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WO2012122075A1 - Dérivés de lactame en tant qu'inhibiteurs de dgat-1 - Google Patents

Dérivés de lactame en tant qu'inhibiteurs de dgat-1 Download PDF

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Publication number
WO2012122075A1
WO2012122075A1 PCT/US2012/027655 US2012027655W WO2012122075A1 WO 2012122075 A1 WO2012122075 A1 WO 2012122075A1 US 2012027655 W US2012027655 W US 2012027655W WO 2012122075 A1 WO2012122075 A1 WO 2012122075A1
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Prior art keywords
group
compound
pharmaceutically acceptable
phenyl
amino
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Inventor
Thomas H. Graham
Dong-Ming Shen
Ravi P. Nargund
Robert J. Devita
Yang Yu
Wensheng Liu
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention is directed to lactam derivative compounds.
  • the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1 and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
  • DGAT1 diacylglycerol O-acyltransferase type 1 inhibitors
  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after meals. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type 1 diabetes or insulin- dependent diabetes mellitus (IDDM)
  • IDDM insulin- dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • Type 2 diabetes which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food
  • TG synthesis pathways In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine.
  • Diacylglycerol acyltransferases DGATs, EC 2.3.1.20
  • DGATs diacylglycerol acyltransferases
  • the final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog.
  • DGAT-1 Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261, 2004.
  • DGAT-2 There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001).
  • DGAT-1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005).
  • DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed.
  • DGAT1 KO mice show a lack of postprandial rise of plasma TG, suggesting an important role for DGAT1 in the regulation of fat absorption.
  • DGAT1- deficient mice are resistant to high fat diet-induced obesity and have increased sensitivity to insulin and leptin.
  • the KO mice are protected against hepatic steatosis and were shown to have decreased levels of tissue TG.
  • the DGAT1 KO mice have improved glucose metabolism, with lower plasma glucose levels after glucose load or insulin injection.
  • DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis,
  • DGAT-l inhibitors which are useful in the treatment of type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.
  • R 1 is selected from the group consisting of: hydrogen;
  • Cs-doalkyl wherein the Cs-Cioalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-C 6 alkoxy and -OH;
  • -(CH 2 ) P R wherein the -(CH 2 )pR is unsubstituted or substituted with one or more substituents selected from the group consisting of Q-Cealkyl, halogen, -NH 2 , phenyl, Cr C 6 aIkoxy and -OCs-Cgcycloalkyl, wherein R 2 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and wherein p is 0, 1, 2, 3 or 4; and
  • R 3 is independently selected from the group consisting of hydrogen and Cj-Cealkyl.
  • R 1 is hydrogen
  • R 1 is Cs-Qoalkyl, wherein the C5 ⁇ C 10 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-C 6 alkoxy and -OH.
  • R 1 is Cs-Cioalkyl In certain embodiments R 1 is C5-(1 ⁇ 4alkyl. In other embodiments R 1 is C 6 -Cioalkyl. In still other embodiments R 1 is Ce-Cpalkyl. In any of the embodiments described herein the alkyl can be branched or straight.
  • R 1 is Csalkyl such as, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2- dimethylpropyl and 1-ethylpropyl.
  • R 1 is Cgalkyl, such as n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1 -ethylbutyl, 1.1,2- trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl and 1 -ethyl- l-methylpropyl.
  • R 1 is Cvaikyl, such as n-heptyl, 1-methylhexyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, 2-ethylpentyl, 1-ethylpentyl and 4,4- dimethylpentyl.
  • R 1 is Cgalkyl such as, n-octyl, 1-methylheptyl, 2- methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 4-ethylhexyl, 3- ethylhexyl, 2-ethylhexyl, 1-ethylhexyl, 4,4-dimethylhexyl and 5,5-dimethylhexyL
  • R 1 is C 9 alkyl such as, n-nonyl, 1-methyloctyl, 2-methyloctyl, 3-methyloctyl, 4- methyloctyl, 5-methyloctyl, 6-methyloctyl, 7-methyIoctyl, 5-ethyIheptyl, 4-ethylheptyl, 3- ethylheptyl, 2-ethylheptyl, 1-eth
  • R 1 is Cioalkyl such as, n-decyl, 1 -methylnonyl, 2- methylnonyl, 3 -methylnonyl, 4-methylnonyl, 5 -methylnonyl, 6 ⁇ methylnonyl, 1-ethyloctyl, 4,4- dimethyloctyl, 5,5-dimethyloctyl, 6,6-dimethyloctyl and 7,7-dimethyloctyl.
