions with ⁇ -adrenergic receptor subtypes" Ph. D.
  • trimetoquinol analogs may interact with the same amino acid residues in the binding site as isoproterenol, the contribution of catechol interactions with these mutated ⁇ Adrenoreceptors is less significant in terms of ligand binding and may well be overshadowed by the binding contributions of the trimethoxybenzyl group of trimetoquinol.
  • trimetoquinol analogs interact with an auxiliary site through the substituted benzyl group in addition to the binding site shared by catecholamines. This subsite can be used to advantage in the development of more site-selective agents.
  • the high potency of compound 2 seems to suggest that this auxiliary site is hydrophobic in nature.
  • the complementary binding sites for trimetoquinol analogs are essentially unknown.
  • compound 2 is a more potent TP receptor antagonist than trimetoquinol further suggesting that 1- benzyl ring modifications are appropriate to develop agents with greater selectivity on ⁇ -Adrenoreceptor versus TP receptors and vice versa.
  • Adrenoreceptor and ⁇ Adrenoreceptor agonists include Isoproterenol, X and Y, having the structures:
  • the present invention is based on the provision of ⁇ 3-Adrenoreceptor agonists in pharmaceutically acceptable carrier formulations for administration to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • the present invention additionally provides a method for safe and effective administration of ⁇ 3-Adrenoreceptor agonists for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • Compounds which are highly potent and highly specific ⁇ 3-Adrenoreceptor agonists are provided.
  • the compounds are formulated into pharmaceutical preparations and administered for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
  • the compounds of the invention have the structure:
  • Ri and R2 are each independently members selected from the group consisting of H, OH, Cl, NO2, CH3S02NH, NH2, CH3O and weak acids of the structure R7-NH, where R7 is an acyl group, wherein at least one of Ri and R2 is OH. It is generally preferred that R2 be OH.
  • R3, R. and R5 are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
  • R4 and R5 are each a halogen, the same or different.
  • R5 is an acid moiety which forms an acid salt with the NH group.
  • Re is desirably HCl or (COOH) 2 .
  • racemic mixtures are active, selective, and bioavailable, we have found that the isolated isomers are ordinarily of more particular interest.
  • the S(-) isomers are preferred, as they will be found to have the highest selectivity and the highest bioavailability.
  • the R(+) isomers are also effective.
  • the compounds of the present invention be further qualified and limited to those with high bioavailability, high selectivity and high activity for the ⁇ 3-Adrenoreceptor.
  • selectivity is highest for the S-isomers, and these are generally preferred for these reasons.
  • preferred species are the following:
  • moieties X, Y, and Z are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl.
  • X and Z are each a halogen, the same or different:
  • Formula C-R Preferred species of these structures having particularly good properties include the following compounds:
  • the tetrahydroisoquinolines 6a-c were synthesized from the O-methyl or O-benzyl protected catecholamines 3a or 3b, respectively, and 4- nitrophenylacetic acid (4a) or 3,5-bis-trifluoromethylphenylacetic acid (4b) using methods described previously. Clark, M. T.; Adejare, A.; Shams, G.; Feller, D. R.; Miller, D. D. "5-fluoro- and 8- fluorotrimetoquinol: selective beta 2-adrenoceptor agonists" / Med Chem 1987, 30, 86-90.; Harrold, M. W.; Gerhardt, M. A.; Romstedt, K.; Feller, D.
  • Isolation of the stereo isomers is performed by known techniques, including recrystallization, column separation using HPLC, adsorption chromotography, and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés qui sont des agonistes très efficaces et très spécifiques du récepteur adrénergique β3. Ces composés sont formulés dans des préparations pharmaceutiques et sont administrés pour stimuler, réguler et moduler le métabolisme des graisses dans des tissus adipeux d'animaux, en particulier chez les humains et d'autres mammifères. Ces composés présentent la structure suivante : formule A dans laquelle R1 et R2 désignent chacun indépendamment l'un de l'autre, des membres sélectionnés comprenant H, OH, Cl, NO2, CH2SO2NH, NH2, CH3O et des acides inférieurs de la structure R7-NH, où R7 désigne un groupe acyle, où au moins R1 et R2 désignent OH. De manière générale, il est préférable que R2 désigne OH ; que R3, R4 et R5 désignent indépendamment les uns des autres et différemment les uns des autres des membres sélectionnés dans le groupe comprenant I, Br, Cl, F, OCH3, CH3, alkyle, alkylaryle, aminoalkyle, thioalkyle et O-alkyle. R4 et R5 désignent de préférence chacun un halogène, identique ou différent, R6 désigne une fraction acide qui forme un sel acide avec le groupe NH. Il est souhaitable que R6 désigne HCl ou (COOH)2. Alors que les mélanges racémiques sont actifs, sélectifs et biodisponibles, nous avons observé que les isomères isolés relèvent habituellement d'un intérêt particulier. Les S(-)-isomères ont la préférence car ils présentent la plus grande sélectivité et la plus grande biodisponibilité. Les R(+)isomères présentent également un intérêt, du fait que les R-isomères sont dans certains cas plus aisés à isoler. Les composés sont formulés dans des excipients pharmaceutiques afin d'être utilisés comme agonistes très sélectifs, efficaces et fiables du récepteur adrénergique β3 afin de garantir une surveillance du poids à long terme. Chez l'homme, ces compositions sont administrées afin de réguler les niveaux d'adiposité et de maintenir des niveaux d'adiposité acceptable dans le temps. Chez les animaux domestiques, ces compositions sont administrées afin d'obtenir une faible teneur en graisse dans les viandes en carcasse destinées à l'alimentation humaine.
PCT/US2001/010376 2001-03-29 2001-03-29 Agonistes de recepteur adrenergique, compositions agonistes et procedes permettant de les preparer et de les utiliser WO2001074782A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/149,953 US6593341B2 (en) 2001-03-29 2001-03-29 β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same
AU87298/01A AU782148B2 (en) 2001-03-29 2001-03-29 Beta3-adrenoreceptor agonists, agonist compositions and methods of making and using the same
EP01964673A EP1373212A4 (fr) 2001-03-29 2001-03-29 Agonistes de recepteur adrenergique-beta-3, compositions agonistes et procedes permettant de les preparer et de les utiliser
PCT/US2001/010376 WO2001074782A1 (fr) 2001-03-29 2001-03-29 Agonistes de recepteur adrenergique, compositions agonistes et procedes permettant de les preparer et de les utiliser

