WO2012064569A1 - Dérivés d'imidazole - Google Patents

Dérivés d'imidazole Download PDF

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Publication number
WO2012064569A1
WO2012064569A1 PCT/US2011/059033 US2011059033W WO2012064569A1 WO 2012064569 A1 WO2012064569 A1 WO 2012064569A1 US 2011059033 W US2011059033 W US 2011059033W WO 2012064569 A1 WO2012064569 A1 WO 2012064569A1
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Prior art keywords
pharmaceutically acceptable
compound
alkyl
acceptable salt
halogen
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PCT/US2011/059033
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English (en)
Inventor
Donald M. Sperbeck
Robert J. Devita
James M. Balkovec
Mark L. Greenlee
Zhicai Wu
Yang Yu
Petr Vachal
Gang Zhou
Heping Wu
Rongze Kuang
Pauline Ting
Robert Aslanian
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Merck Sharp & Dohme Corp.
Schering Corporation
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Publication of WO2012064569A1 publication Critical patent/WO2012064569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is directed to novel imidazole 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
  • Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and increased health problems.
  • obesity is recognized as an upstream risk factor for many conditions such as diabetes mellitus, lipidosis and hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006).
  • the need to treat obesity is recognized to be important, there are extremely limited drug therapies for obesity that are currently available, and thus, the advent of novel antiobesity drugs having more definite action and few side-effects is desired.
  • TG triacylglycerol
  • adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing.
  • TG triacylglycerol
  • a glycerol phosphate pathway which is present in most organs and causes de novo TG synthesis
  • 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 EC 2.3.1.20
  • 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. Lipid Res., 43,134-176, 2004 and Ann. Med., 36, 252-261, 2004).
  • DGAT1 subtypes of DGATs: DGAT1 and DGAT2.
  • DGAT2 which are encoded by different genes (Proc. Natl. Acad. Sci.USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001).
  • DGAT1 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).
  • a DGAT1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver.
  • DGAT1 -knockout mice deficient in DGAT1 at the genetic level were produced and analyzed.
  • the DGAT1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002).
  • DGAT1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with obesity.
  • X is selected from the group consisting of - CH- or ⁇ N-;
  • Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;
  • R ⁇ R 2 and R 3 are independently selected from the group consisting of a;
  • a is selected from the group consisting of halogen, Ct-Cealkyl, halogen- substitutedCi ⁇ C 6 alkyl, COCi-Cgalkyl, COhalogen-substitutedCrC 6 alkyl 5 oxo, -OH, Cp
  • n independently selected from the list consisting of 1 or 2, DETAILED DESCRIPTION OF THE INVENTION
  • X is -CH- or -N-. In certain embodiments, X is -
  • X is -N-.
  • each occurrence of n is independently selected from the list consisting of 1 or 2. In other embodiments, n is 1. In still other embodiments, n is 2.
  • Z is selected from the group consisting of phenyl and nitrogen containing heterocycle, wherein the phenyl and nitrogen containing heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a.
  • Z is unsubstituted.
  • Z is substituted with 1 substituent selected from a.
  • Z is substituted with 2 substituents selected from the group consisting of a.
  • Z is substituted with 3 substituents selected from the group consisting of a.
  • Z is substituted with 1 or 2 substituents selected from the group consisting of a.
  • Z is substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-C 6 alk l, halogen-substitutedQ- Cealkyl, -OC C 6 alkyl, -COOH, -COOC Cealkyl, -d-CealkylCOOCrCealkyl, -C r
  • Z is phenyl. In some embodiments, the phenyl Is unsubstituted. In other embodiments, the phenyl is substituted. In embodiments, Z is phenyl, wherein the phenyl is substituted with halogen, CrCsalkyl, halogen- substitutedCi-C 6 alkyl, -OCrQalkyl, -COOH, ⁇ COOCi-C 6 alkyl, -C r C 6 alkylCOOCi-C 6 alkyl ; - C r C 6 alkylCOOH, -S0 2 C r C 6 alkyl, -CN, Ci-C 6 alkylCON3 ⁇ 4 and -CON3 ⁇ 4.
