WO1996026948A1 - Derives phosphates d'urees et de thiourees bisubstituees - Google Patents

Derives phosphates d'urees et de thiourees bisubstituees Download PDF

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Publication number
WO1996026948A1
WO1996026948A1 PCT/EP1996/000781 EP9600781W WO9626948A1 WO 1996026948 A1 WO1996026948 A1 WO 1996026948A1 EP 9600781 W EP9600781 W EP 9600781W WO 9626948 A1 WO9626948 A1 WO 9626948A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
ureidomethyl
alkyl
Prior art date
Application number
PCT/EP1996/000781
Other languages
English (en)
Inventor
Daniele Fancelli
Dino Severino
Augusto Chiari
Pierpaolo Lovisolo
Giancarlo Ghiselli
Original Assignee
Pharmacia & Upjohn S.P.A.
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 Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to AU49415/96A priority Critical patent/AU4941596A/en
Publication of WO1996026948A1 publication Critical patent/WO1996026948A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention relates to novel compounds having ACAT inhibitory activity, to a process for their preparation and to pharmaceutical compositions containing them
  • the inhibition of the enzime acylCoAxholesterol acyltransferase is generally considered one of the most appealing approaches to the treatment of dyslipidemias and to the prevention of the atherosclerotic process (Exp Opin Invest Drugs (1994) 3(5) 427-436)
  • ACAT inhibitors are well known in the art, for instance, the inventors of the present invention in EP 0500348 disclosed a new class of urea and thiourea derivatives endowed with high //; vitro ACAT inhibitory activity
  • urea and thiourea derivatives similarly to most of the known ACAT inhibitors, were characterized by high lipophilicity, extreme low aqueous solubility and low bioavailability; by consequence their effects on blood and tissutal cholesterol levels were indirect and appeared almost exclusively related to a reduction of the intestinal cholesterol absorption
  • Y is independently O or S; one of Ri and R2 is OPO(OH) 2 and the other is hydrogen, Cj-Cg alkyl, halo, hydroxy, Cj-
  • each of R 3 and R 4 being the same or different, is C j -C ⁇ alkyl; or R 3 and R , taken together, form a C 2 -C 4 alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halo or C1-C3 alkyl; and the pharmaceutically acceptable salts thereof.
  • the alkyl and alkoxy groups may be branched or straight groups.
  • Representative examples of Cj-C ( 5 alkyl groups include methyl, ethyl, n- and /.vo-propyl, «-, ⁇ VO-, sec- and tert-butyl.
  • CJ-C 4 alkoxy groups include methoxy or ethoxy.
  • a C 1 -C3 alkyl group is in particular methyl or ethyl.
  • Halo includes fluoro, bromo, chlorine or iodine, in particular chlorine or bromine.
  • R 3 and R 4 taken together, are a C2-C4 alkylene chain and X is oxygen, then the resulting pentatomic, hexatomic or heptatomic 1,3-dioxalkyl ring is respectively a 1,3- dioxolan, 1,3-dioxan or 1,3-dioxepan ring which may be represented by the formula
  • R3-R 4 represents a C 2 -C 4 alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halogen, in particular chlorine or C1-C alkyl, in particular methyl.
  • R 3 and R 4 taken together, are a C 2 -C 4 alkylene chain and X is sulfur, then the resulting pentatomic, hexatomic or heptatomic 1 ,3-dithialkyl ring is respectively a 1,3- dithiolan, 1 ,3-dithian or 1,3-dithiepan ring which may be represented by the formula
  • R3-R 4 represents a C2-C 4 alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halogen, in particular chlorine or C j -C ⁇ alkyl, in particular methyl.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include the salts of inorganic bases, for example hydroxides of alkaly metals, e.g. sodium or potassium, or alkaline-heart metals, e.g. calcium or magnesium, and the salts of organic bases organic bases, such as for example aliphatic amines, e.g. methylamine, ethylamine, diethylamine, trimethylamine, or heterocyclic amines, e.g. piperidine.
  • inorganic bases for example hydroxides of alkaly metals, e.g. sodium or potassium, or alkaline-heart metals, e.g. calcium or magnesium
  • organic bases organic bases such as for example aliphatic amines, e.g. methylamine, ethylamine, diethylamine, trimethylamine, or heterocyclic amines, e.g. piperidine.
  • the present invention also include within its scope all the possible isomers, stereoisomers, and their mixtures and both the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I).
  • Preferred compounds of the invention are the compounds of formula (I) wherein:
  • X is O ;
  • Y is O ; one of Rj and R 2 is OPO(OH) 2 and the other is hydrogen; R 3 and R 4 , taken together, are a C2-C alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halo or C ⁇ -C 2 alkyl; and the pharmaceutically acceptable salts thereof.
  • the compounds of the invention and the salts thereof can be obtained by a process comprising the hydrogenolysis of a compound of formula (II)
  • Bn means benzyl and R2, R3, R4, Y and X are as defined above by reaction with hydrogen in the presence of a catalyst; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or resolving a mixture of compounds of formula (I) into the single isomers and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
  • the hydrogenolysis reaction of a compound of formula (II) to obtain a compound of formula (I) can be carried out according to well known methods in the art.
  • the reaction can be performed in a suitable organic solvent e.g. methyl alcohol, at room temperature, in the presence of a hydrogenation catalyst such as e.g. palladium on chaorcal or platinum black under a low pressure e.g. from 1 to 5 atm of hydrogen.
  • a hydrogenation catalyst such as e.g. palladium on chaorcal or platinum black under a low pressure e.g. from 1 to 5 atm of hydrogen.
  • R 2 , R3, R 4 , Y and X are as defined above, by reaction with dibenzylpyrophosphate in an opportune organic solvent such as e g dimethylformamide or acetonitrile in the presence of a base such as e.g. potassium tert-butylate or sodium hydride at a temperature ranging from 0 to 50°C, according to well known procedures.
  • an opportune organic solvent such as e g dimethylformamide or acetonitrile
  • a base such as e.g. potassium tert-butylate or sodium hydride
  • Hydroxy compounds of formula (III) can be prepared as described in EP 0 500 348 Al .
  • the compounds of the present invention show inhibitory activity of the enzyme acyl Co A: cholesterol acyltransferase (ACAT-EC 2.3 1.26) which regulates the intracellular esterification of cholesterol (J Lip Res ( 1985) 26 647) and thus the intracellular accumulation of cholesteryl esters
  • acyl Co A cholesterol acyltransferase
  • This enzyme increases to the greatest extent during the atherosclerotic process in which the accumulation of esterified cholesterol in the atherosclerotic plaque is one of the predominant events (B B A ( 1980) 617 458)
  • compounds of the present invention contrary to those disclosed in EP 0500348, can be included into injectable preparations, therefore they can reach high plasmatic levels, that are useful for the direct and efficient inhibition of the liver and aortic enzyme
  • the compounds of the present invention besides having antidyslipidemic activity, can also act as direct antiatherosclerotic agents, able to inhibit the development of the atheromatous plaque, and therefore M_, are useful in particular for
  • Plasma lipids (mg/dl) a
  • FC free cholesterol
  • CE cliole .teiol estei s
  • TG t ⁇ gl ⁇ cendes
  • PL phosphohpids
  • the dosage level suitable for administration to adult humans depends on the age, weight, conditions of the patient and on the administration route, for example, the dosage adopted for oral administration e g for the representative compound of the invention FCE 28654A may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily
  • the compounds cf the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e g intramuscolarly, or by intravenous injection or infusion.
  • the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
  • compositions containing the compounds of the invention are usually prepared following onventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, destrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e g starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, destrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersion for oral administration may be e.g syrups, emulsions and suspension.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspension and the emulsion may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol
  • the suspension or solutions for intramuscolar injections may contain, togethr with the active compound, a pharmaceutically acceptable carrier, e g sterile water, olive oil, ethyl oleate, glycols, e g propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride
  • a pharmaceutically acceptable carrier e g sterile water, olive oil, ethyl oleate, glycols, e g propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride
  • the solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e g cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin
  • a pharmaceutically acceptable carrier e g cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin
  • Example 1 Preparation of (-)-4- ⁇ (4R, 5R)2-[3-(2,6-d ⁇ sopropyl-phenyl)ureidomethyl]- 4,5-dimethyl- 1 ,3-dioxoIan-2-yl ⁇ phenylphosphate monosodium salt (FCE 28654 A).
  • the phosphate was conveniently isolated as the monosodium salt by adding to the acid in ethyl alcohol i equivalent of sodium acetate in acqueous ethyl alcohol After evaporation of the solvent the residue was taken up with n-hexane/diethyl ether, filtered and dried yielding 450 mg of the title compound as a colorless powder.
  • preparation can be made of capsules having the following composition

