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WO2003047575A1 - Derives de benzamide therapeutiques - Google Patents

Derives de benzamide therapeutiques Download PDF

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Publication number
WO2003047575A1
WO2003047575A1 PCT/EP2002/013591 EP0213591W WO03047575A1 WO 2003047575 A1 WO2003047575 A1 WO 2003047575A1 EP 0213591 W EP0213591 W EP 0213591W WO 03047575 A1 WO03047575 A1 WO 03047575A1
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WO
WIPO (PCT)
Prior art keywords
biphenyl
carboxylic acid
piperazin
amide
phenyl
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.)
Ceased
Application number
PCT/EP2002/013591
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English (en)
Inventor
Alain Claude-Marie Daugan
Nerina Dodic
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to AU2002358574A priority Critical patent/AU2002358574A1/en
Publication of WO2003047575A1 publication Critical patent/WO2003047575A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the invention relates to therapeutic benzamide derivatives and their use in inhibiting hepatic production of apoprotein B-100 (apoB-100) and intestinal production of chylomicrons or apoprotein B-48 (apoB-48) and MTP.
  • ApoB-100 is the main protein component of low density lipoprotein-cholesterol (LDL-c). High LDL-c plasmatic levels are a major risk factor for atherosclerosis and coronary artery diseases. ApoB-48 is the main protein component of chylomicrons.
  • MTP microsomal triglyceride transfer protein
  • triglyceride transfer protein catalyses the transfer of triglycerides, cholesteryl esters and phosphatidylcholine between small unilamellar vesicles.
  • MTP is expressed in liver and intestine, both organs which produce lipoproteins.
  • MTP is able to lipidate neosynthesized apoB-100 within the liver, and neosynthesized apoB-48 within the intestine, therefore leading to the production of triglyceride-rich lipoparticles such as VLDL and chylomicrons respectively.
  • MTP inhibitors have the potential to decrease LDL-c and triglyceride plasmatic levels, and also intestinal lipid absorption.
  • MTP inhibitors may be used in the treatment of non- insulin dependent diabetes mellitus, coronary heart disease, pancreatitis, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipemia, post-prandial hyperlipemia, atherosclerosis and obesity.
  • R 1 represents C- ⁇ -4 alkyl, C 2-6 alkenyl, C 1-4 alkylsulfonyl, C 1-4 acyl or CH 2 -R 4 ;
  • R 2 represents isopropyl or trifluoromethyl
  • R 3 represents methyl or methoxy
  • R 4 represents: i) a 5 or 6-membered heteroaromatic group selected from thienyl, thiazolyl and furanyl, optionally substituted by halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3- 7 cycloalkyl, ii) a 2-pyrrolyl substituted by either 4- or 5- cyano, iii) C 3-7 cycloalkyl, iv) cyano, v) hydroxycarbonyl or vi) C 1-4 alkoxyC 1-4 alkyl, hydroxyC 1- alkyl or vii) trifluoromethylC 1-4 alkyl; or a physiologically acceptable salt, solvate or derivative thereof.
  • Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic and inorganic acids for example, citrates, hydrochlorides, hydrobromides, or sulphates. Particularly preferred salts are citrates or hydrochloride salts.
  • the solvates may, for example, be hydrates.
  • references hereinafter to a compound according to the invention include both compounds of formula (I) and their physiologically acceptable salts together with physiologically acceptable solvates.
  • alkyl groups include methyl and ethyl groups.
  • alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl and ethyl groups
  • examples of alkylene groups include methylene and ethylene groups
  • examples of alkoxy groups include methoxy and ethoxy groups.
  • alkenyl includes both straight and branched chain saturated hydrocarbon groups containing one double bond, e.g. 3- methyl-but-2-ene and propen-2-yl.
  • heteroaromatic group unless otherwise defined, means any single aromatic ring containing at least one ring heteroatom independently selected from O, N and S.
  • reference to a halogen group includes fluoro, chloro, bromo and iodo groups.
  • R 1 is suitably selected from C 1-4 alkyl, e.g. methyl, ethyl, isopropyl, propyl or isobutyl, C 2-
  • R 4 is suitably cyano, ethoxycarbonyl, hydroxycarbonyl, C 1-4 alkoxymethyl e.g. methoxymethyl, trifluoromethylC 1- alkyl, e.g. 1 ,1 ,1 -trif luoroethyl, C 3-7 cycloalkyl e.g.
  • R 1 is more suitably methyl, propyl, isopropyl, propen-2-yl, methoxyethyl, 1 ,1 ,1- trifluoropropyl, an optionally substituted 3-thienylmethyl or 2-furanylmethyl group, where optional substitution is effected by methyl or cyano, or a 2-pyrrolylmethyl, substituted by either 4- or 5- cyano.