  • Z is phenyl, wherein the phenyl can be substituted with -COOH, -CH 2 COOH, -(CH 2 ) 2 COOH, -C(CH 3 ) 2 COOH, -COOMe, - C(CH 3 ) 2 COOCH 3 , -OMe, -COOMe, -CH 2 COOCH 2 CH 3 , fluorine, methyl, -OH, triflouromethyl, -S0 2 Me, -CH 2 CONH 2 , -C(CH 3 ) 2 CONH 25 CONH 2 or -CN.
  • the nitrogen-containing heterocycle is N-containing heterocycle. In some embodiments, the nitrogen-containing heterocycle is N-containing heterocycle.
  • the nitrogen-containing heterocycle is substituted.
  • Suitable examples of a nitrogen-containing heterocycle include, but are not limited to, benzimidazole, pyrimidine or pyridine.
  • Z is nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted with substitutedCi-Cealkyl, -COOH, - COOCi-Cgalkyl, -CrQalkylCOOH, -CN and ⁇ CONH 2 ,
  • Z benzimidazole, pyrimidine or pyridine wherein the benzimidazole, pyrimidine or pyridine can be substituted with -COOH, halogen-substitutedC]- C 6 alkyl or -C CealkylCOOH.
  • Z is benzimidazole, pyrimidine or pyridine, wherein the benzimidazole, pyrimidine or pyridine can be unsubstituted
  • R 1 is selected from a.
  • R 1 is selected from the group consisting of halogen, -OCrC 6 alkyl, halogen-substitutedCi-Cealkyl.
  • Suitable examples of R 1 include, but are not limited to, chlorine, fluorine, methoxy and trifluromethyl.
  • R 1 can be positioned as follows:
  • R is selected from the group consisting of a.
  • R z is selected from the group consisting of hydrogen, halogen and halogen- substitutedC]-C 6 alkyL
  • R is hydrogen.
  • R is halogen.
  • Suitable halogens include, but are not limited to, chlorine and fluorine.
  • R 2 is halogen-substitutedCi-C 6 alkyl. Suitable examples include, but are not limited to, trifluoromethyl.
  • R is selected from the group consisting of hydrogen and -Cgalkyl.
  • R 2 is hydrogen.
  • R 3 is C Cealkyl. Suitable examples include, but are not limited to, methyl.
  • a is selected from the group consisting of halogen, Ci ⁇ C 6 alkyl, halogen-substitutedCrCealkyl, COCrCgalkyl, COhalogen-substitutedC C 6 alkyl, oxo, -OH, C r C 6 alkylOH, Cj-CealkylOHCOOH, halogen-substitutedC C 6 alkylOH, - OC C 6 alkyl, -Ohalogen-substitutedd-Cealkyl, -COOH, -COCOOH, -COOC C 6 alkyl, -C r C 6 alkylCOOCi-C 6 aikyl, -C C 6 alkylCOOH, -OC C 6 alkylCOOH, -CN ; d-CealkylCN, -NO 3 ⁇ 4 NH 2 , NHC,-C 6 alkyl, N(C r C 6
  • R 1 , R 3 and Z are defined as above.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • CpC galkyl encompasses straight alk l having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1, ,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-
  • Cycloalkyl encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. “Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. C3-C 6 cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,
  • -OCi -C 6 alkyl 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.
  • -OCi-C 6 alkylCOOH refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.
  • halogen-substitutedCrC 6 alkyl encompasses CpC 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifiuoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -Ohalogen-substitutedCpCealky means a -OCpCealkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
  • -COCpC 6 arky means groups having CpC 6 alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.
  • -COhalogen-substi ted -Cealkyl means a -COCi ⁇ C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.
  • Ci-C 6 alkylOH means a Q-Cealkyl substituted with an alcohol (-OH).
  • Examples include methanol, propanol, butanol and t-butanoL
  • halogen-substitutedCrCealkylOH means a halogen- substitedQ-Qatkyl, as defined above, substituted with an alcohol (-OH).
  • r C 6 alkyIOHCOOH means a C C 6 alkyl substituted with an alcohol (-OH) and a carboxylic acid group (-COOH).