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à un nouveau composé présentant une activité inhibitrice par rapport à l'enzyme acyle CoA cholestérol acyltransférase (ACAT) et répondant à la formule (I) dans laquelle les substituants X, qui sont identiques, représentent O ou S; Y représente indépendamment O ou S; l'un des symboles R1 et R2 représente OPO(OH)2, et l'autre représente hydrogène, alkyle C1-C6, halo, hydroxy, alcoxy C1-C4 ou OPO(OH)2; R3 et R4, qui sont identiques ou différents, représentent chacun alkyle C1-C6; ou R3 et R4 forment ensemble une chaîne alkylène C2-C4 dans laquelle chaque atome de carbone peut éventuellement être substitué par 1 ou 2 substituants indépendamment choisis entre halo et alkyle C1-C3; ainsi qu'à leurs sels pharmaceutiquement acceptables.
PCT/EP1996/000781 1995-03-01 1996-02-26 Derives phosphates d'urees et de thiourees bisubstituees WO1996026948A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49415/96A AU4941596A (en) 1995-03-01 1996-02-26 Phosphate derivatives of disubstituted ureas and thioureas

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9504066.3A GB9504066D0 (en) 1995-03-01 1995-03-01 Phosphate derivatives of ureas and thioureas
GB9504066.3 1995-03-01

Publications (1)