  • the alkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-C 6 alkoxy and -OH.
  • the alkyl is unsubstituted.
  • the alkyl is substituted with one or more Ci-C 6 alkoxy. Suitable alkoxys include methoxy, ethoxy, butoxy and propoxy.
  • R 1 is Cs-Cioalkyl, wherein Cs-Cjoalkyl is substituted with methoxy.
  • R 1 is Cs-Qoalkyl the alkyl is substituted with -OH.
  • R 1 is halogen-substitutedC f - doalkyl.
  • Suitable halogen-substituted alkyls include fluoromethyl, difluoromethyl,
  • R 1 trifluoromethyl, fluoroethyl, difluorethyl, trifluoropropyl, trifluorobutyl, fluoropentyl, difluoropentyl, trifluoropentyl, fluorohexyl, difluorohexyl, difluorohexyl.
  • -(CH2) m O(CH 2 ) n CH3 is unsubstituted or substituted with at least one Ci-Cealkyl, and wherein m is selected from the group consisting of 1, 2, 3 or 4 and n is selected from the group consisting of 0, 1, 2 ⁇ 3 or 4.
  • R 1 is -(CH 2 ) m O(CH 2 ) n CH 3
  • m is selected from the poup consisting of 1, 2, 3 or 4.
  • n is 1. In another embodiment, m is 2. In still another embodiment, m is 3. In yet another embodiment, m is 4. Additionally, when R 1 is n is selected from the group consisting of 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 1. In another embodiment, n is 2. In still another embodiment, n is 3. In yet another
  • n 4.
  • R 1 is - (CH2)mO(CH 2 ) n CH3, wherein -(CH2) m O(CH 2 ) t iCH3 is unsubstituted or substituted with at least one Ci-C 6 aIkyL
  • ⁇ CH2) m O(CH 2 ) n CH3 is unsubstituted.
  • -(CH 2 )mO(CH 2 )nCH3 is substituted with at least one Ci-C 6 alkyl.
  • Suitable alkyls include, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • R 1 is - (CH2) 2 0(CH 2 )CH(CH 3 )2. In other embodiments, R 1 is -(CH 2 ) 3 OCH(CH 3 )2. In another embodiment, R 1 is -(CH 2 ) 2 0(CH 2 )20CH3.
  • R 1 isTM(CH2) R 2 , wherein the H ⁇ CH 2 )p 2 is unsubstituted or substituted with Ci-Cealkyl, halogen, -Nl3 ⁇ 4 5 phenyl, Cj-C 6 alkoxy or -OCi-Cecycloalkyl, wherein R 2 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and wherein p is 0, 1, 2, 3 or 4.
  • p is 0. In other embodiments, p is 1. In still other embodiments, p is 2. In yet other embodiments, p is 3. In another embodiment of the compounds described herein, p is 4. In other embodiments, p is 0, 1 or 2. In other embodiments, p is 0, 1 , 2 or 3. In still other embodiments, p is 1 , 2, 3 or 4.
  • R 1 is - ⁇ CH2) p 2 i wherein R 2 is aryl. Suitable aryls include phenyl, naphthyl and tolyl. In certain embodiments R 2 is phenyl. In other embodiments, R is fluorophenyl
  • R 1 is -(CH2) P R 2 , wherein R 2 is heteroaryl.
  • Suitable heteroaryls include 5- or 6-membered monocyclic or 8- to 14-membered polycyclic heteroaromatic cyclic groups containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring- constitutive members.
  • Suitable examples include a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a tetrazolyl group, a pyridazinyl group, a pyrazinyl group, a furyl group, a thienyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzotbiazolyl group,
  • R 1 is -(CH 2 ) P R 2 , wherein R 2 is cycloalkyl.
  • Suitable cycloalkyls include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a bicyclohexyl group and an adamantyl group.
  • R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 is - (CH 2 )cyclopropyI, ⁇ (CH 2 ) 2 cyclopropyl, -(CH ⁇ bcyclopropyl or -(CH 2 ) 4 cyclopropyl.