  • R 1 is preferably propen-2-yl or 3-thienylmethyl. Alternatively, R 1 is preferably methyl, propyl, propen-2-yl, 2-furanylmethyl substituted by cyano or 3-thienylmethyl.
  • R 1 is most preferably propen-2-yl.
  • R 2 is preferably isopropyl.
  • R 3 is preferably methoxy. R 3 is equally preferably methyl.
  • Particularly preferred compounds of the invention include those in which each variable in formula (I) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in formula (I) is selected from the more preferred or most preferred groups for each variable.
  • Suitable compounds of the invention include:
  • physiologically functional derivative refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester or amide, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof.
  • physiologically acceptable derivative of a compound of the present invention for example, an ester or amide, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof.
  • Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry
  • the compounds of the invention are inhibitors of hepatic production of apoB-100 and MTP and are thus of use in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • the ability of the compounds of this invention to inhibit human MTP activity is measured by an in vitro assay where MTP transfers 3H-triolein between phosphatidylcholine liposomes.
  • the specificity of the compounds of the invention is established by comparing the effects on apoB-100 and apoprotein A-1 production. A specificity of at least 100 is preferred.
  • the in vivo profile of the compounds is determined by acute oral administration of the compounds of the invention to DBA/2 mice and Wistar rats. Potency of the active compounds is evaluated by measuring plasmatic lipids (total cholesterol, triglyceride, LDL cholesterol and HDL cholesterol) and apoproteins (apoB-100, apoB-48 and apoA-
  • the compounds of the invention are potent and specific inhibitors of hepatic production of apoB-100 and MTP, which furthermore exhibit good oral bioavailability and duration of action.
  • the compounds of the present invention exhibit significant oral activity compared with compounds of the prior art. They also possess favourable pharmacokinetic profiles compared with compounds of the prior art.
  • Compounds of the invention are of use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity.
  • NIDDM non-insulin dependent diabetes mellitus
  • Compounds of the invention are also useful in lowering serum lipid levels, cholesterol and/or triglycerides, and are of use in the treatment of hyperlipemia, hyperlipidemia, post-prandial hyperlipemia, mixed dislipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
  • the invention therefore provides a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof for use in therapy, in particular in human medicine.
  • a method for the treatment of a mammal comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof in particular in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • a mammal including man
  • administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof in particular in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof and formulated for administration by any convenient route.
  • a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof and formulated for administration by any convenient route.
  • Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the compounds of formula (I) may be formulated for oral, buccal, parenteral, transdermal, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the compounds of formula (I) may, if desired, be administered with one or more therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art.
  • the compounds of formula (I) may be administered in combination with an HMG CoA reductase inhibitor.
  • a compound of formula (I), or a physiologically acceptable salt, solvate or derivative thereof, may be prepared by the general methods outlined hereafter.
  • the groups R 1 ,R 2 and R 3 are as previously defined for compounds of formula (I), unless specified otherwise.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula R 1 -L
  • L represents a suitable halide leaving group, e.g. chloride, under standard displacement conditions.
  • a compound of formula (II) may be prepared by reaction of a compound of formula (III) with a compound of formula (IV)
  • L' is a suitable leaving group, such as chloride, or an OH group and P is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc), under standard coupling conditions for an acid and amine coupling, followed by deprotection of the protecting group under suitable conditions, e.g. acidic removal of a Boc group.