  • CrC 6 alkylCN means a C
  • COOCi-Cealkyl means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, eihoxycarbonyl and butoxycarbonyl.
  • the term means a group having Ci-C 6 alkyl bonded to sulfonyl (-S0 2 ⁇ ). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.
  • NHQ-Cealkyl means a group with one of the hydrogen atoms of amino (- N3 ⁇ 4) being substituted with a C 1-6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like.
  • NCCi-Cealk iy means a group with the two amino hydrogen atoms each being substituted with a C 1-6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethyiamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.
  • NHCOiCrQalkyl means a group with one of the amino hydrogen atoms being substituted with C 1-6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycafbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like.
  • NRCOCrC 6 alkyr means a group with one of the amino hydrogen atoms being substituted with Ci-6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylamino, and the like.
  • CONHCrC 6 alkyl means a group with one of the hydrogen atoms of carbamoyl (-CONH 2 ) being substituted with Ci -6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbarnoyl, n-propyl carbamoyl, isopropylcarbamoyl, n-butylcarbamoyl ⁇ sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.
  • CONtCi-Csalkyiy means a group with the two carbamoyl hydrogen atoms each being substituted with Ci -6 alkyt. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,, di(n-propyl)carbamoyl, methyl (n-propyl)carbamoyl s diisopropylcarbamoyl, and the like.
  • NHSChQ-Cgalkyl means a group with one of the amino hydrogen atoms being substituted with C 1-6 alkylsulfonyl. Specific examples thereof include
  • Heterocycle unless otherwise specified, means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (including bicyclic) ring having at least one ring heteroatom selected from O, S and N.
  • heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazoJyl, pyridinyi, 2-oxo-(lH) ⁇ pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, ihienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indoliny
  • heterocycle also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2 J 3-dihydrofuro(2,3-£>)pyridyi, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l-&]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, 2- or 4-pyridones attached through the nitrogen or jV-substituted-(lH, 3H)-pyrimidine-2,4-diones (JV-substituted uracils).
  • the term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2 ⁇ azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl.
  • 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, bitartrate, 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 argi ine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamme, N-ethylmorpholine, N-ethylpiperidme, 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 argi ine, betaine, caffeine,
  • 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.
  • racemic 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 enantiomericaliy 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 racermc 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.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium (2H).
  • Protium 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, formula la or formula lb.
  • 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 gain, 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.
  • 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, formula la or formula lb in the manufacture of a medicament for use in treating various DGAT1- 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/congesti e 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
  • the present invention is directed to the use of a compound of structural formula I, formula la or formula lb 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, formula la or formula lb in the manufacture of a medicament for use in treating obesity.
  • 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 ordinarily used in the field of pharmaceutical preparations are usable.
  • gelatin lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, macrocrystalline wax, white petrolatum, magnesium metasiiicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyleellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, poiyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.
  • 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, elixirs, injections. These 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 for their use.
  • the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.
  • the pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition.
  • 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 range of the intended remedial effect.
  • the dose when orally administered, may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at one time or at several times.
  • the dose is preferably from about 0.01 to about 25 mg kg/day, more preferably from
  • compositions are preferably
  • 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 therapeui 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, formula la or formula lb 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 administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I, formula la or formula lb.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I, formula . or formula lb is preferred.
  • the combination therapy may also include therapies in which the compound of formula I, formula la or formula lb and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or mc other active ingredients, the compounds of the present invention and the other active ingredients may t used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions oft present invention include those that contain one or more other active ingredients, in addition to a compound of formula I, formula la or formula lb. Examples of other active ingredients that may be administered in combination with a compounc of formula I, formula la or formula lb, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
  • insulin sensitizers including (i) 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 muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPA a agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO
  • salts in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®;
  • PTP-1B protein tyrosine phosphatase- IB
  • 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 1998/04528, WO 1999/0142; WO 2000/39088, and WO 2000/69810;
  • incretin mimetics such as GLP-1, GLP- analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVE0010, CJC- 1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) H G-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fiuvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, coiesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
  • H G-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
  • nicotinic acid receptor agomsts nicotinic acid receptor agomsts
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • antihypertensive agents such as ACE inhibitors (such as enalapril, iisinopril, 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
  • ACE inhibitors such as enalapril, iisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan,
  • GKAs glucokinase activators
  • Patent No. 6,730,690 WO 2003/104207; and WO 2004/058741;
  • 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 WO 2009/042053, including, b 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 isoforrns, such as SGLT-1; SGLT-2, such as dapagliflozm and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and h BAR.