  • R 1 is ⁇ (CI3 ⁇ 4)cyclobutyl s - ⁇ (Cl3 ⁇ 4) 2 cyclobutyl 5 cyclopentyl, -(CH 2 )cyclopentyl, - (CH2) 2 cyclopentyl, -(CH 2 ) 3 cyclopentyl, ⁇ CH 2 )cyclohexyl or -(CH 2 ) 2 cyclohexyl.
  • R 1 is -(CH 2 )pR 2 , wherein R 2 is cycloheteroaikyl.
  • Suitable cycloheteroalkyls include an aziridine ring, oxolan ring, pyrrolidine ring, piperidine ring, tetrahydropyran ring, tetrahydrofuran ring, oxodihydropyridinyl ring, dioxane ring and morpholine ring.
  • R 2 is pyrrolidine or piperidine.
  • R 2 is tetrahydrofuran, dioxane or morpholine.
  • -(CH 2 ) P R is unsubstituted.
  • ⁇ (C3 ⁇ 4) P R 2 is substituted with one or more substituents selected from the group consisting of CrCealkyl, halogen, -N3 ⁇ 4, phenyl, Q-Csalkoxy or -OCi-Cecycloalkyl.
  • - ⁇ CH 2 ) P R 2 is substituted with one or more Q-Cealkyls.
  • Suitable Q-Cealkyls include methyl, ethyl, butyl, propyl and hexyl.
  • ⁇ (CH 2 )pR 2 is substituted with one or more halogens. Suitable halogens include fluorine, chlorine, bromine and iodine.
  • - ⁇ CH ⁇ pR 2 is substituted with one or more phenyl group.
  • -(CH 2 ) P R 2 is substituted with one or more C)-C 6 alkoxy. Suitable alkoxys include methoxy, ethoxy, butoxy and propoxy.
  • -(CH 2 ) P R 2 is substituted with one or more -OC3-C 6 cycloalkyl. Suitable -OC3-C 6 cycloalkyl include - Ocyclopropyl, -Ocyclobutyl, -Ocyclopentyl and -Ocyclohexyl.
  • -(C3 ⁇ 4) P R 2 is substituted with one or more -NH 2 .
  • R 1 is -(CH 2 ) P R 2 , wherein - (CH 2 ) p is substituted with one or more substituents selected from the group consisting of Ci- C 6 alkyl, halogen or Ci-C 6 alkoxy.
  • ⁇ CH 2 ) P is substituted with one or more Ci-Cealkyls.
  • Suitable CrCealkyls include methyl, ethyl, butyl, propyl and hexyl.
  • ⁇ -( ⁇ 3 ⁇ 4) is substituted with one or more halogens.
  • Suitable halogens include fluorine, chlorine, bromine and iodine.
  • -( ⁇ 3 ⁇ 4) ⁇ is substituted with one or more Ci-C 6 alkoxy. Suitable alkoxys include methoxy, ethoxy, butoxy and propoxy.
  • R 3 is independently selected from the group consisting of hydrogen and Cj-C 6 alkyl. In certain embodiments, R 3 is hydrogen, as shown in formula la:
  • R 3 is Ci-Cealkyl.
  • Suitable d-Cealkyl include methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • Examples of the compounds described herein include, but are not limited to:
  • halogen includes “halogen”, fluorine, chlorine, bromine and iodine.
  • C5-C l oalkyl encompasses straight alkyl having a carbon number of 5 to 10 and branched alkyl having a carbon number of 5 to 10.
  • n-pentyl isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, l-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2- methylpropyl, 1 -ethyl- 1-methylpropyl, and the like.
  • -OQ-C 6 alkyl or "Cj-C 6 alkoxy” refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.
  • halogen-substitutedC f Cio alkyl encompasses Cj-Qoaikyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,3- difluorobutyl and the like.
  • aryl examples include phenyl, naphthyl, tolyl, and the like.
  • heteroaryl includes a 5- or 6-membered monocyclic or 8- to 14-membered polycyclic heteroaromatic cyclic group containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring- constitutive members; and concretely, for example, it includes a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a tetrazolyl group, a pyridazinyl group, a pyr
  • cycloalkyl includes a monocyclic or polycyclic, saturated or partially- unsaturated carbocyclic group having from 3 to 10, preferably from 3 to 8 carbon atoms, concretely, for example, a cyclopropyl group, a cyclobutenyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a bicyclohexyi group, an adamantyl group and the like.