  • a suitable leaving group such as chloride, or an OH group
  • P is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc)
  • a compound of formula (IV) may be prepared by the two step reaction of a compound of formula (V)
  • compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (VI)
  • Compounds of formula (VI) may be prepared by reaction of a compound of formula (V) with a compound of formula R 1 -L, where L is defined above, followed by reduction of the nitro group under hydrogenation or reductive tin chloride conditions.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (VII)
  • R 1 ' represents R 1 minus a methylene group, under standard reductive amination conditions, e.g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.
  • a compound of formula (III), where U is a hydroxy group may be prepared firstly by coupling a boronic acid with a suitable leaving group, represented by a compound of formula (VIII) and a compound of formula (IX)
  • PG represents a protected carboxylic acid and A and D represent either the boronic acid or the suitable leaving group, such as triflate or bromide, followed by deprotection of the protecting group under standard conditions, such as base removal of an ester group.
  • L' represents a halide leaving group
  • the carboxylic acid product can be treated with a suitable reagent, such as thionyl chloride, to give the corresponding chloride leaving group.
  • a compound of formula (I) may be prepared from a different compound of formula (I), using standard techniques well known in the art.
  • compounds of formula (I) where R 3 comprises a group containing a carboxylic acid group may be prepared from the compound of formula (I) where the corresponding position comprises a carboxylic ester group.
  • Well known methods in the art may be employed to facilitate the transformation of an ester to an acid.
  • Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.
  • the compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent to give the corresponding solvates.
  • a specific enantiomer of a compound of general formula (I) when required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods.
  • an appropriate optically active acid may be used to form salts with the enantiomeric mixture of a compound of general formula (I).
  • the resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.
  • enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
  • 6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenvD-amide as white crystals (0.9 g), m.p. : 155-157°C from 4- ⁇ 4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl ⁇ -piperazine- 1 -carboxylic acid tert-butyl ester (1.5 g).
  • Example 3 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -vP-phenyll-amide as white crystals (110 mg), m.p. : 107-109°C mass spec m/z : 454 (M+1 ). from 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (500 mg) and 3-bromo-propene (160 mg).
  • Example 6 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-thiazol-2-ylmethyl-piperazin-1 - vP-phenyll-amide as a cream powder (104 mg), m.p. : 132°C mass spec m/z : 527 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (220 mg) and thiazole-2-carboxaldehyde (58 mg).
  • hepatocytes Primary human hepatocytes were seeded at 50 000 cells/well in 96 well plates. After an overnight adhesion phase, cells were incubated with compounds for 8 hours in RPMI medium containing 1 % FCS, 4 ⁇ g/ml insulin, 100 nM dexamethasone and 50 ⁇ Ci/ml 35 S-methionine. Compounds were dissolved in DMSO and tested onto cells from 1 ⁇ M to 1.6 nM. Production of radiolabeled apoB-100 and apoA-1 (used as a selectivity control) was quantified by analysis of supernatants using SDS PAGE and exposure of gels onto Phosphorlmager screens. Inhibition of apoB-100 and apoA-1 secretion by compounds was calculated taking untreated cells as controls, and 1C 50 of each compound was determined on both apoproteins.
  • the human MTP activity assay was established using SPA technology.
  • Donor liposomes were prepared with 3H-triolein and phosphatidylcholine, while acceptor liposomes contained biotinylated phosphatidylethanolamine and phosphatidylcholine.
  • the MTP-mediated 3H-triolein transfer onto acceptor liposomes was allowed by a 25 min incubation at 37°C, and quantified by the addition of streptavidin-SPA beads.
  • Examples of the invention were tested in vitro, using the biological assays described above. All of the compounds had an IC 50 value of 0.8 nM or below in the MTP assay.