  • Dipeptidyl peptidase-IY (DPP-4) inhibitors that can be used in combination with compounds c formula I, formula la or formula lb include, but are not limited to, sitagliptin (disclosed in US Patent IS 6,699,871), vildagliptin, saxagliptin, alogliptin, denagiiptin, 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, formula la or formula lb include, but are not limited to: (2i?3 ⁇ 5J?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2 I 4,5- trifluorophenyl)tetrahydro-2H-pyran-3 -amine ;
  • Antiobesity compounds that can be combined with compounds of formula I, formula la or formula lb include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topirama and phentermine; fenfluramine; dexfenfiuramine; sibutramine; lipase inhibitors, such as oriistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant am taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula formula la or formula lb include, but are not limited to:
  • Inhibitors of stearoyl-coenzyme A delta-9 desaturase that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Glucokinase activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • rac-c is 5 -chloro-2- ⁇ 4- [2-(2- ⁇ [5-(methylsulfonyl)pyridin-2-yl] oxy ⁇ ethyl)cyclopropyl] piperidin- 1 - yl ⁇ pyrimidine;
  • Selective PPARy modulators that can be used in combination with the compoun of formula I, formula la or formula lb include, but are not limited to:
  • Inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I, formula la or formula lb include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 that can be used in combination with the compounds of formula 1, formula la or formula lb include, but are not limited to: 3- ⁇ r-[(l-cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyi]-4-oxospiro[chroman- 2,4'-piperidm]- 6-yl ⁇ benzoic acid;
  • 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
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrat and bezaflbrate)
  • 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 phosphatas
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • 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 rosuvastatir (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelara hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatir
  • 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-52 and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal an inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal an inflammatory 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;
  • 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
  • GKAs glucokmase activators
  • LY2599506 LY2599506
  • inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 LY2599506
  • 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 and remogliflozin; and SGLl 3;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPRI31 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 vary and will depend upon the effective dose of each ingredient. Generally, an effective dose of eacl 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. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Na 2 S0 4 sodium sulfate
  • Step 1 methyl 6-fpiperazin-l-yl pyrazine-2-carboxylate
  • Step 2 ethyl 6-(4-(5-(5-(trifluoromethvI -lH-berizofd]imidazol-2-yl)pyridin-2-yl)piperazin-l- yl)pyrazine-2-carboxyiate
  • Step 3 6-(4-(5 -(5 -f trifluororoethvO- 1 H-benzo [dl imidazol-2- yl)pyridin-2-yl)piperazin- 1 - yl)pyrazine-2-carboxylic acid
  • 5-((l-(5-(5-chloro-lH-benzo[d]imidazol-2-yl)pyridin-2-yl)piperidi yl)methoxy)isophthalate 48 mg, 0.10 mmol
  • MeOH 3.0 mL
  • THF 3.0 mL
  • water 2.0 mL
  • the reaction mixture was stirred at RT for 5 h then 1 N HCl (2.5 mL) was added, and the solution was concentrated.
  • Step 1 5-chloro-2-(6-fluoropyridin-3 -ylV 1 H-benzo [d] imidazole
  • Step 2 5-chloro-2-[6-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1 -yl]pyridin-3-yl "
  • - IH- benzo [(flimidazole
  • Stepl To a solution of 4-trifluoromet yl-l ⁇ 2-phenylenediamine (l.Og, 5.68mmoI) in THF (lOmL) was added 6-chloro-3-pyridinecarboxaldehyde (800mg, 5.68mmol). The mixture was stirred at T for 2 hours and the solvent was evaporated. The solids were washed with a minimum of methylene chloride and filtered to give 2-(6-chloropyridin-3-yl)-5-(trifiuoromethyl)- lH-benzimidazole as a yellow solid.