  • cycloheteroalkyl includes an aziridine ring, oxolan ring, pyrrolidine ring, piperidine ring, tetrahydropyran ring, tetrahydrofuran ring, dioxane ring, morpholine ring and the like.
  • pharmaceutically acceptable salt refers to salts prepared from
  • salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bi tartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbro
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine, cho
  • the compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of these compounds.
  • Some of the compounds described herein contain substituted cycloalkanes having cis-and trans-isomers, and unless specified otherwise, are meant to include both cos- and trans- geometric isomers.
  • raceraic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein.
  • H isotopic forms of hydrogen
  • protium lH
  • deuterium 2H
  • Protiura is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or Intermediates.
  • DGATl -related diseases are effective in preventing or treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatos
  • One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I, la, lb or Ic.
  • Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of treatment may be preventing body weight, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • arteriosclerosis such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance. More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
  • Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
  • the present invention is also directed to the use of a compound of structural formula I, la, lb or ic in the manufacture of a medicament for use in treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension,
  • metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like
  • circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension,
  • central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis.
  • the compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
  • the present invention is directed to the use of a compound of structural formula I, la, lb or Ic in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
  • the present invention is directed to the use of a compound of structural formula I, la, lb or Ic in the manufacture of a medicament for use in treating diabetes.
  • Compounds of the invention may be administered orally or parenterally.
  • the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
  • the compound of the invention In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered.
  • pharmaceutically acceptable it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • additives various additives
  • Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as
  • syrups may be formulated according to conventional methods known in the field of pharmaceutical preparations.
  • the liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use.
  • the preparations may be dissolved or suspended in
  • physiological saline or glucose liquid may be optionally added
  • compositions may contain the compound of the invention in an
  • compositions may further contain any other therapeutically-effective compounds.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the
  • the dose when orally administered, the dose may be any suitable remedial effect.
  • the dose when orally administered, the dose may be any suitable remedial effect.
  • the dose when orally administered, the dose may be any suitable remedial effect.
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from
  • compositions are preferably
  • tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250,
  • This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of formula I, la, lb or Ic or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I, la, lb or Ic.
  • Examples of other active ingredients that may be administered in combination with a compound of formula I, la, lb or Ic and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1)
  • PPARy agonists such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1)
  • PPARa/ ⁇ dual agonists such as muragHtazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARyM's selective PPARy modulators
  • insulin or insulin analogs such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
  • amylin and amylin analogs such as pramlintide
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • -glucosidase inhibitors such as acarbose, voglibose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO
  • incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVEOOIO, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoAxholesterol acyltransferase inhibitors, such as avasimibe;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof
  • MK-524A which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • Patent No. 6,730,690 WO 03/104207; and WO 04/058741;
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS);
  • GPR-105 antagonists such as those disclosed in WO 2009/000087;
  • inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozm, canagliflozin and remoghflozin and those described in WO2010/023594 such as PF-04971729; and SGLT-3;
  • SGLT sodium-glucose transporter
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR.
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, la, lb or Ic include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
  • DPP-4 dipeptidyl peptidase-IV
  • Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, la, lb or Ic include, but are not limited to:
  • Antiobesity compounds that can be combined with compounds of formula I, la, lb or Ic include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfiuramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists
  • Fernandez-Lopez, et al. "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915 ⁇ 944 (2002); and K.M. Gadde, et al, "Combination pharmaceutical therapies for obesity,” Exp. Opin. Pharmacother., 10: 921-925 (2009).
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • SCD stearoyl-coenzyme A deIta-9 desaturase
  • Glucokinase activators that can be used in combination with the compounds of formula I, la, lb or Ic, but are not limited to: 3-(6-ethanesulfonyIpyridin-3 -yloxy)-5-(2-hydroxy- 1 -methyl-ethoxy)-N-( 1 -methyl- 1 H-pyrazol-3- yl)benzamide;
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • SPPARyM's Selective PPARy modulators that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • Inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I, la, lb or Ic include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 include, but are not limited to:
  • composition which comprises one or more of the following agents:
  • DPP-4 dipeptidyl peptidase-IV
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ dual agonists such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PP ARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARyM's selective PPARy modulators
  • PPARy partial agonists include (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and
  • GlucophageXR® (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repagli ide;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
  • lovastatin simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatin
  • bile acid sequestering agents such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran
  • inhibitors of cholesterol absorption such as ezetimibe
  • acyl CoA holesterol acyltransferase inhibitors such as avasimibe
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists including, but not limited to, neuromedin S (NMS);
  • (22) inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin, canagliflozin and
  • SGLT sodium-glucose transporter
  • remogliflozin and those described in WO2010/023594 such as PF-04971729; and SGLT-3; (23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • TLC analytical thin layer chromatography
  • RP-HPLC reverse phase high performance liquid chromatography
  • Step A methyl [4 ⁇ ( -hvdroxyphenyl)cyclohexylidene]acetate.