Publication Number Publication Date
WO1996026948A1 true WO1996026948A1 (fr) 1996-09-06

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Country Status (3)

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AU (1) AU4941596A (fr)
GB (1) GB9504066D0 (fr)
WO (1) WO1996026948A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135586B2 (en) 2000-11-21 2006-11-14 Janssen Pharmaceutica, Nv Biphenylcarboxamides useful as lipid lowering agents
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
US7642378B2 (en) 2001-04-06 2010-01-05 Janssen Pharmaceutica Nv Lipid lowering biphenylcarboxamides
WO2010093601A1 (fr) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Nouveaux thyromimetiques contenant de l'acide sulfonique et methodes d'utilisation associees
US7923573B2 (en) 2004-10-27 2011-04-12 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
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
WO2011145022A1 (fr) 2010-05-21 2011-11-24 Pfizer Inc. 2-phénylbenzoylamides
EP2392567A1 (fr) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Derives de benzothiazine et leurs utilisation comme modulateurs de lxr
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
EP2428516A1 (fr) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Nouvelles substances thyromimetiques contenant du phosphore
US8258304B2 (en) 2002-08-12 2012-09-04 Janssen Pharmaceutica N.V. N-aryl piperidine substituted biphenylcarboxamides
WO2012120414A2 (fr) 2011-03-04 2012-09-13 Pfizer Inc. Peptides de type edn3 et utilisations associées
US8354402B2 (en) 2000-09-04 2013-01-15 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
WO2014170786A1 (fr) 2013-04-17 2014-10-23 Pfizer Inc. Dérivés de n-pipéridin-3-ylbenzamide dans le traitement des maladies cardiovasculaires
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
WO2016055901A1 (fr) 2014-10-08 2016-04-14 Pfizer Inc. Composés d'amide substitué
EP3025727A1 (fr) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Procédés de traitement des maladies du foie
WO2020150473A2 (fr) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Inhibiteurs de pcsk9 et leurs procédés d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0500348A1 (fr) * 1991-02-19 1992-08-26 PHARMACIA S.p.A. Urées et thiurées disubstituées
WO1995004053A1 (fr) * 1993-08-03 1995-02-09 Pharmacia S.P.A. Derives de l'uree et de la thiouree et procede pour leur preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0500348A1 (fr) * 1991-02-19 1992-08-26 PHARMACIA S.p.A. Urées et thiurées disubstituées
WO1995004053A1 (fr) * 1993-08-03 1995-02-09 Pharmacia S.P.A. Derives de l'uree et de la thiouree et procede pour leur preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHIARI A ET AL: "Synthesis and pharmacological profile of FCE 28654: a water-soluble and injectable ACAT inhibitor", BIOORG. MED. CHEM. LETT. (BMCLE8,0960894X);95; VOL.5 (15); PP.1581-6, PHARM. PHARMACEUTICALS MILAN RES. INST.;NERVIANO; 20014; ITALY (IT), XP000573760 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8354402B2 (en) 2000-09-04 2013-01-15 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
US7135586B2 (en) 2000-11-21 2006-11-14 Janssen Pharmaceutica, Nv Biphenylcarboxamides useful as lipid lowering agents
US7405307B2 (en) 2000-11-21 2008-07-29 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7538124B2 (en) 2000-11-21 2009-05-26 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7642378B2 (en) 2001-04-06 2010-01-05 Janssen Pharmaceutica Nv Lipid lowering biphenylcarboxamides
US8258304B2 (en) 2002-08-12 2012-09-04 Janssen Pharmaceutica N.V. N-aryl piperidine substituted biphenylcarboxamides
EP2428516A1 (fr) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Nouvelles substances thyromimetiques contenant du phosphore
US11554113B2 (en) 2004-03-05 2023-01-17 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US10555938B2 (en) 2004-03-05 2020-02-11 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US10016404B2 (en) 2004-03-05 2018-07-10 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9433617B1 (en) 2004-03-05 2016-09-06 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9364470B2 (en) 2004-03-05 2016-06-14 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US7923573B2 (en) 2004-10-27 2011-04-12 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
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
EP2392567A1 (fr) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Derives de benzothiazine et leurs utilisation comme modulateurs de lxr
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
EP3025727A1 (fr) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Procédés de traitement des maladies du foie
WO2010093601A1 (fr) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Nouveaux thyromimetiques contenant de l'acide sulfonique et methodes d'utilisation associees
WO2011145022A1 (fr) 2010-05-21 2011-11-24 Pfizer Inc. 2-phénylbenzoylamides
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012120414A2 (fr) 2011-03-04 2012-09-13 Pfizer Inc. Peptides de type edn3 et utilisations associées
WO2014170786A1 (fr) 2013-04-17 2014-10-23 Pfizer Inc. Dérivés de n-pipéridin-3-ylbenzamide dans le traitement des maladies cardiovasculaires
WO2016055901A1 (fr) 2014-10-08 2016-04-14 Pfizer Inc. Composés d'amide substitué
WO2020150473A2 (fr) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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AU4941596A (en) 1996-09-18
GB9504066D0 (en) 1995-04-19

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