  • Step 1 To a solution of ethyl (4-bromophenylacetate)(1.02g, 4.20mmol), 1- benzylpiperazine(740mg, 4.20 ⁇ 1), palladium acetate (47mg, 0.21mmol) s
  • Step 1 A solution of 6-chloropyridme-3-carboxamide (lOOmg, 0.639mmol), /ert-butyl piperazine-1-car.boxylate (119mg, 0.639mmol) and ⁇ , ⁇ -diisopropylethylamine (248mg, 1.91mmol) in dry DMA (3mL) was heated to 150° C in a microwave for 2 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was twice washed with water and dried over Na 2 S0 4 . The solvent was evaporated to give /eri-butyl 4-(5- carbamoylpyridin-2-yl)piperazine-l-carboxylate as a tan solid.
  • LC-MS (M+H) 307
  • Step 2 To a suspension of fert-butyl 4-(5-carbamoylpyridin-2"yl)piperazine-l-carboxylate (120mg, 0.392mmol) was added 4M HCl in dioxane (4mL). The mixture was stirred at RT for 3 hours and evaporated to dryness to give a tan solid. The solid was dissolved in DMA (2mL) and 5-chloro-2- (6-chloropyridin-3-yl)- lH-benzimidaole (55mg, 0.208mmol) was added followed by ⁇ , ⁇ -diisopropylethylamine (27mg, 0.208mmol). The mixture was heated to 110° C overnight.
  • the mixture was purified by reverse phase Prep HPLC using 30-100% CH 3 CN/H 2 O/0.1%TFA as gradient to give 6- ⁇ 4- 5-(5- cWoro-lH-beixzimidazol-2-yl)pyridin-2-yl]piperazin-l-yl ⁇ pyridi as the TFA salt.
  • Step 1 A solution of 2-methyl-2-(4-nitrophenyl)propanoic acid (1.02g, 4.88mrnol) in 1.25M methanolic HCL (lOmL) was stirred at RT overnight. The mixture was partitioned between ethyl acetate and sodium bicarbonate soln. The organic layer was dried over Na 2 S0 4 and concentrated to give methyl 2-methyl-2-(4-nitrophenyl)propanoate which was dissolved in methanol (lOmL). The solution was treated with 10% palladium on carbon (lOOmg) and stirred under latm of hydrogen for 3 hours.
  • lOOmg 10% palladium on carbon
  • Step 5 A solution of methyl 2-(4- ⁇ 4-[5-(5-cWoro ⁇ lH-benzimidazol-2-yl)pyridin-2-yl]piperazin- l-yl ⁇ phenyl)-2-methylpropanoate (30mg, 0.061mmol) in methanol (2mL) was treated with 5N NaOH (122uL, 0. 1rnmol) and the mixture was heated to 50° C overnight. An additional lOOuL of 5N NaOH solution was added and the mixture was heated to reflux for 2 hours. The solvent was evaporated and the residue was taken up in water (2mL). The pH was adjusted to 7 by addition of IN HC1.
  • Step 2 To a solution of 5-chloro-2-(6-cWoro-5-fluoropyridin-3-yl)-lH-beri2imidazole (60mg, 0.213mmol) in dry DMA (2mL) was added ethyl [4-(piperazin-l-yl)phenyl] acetate (53 ⁇ 3 ⁇ 4, 0.213mmol) and ⁇ , ⁇ -diisopropyletliylamine (82mg, 0.638mmol). The mixture was heated to 150° C for 90 min. The cooled mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na 2 S0 4 and concentrated.
  • Step 3 A solution of ethyl (4- ⁇ 4-[5-(5-cUoro-lH-benzimidazol-2-yl)-3-fluoropyridin-2- yljpiperazin-l-yl ⁇ phenyl)acetate (40mg 5 0.081mmol) in ethanol (4mL) was treated with 5N NaOH (O.SlOmmol). The mixture was heated to 60° C for 2 hours. The solvent was evaporated and the residue was taken up in water (5mL). The solution was neutralized with I N HC1 and extracted with ethyl acetate containing 10% ethanol.