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PCT/US2001/010376 WO2001074782A1 (fr) 2001-03-29 2001-03-29 Agonistes de recepteur adrenergique, compositions agonistes et procedes permettant de les preparer et de les utiliser

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US10/269,438 Continuation-In-Part US6596734B1 (en) 2002-10-11 2002-10-11 Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists

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WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
WO2007029847A1 (fr) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Dérivé de pyridone substitué aromatique bicylique
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007049798A1 (fr) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Nouveau derive de benzoxathiine
WO2007055418A1 (fr) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Derive spiro aza-substitue
WO2008038692A1 (fr) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. dÉrivÉ de diarylcÉtimine
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EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2009110510A1 (fr) 2008-03-06 2009-09-11 萬有製薬株式会社 Dérivé d'alkylaminopyridine
WO2009119726A1 (fr) 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine
WO2010013595A1 (fr) 2008-07-30 2010-02-04 萬有製薬株式会社 Dérivé de cycloalkylamine à noyaux fusionnés à (5 chaînons)-(5 chaînons) ou (5 chaînons)–(6 chaînons)
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EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
EP2332526A2 (fr) 2005-10-21 2011-06-15 Novartis AG combinaison d'un inhibiteur de rénine avec un agent anti-dyslipidémique ou un agent anti-obèse
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2016030534A1 (fr) 2014-08-29 2016-03-03 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2018069532A1 (fr) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
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WO2020104456A1 (fr) 2018-11-20 2020-05-28 Tes Pharma S.R.L Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
US11357757B2 (en) 2017-09-13 2022-06-14 Atrogi Ab Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia
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US11648216B2 (en) 2017-09-13 2023-05-16 Atrogi Ab Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia
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WO2023203223A1 (fr) 2022-04-22 2023-10-26 Atrogi Ab Combinaisons d'agonistes du récepteur bêta 2-adrénergique et d'agonistes du récepteur bêta 3-adrénergique et leurs utilisations médicales

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Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
WO2007029847A1 (fr) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Dérivé de pyridone substitué aromatique bicylique
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
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