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

Abstract

L'invention concerne des dérivés de benzamide actifs sur le plan thérapeutique de formule (I), dans laquelle R1 - R3 sont définis tels que dans la revendication, leurs procédés de préparation, leur utilisation thérapeutique, notamment dans le traitement ou la prophylaxie de troubles améliorés par un inhibiteur de l'apoprotéine B-100 (apoB-100) et/ou du système protéinique microsomique de transfert des triglycérides (MTP), et des compositions pharmaceutiques à utiliser dans une telle thérapie.
PCT/EP2002/013591 2001-12-04 2002-12-02 Derives de benzamide therapeutiques Ceased WO2003047575A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002358574A AU2002358574A1 (en) 2001-12-04 2002-12-02 Therapeutic benzamide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0129013.9 2001-12-04
GB0129013A GB0129013D0 (en) 2001-12-04 2001-12-04 Compounds

Publications (1)

Publication Number Publication Date
WO2003047575A1 true WO2003047575A1 (fr) 2003-06-12

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GB (1) GB0129013D0 (fr)
WO (1) WO2003047575A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2856685A1 (fr) * 2003-06-25 2004-12-31 Merck Sante Sas Derives de thiazolylpiperidine, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent
WO2006038039A1 (fr) * 2004-10-01 2006-04-13 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Modulateurs de la replication de hcv
WO2008143127A1 (fr) 2007-05-17 2008-11-27 Ajinomoto Co., Inc. Procédé de mesure de l'activité d'une enzyme modifiée par un lipide
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
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
US8853218B2 (en) * 2006-06-28 2014-10-07 Glaxo Group Limited Compounds

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WO1996040640A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. DERIVES DE BIPHENYL-2-ACIDE CARBOXYLIQUE-TETRAHYDRO-ISOQUINOLEINE-6-YL AMIDES, PREPARATION DE CES AMIDES ET UTILISATION EN TANT QU'INHIBITEURS DE LA PROTEINE DE TRANSFERT DE TRIGLYCERIDE MICROSOMAL ET/OU DE LA SECRETION D'APOLIPOPROTEINES B (Apo B)
WO2000032582A1 (fr) * 1998-12-03 2000-06-08 Glaxo Group Limited Derives benzamidiques et leur utilisation comme inhibiteurs de la secretion d'apob-100
WO2001092241A1 (fr) * 2000-06-01 2001-12-06 Glaxo Group Limited Derives de benzamide et leur utilisation comme inhibiteurs d'apob-100 et de mtp
WO2001097810A2 (fr) * 2000-06-01 2001-12-27 Glaxo Group Limited Utilisation de benzamides therapeutiques
WO2002020501A2 (fr) * 2000-09-04 2002-03-14 Janssen Pharmaceutica N.V. Polyarylcarboxamides utilises comme agents hypolipidemiants

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040640A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. DERIVES DE BIPHENYL-2-ACIDE CARBOXYLIQUE-TETRAHYDRO-ISOQUINOLEINE-6-YL AMIDES, PREPARATION DE CES AMIDES ET UTILISATION EN TANT QU'INHIBITEURS DE LA PROTEINE DE TRANSFERT DE TRIGLYCERIDE MICROSOMAL ET/OU DE LA SECRETION D'APOLIPOPROTEINES B (Apo B)
WO2000032582A1 (fr) * 1998-12-03 2000-06-08 Glaxo Group Limited Derives benzamidiques et leur utilisation comme inhibiteurs de la secretion d'apob-100
WO2001092241A1 (fr) * 2000-06-01 2001-12-06 Glaxo Group Limited Derives de benzamide et leur utilisation comme inhibiteurs d'apob-100 et de mtp
WO2001097810A2 (fr) * 2000-06-01 2001-12-27 Glaxo Group Limited Utilisation de benzamides therapeutiques
WO2002020501A2 (fr) * 2000-09-04 2002-03-14 Janssen Pharmaceutica N.V. Polyarylcarboxamides utilises comme agents hypolipidemiants

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003128A1 (fr) * 2003-06-25 2005-01-13 Merck Patent Gmbh Derives de la thiazolylpiperidine, inhibiteurs de la mtp
US7674803B2 (en) 2003-06-25 2010-03-09 Merck Patent Gmbh Thiazolypiperidine derivatives as MTP inhibitors
FR2856685A1 (fr) * 2003-06-25 2004-12-31 Merck Sante Sas Derives de thiazolylpiperidine, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent
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
US8012982B2 (en) 2004-10-01 2011-09-06 Istituto Di Ricerche Biologia Molecolare P. Angeletti Spa Modulators of HCV replication
WO2006038039A1 (fr) * 2004-10-01 2006-04-13 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Modulateurs de la replication de hcv
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