  • Step 1 To a solution of 1 -benzylpiperazine (500mg, 2.84mmol) and methyl 3-(4- bromophenyl)propanoate (690mg, 2.84mmol) in dry DMA (5mL) was added
  • Step 2 A solution of methyl 3-[4-(4-benzylpiperazin-l-yl)phenyl]propanoate (720mg >
  • Step 3 To a solution of 2-(6-chloropyridin-3-yl)-5-chloro-lH-benzimidazole (60mg,
  • Step 4 A suspension of methyl 3-(4- ⁇ 4-[5 ⁇ (5-chloro-lH-benzimidazol-2-yl)pyridin-2- yl]piperazin-l-yl ⁇ phenyl)propanoate TFA salt (12mg, 0.025mmol) in methanol and treated with 5N NaOH (200uL). The mixture was heated to 50° C for 4 hours.
  • Step, 1 To a solution of 2-(6-bromopyridin-3-yl)-5-(trifluoromemyi)-lH-benzimidazoie, prepared in the same manner as Example 4, (300mg, 0.877mmol) in dry DMA (3mL) was added 1-benzylpiperazine (155mg, 0.877mmol) and N s N-diisopropylethylamine (227mg, 1.75mmoI).
  • Step 2 A solution of 2-[6-(4-benzylpiperazin- 1 -yl)pyridin-3 -yl] -5 -(trifluoromethyl)- 1 H- benzimidazole (200mg, 0.457mmol) in methanol (5mL) was treated with 20% Pd(OH) 2 on carbon (80mg). The mixture was stirred under 1 aim of hydrogen for 16 hours. The catalyst was filtered and the solvent evaporated to give 2-[6-(piperazin-l-yl)pyridin-3-yl]-5-(trifluoromethyl)- lH-benzimidazole.
  • Step 1 To a solution of 6-fluoro-3-pyridinecarboxaldehyde (1.76g, 14.0mmol) and 4-chloro ⁇ l,2- phenylenediamine (2.0g, 14.0mmol) in DMF (20mL) was added water (2mL).
  • Step 3 To a solution of 5-cMoro-2-[6- ⁇ iperazin-l-yl)pyridin-3-yl]-lH-benzimidazole (200mg, 0.637mraol) in dry NMP (2mL) under argon was added ethyl (5,6-difiuoropyridin-3-yl)acetate, prepared in the same manner as in patent WO 2007/120729, (128mg, 0.637mmol). Sodium bicarbonate (268mg, 3.19mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave.
  • Step 4 A solution of ethyl (6- ⁇ 4-[5-(5-cMoro-lH-benzimidazol-2-yl)pyridin-2-yl]piperazin-l- yl ⁇ -5-fluoropyridin-3-yl)acetate TFA salt (lOOmg, 0.202mmol) in ethanol (5mL) was treated with 5N NaOH (404uL, 2.02mmol) and the mixture was heated to 50° C for 2 hours.
  • Acetic acid 16uL, 2.02mmol was added and the mixture was purified by reverse phase Prep HPLC using 10-100% C3 ⁇ 4CN/H 2 O/0.1%TFA as gradient to give (6- ⁇ 4-[5-(5-chloro-lH-benzimidazol-2- yl)pyridin-2-yl]piperazin-l-yl ⁇ -5-fluoropyridin-3-yl)acetic acid as the TFA salt.
  • LC-MS (M+H) 467
  • Step 2 To a solution of 2-(6-fluoropyridin-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (44mg, O.lSlmmol) in dry DMA (2mL) under argon was added ethyl [4-(piperazin-l-yl)phenyl]acetate (45mg, O.lSlmmol). Sodium bicarbonate (46mg, 0.543mmol) was added and the mixture was heated to 150° C for 90 min. in a microwave.
  • Step 1 To a solution of 2-(6-fluoropyridm-3-yl)-5-methoxy-3H-imidazo[4,5-&]pyridine (400mg, 1.64mmol) in dry DMA (1 OmL) under argon was added 1 -benzylpiperazine (289mg > 1.64mmol) and sodium bicarbonate (688mg, 8.19mmol). The mixture was heated to 150° C for 60 min. in a microwave. The mixture was partitioned between ethyl acetate and water and the organic layer was dried over Na 2 S0 4 .