  • the resulting solution was stirred for 2 h at room temperature.
  • solution A Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This was followed by the addition of a solution of methyl 2- (dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring.
  • Step B methyl ⁇ tran s-4-( 4-hvdroxyphenyl)cyclohexyl] acetate.
  • the product from step A is methyl ⁇ tran s-4-( 4-hvdroxyphenyl)cyclohexyl] acetate.
  • Step C methyl [trawjr-4-(4- ⁇ i( ' trifluoromethyl sulforiylloxy ⁇ phenyi cyclohexyl '
  • Step A (fr ⁇ -4- ⁇ 4- 4-amino-2-(methylsulfanylV5-oxo-7,8-dihydropyrimido[5,4- f] [ 1 ,41oxazepin-6f 5H)-yl " jphenyl > cyclohexyDacetic acid.
  • step A The product from step A (5.28 g, 11.9 mmol) in THF (100 ml) was treated with magnesium bis(monoperoxyphthalate) hexahydrate (8.88 g, 18.0 mmol) was slowly added portionwise to the suspension. The reaction mixture was stirred for 16 h and concentrated under reduced pressure. The residue was dissolved in DMSO (50 mL) and the solution was poured into water (500 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and the filter cake was washed with water (500 ml) and dried under vacuum to afford the title compound as a colorless solid. HPLC/MS: 474.99 (M+H); R t 1.05 min (LC2).
  • Examples 2-101 were synthesized from the relevant intermediates using procedures adapted from those described in general Scheme 1 and Example 1.
  • Examples 100 and 101 were prepared as shown in Scheme 1 by excluding the aqueous LiOH saponification step (i.e. step 1 in the conversion of 1-6 to 1-7).
  • Examples 95 and 96, where R-OH is equal to 2- (tetxahydrofuran-2-yl)ethanol il the enantiomers of 2-(tetrahydrofuran-2-yl)ethyl benzoate were separated using chiral HPLC (AD column, 30x250mm 5 70ml/min s 5% IPA/hexanes, 230nm). Subsequent saponification (potassium trimethylsilanoate in THF) afforded the single enantiomers which were used in the conversion of 1-7 to examples 95 and 96.

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Abstract

La présente invention a trait à des composés de formule I. Les composés de formule I agissent en tant qu'inhibiteurs de DGAT1 et peuvent être utiles dans la prévention, le traitement ou l'action en tant qu'agent correcteur contre l'hyperlipidémie, le diabète sucré et l'obésité.
PCT/US2012/027655 2011-03-08 2012-03-05 Dérivés de lactame en tant qu'inhibiteurs de dgat-1 Ceased WO2012122075A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013068439A1 (fr) * 2011-11-09 2013-05-16 Intervet International B.V. Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1
WO2014140241A1 (fr) * 2013-03-15 2014-09-18 Intervet International B.V. Dérivés de pyridine en tant qu'inhibiteurs de dgat-1

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2007141538A1 (fr) * 2006-06-10 2007-12-13 Astrazeneca Ab Dérivés d'oxazole et utilisation de ceux-ci dans le traitement du diabète et de l'obésité
WO2009016462A2 (fr) * 2007-08-02 2009-02-05 Pfizer Products Inc. Bicyclolactames substitués

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2007141538A1 (fr) * 2006-06-10 2007-12-13 Astrazeneca Ab Dérivés d'oxazole et utilisation de ceux-ci dans le traitement du diabète et de l'obésité
WO2009016462A2 (fr) * 2007-08-02 2009-02-05 Pfizer Products Inc. Bicyclolactames substitués

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013068439A1 (fr) * 2011-11-09 2013-05-16 Intervet International B.V. Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1
WO2014140241A1 (fr) * 2013-03-15 2014-09-18 Intervet International B.V. Dérivés de pyridine en tant qu'inhibiteurs de dgat-1

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