  • Step 3 To a solution of 5-methoxy-2-[6-(piperazin-l-yl)pyridin-3-yl]-3H-imidazo[4,5- £>]pyridine (54mg ? 0.174mmol) in dry DMA(2mL) degassed with argon was added methyl 5,6- difluoropyridine-3-carboxylate (30mg, 0.174mmol) and sodium bicarbonate (73mg, 0.87mmol). The mixture was heated to 150° C for 60 min. in a microwave.
  • Step 2 To a solution of 3-nitro-6-(trifLuoromethyl)pyridin-2-amine (838mg, 4.05mmol) in methanol (30mL) was added 10% palladium on carbon (400mg). The mixture was hydrogenated on a Parr shaker at 40 psi for 90 min. The catalyst was filtered and the solvent was evaporated to give 6 ⁇ (trifluoromethyl)pyridine-2,3-diamine as a yellow solid.
  • LC-MS (M+H) 178
  • Step 3 To a solution of 5,6-difluoropyridine-3-carboxylic acid (348mg, 2.19mmol) in dry NMP(3mL) was added l-hydroxybenzotriazole (335mg, 2.19mmol),and iV-[3- (dimethylamino)propyl3-N'-ethyicarbodiimide hydrochloride (420mg > 2.19mmol). The mixture was stirred for 10 min. and 6-(trifluoromethyl)pyridine-2, 3 -diamine (388mg, 2.19mmol) was added. The mixture was stirred at RT for 16 hours. Acetic acid (2mL) was added and the mixture was heated to 120° C for 60 min. in a microwave. The cooled mixture was partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was dried over Na 2 S0 4 and concentrated. The mixture was purified by phase Prep HPLC using 10-100%
  • the in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes.
  • the reaction is initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [ 1 C]-palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature.
  • the assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3 -cholamidopropyldimemyl-ammomo-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.
  • Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC50 values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation:
  • the solution is incubated at room temperature for 1 hour after which 20 ⁇ , of a 90 ⁇ 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader. The IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs.
  • Concentration of Test Compound in the reaction is defined as the concentration at which the curve crosses the 50% inhibition line.
  • the inhibitory activity was calculated from the following formula:
  • % inhibition [1 -(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100%
  • Examples 1 -2 were assayed, the compounds were assayed using Assay 1. If Examples 3-36 were assayed, the compounds were assayed using Assay 2.

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Abstract

L'invention concerne des composés de formule (I), de formule la ou de formule lb. Les composés de formule I, de formule la ou de formule lb sont des inhibiteurs de DGATl et peuvent être utiles pour prévenir ou traiter l'hyperlipidémie, le diabète sucré et l'obésité, ou pour agir en tant qu'agent thérapeutique contre ces maladies.
PCT/US2011/059033 2010-11-08 2011-11-03 Dérivés d'imidazole WO2012064569A1 (fr)

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US20130143876A1 (en) * 2011-12-02 2013-06-06 Gerald Juergen Roth New piperidine derivatives, pharmaceutical compositions and uses thereof
US20140088124A1 (en) * 2011-06-02 2014-03-27 Robert J. DeVita Imidazole derivatives
WO2014175330A1 (fr) * 2013-04-24 2014-10-30 塩野義製薬株式会社 Dérivé de 5-oxybenzimidazole et de 5-oxyazabenzimidazole ayant pour effet d'activer l'ampk
JP2019517563A (ja) * 2016-06-09 2019-06-24 プラマーナ ファーマシューティカルズ インコーポレイテッド ベンゾ［ｄ］［１，３］オキサチオール、ベンゾ［ｄ］［１，３］オキサチオール３−オキシドまたはベンゾ［ｄ］［１，３］オキサチオール３，３−ジオキシドを含有する化合物およびＧタンパク質共役型受容体１１９のアゴニストとしてのその方法／使用
WO2023203161A1 (fr) * 2022-04-22 2023-10-26 Universite Paris Cite Composés induisant la production de protéines par des cellules immunitaires

Citations (5)

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US20130143876A1 (en) * 2011-12-02 2013-06-06 Gerald Juergen Roth New piperidine derivatives, pharmaceutical compositions and uses thereof
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