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WO2013068328A1 - Composés d'acide bicyclo[2.2.2]octan-1-ylcarboxylique comme inhibiteurs de la dgat-1 - Google Patents

Composés d'acide bicyclo[2.2.2]octan-1-ylcarboxylique comme inhibiteurs de la dgat-1 Download PDF

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Publication number
WO2013068328A1
WO2013068328A1 PCT/EP2012/071894 EP2012071894W WO2013068328A1 WO 2013068328 A1 WO2013068328 A1 WO 2013068328A1 EP 2012071894 W EP2012071894 W EP 2012071894W WO 2013068328 A1 WO2013068328 A1 WO 2013068328A1
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compound
pharmaceutically acceptable
alkyl
halogen
acceptable salt
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PCT/EP2012/071894
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English (en)
Inventor
Timothy A. Cernak
Robert J. DE VITA
Yang Yu
Zhicai Wu
Kevin D. Dykstra
Andreas Verras
James M. Balkovec
Alan Whitehead
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Intervet International B.V.
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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 anti-obesity 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 aging.
  • 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).
  • DGATs 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).
  • a DGAT-1 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.
  • DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed.
  • the DGAT-1 -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).
  • DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis,
  • the compounds described herein are DGAT-1 inhibitors, which are useful in the treatment of obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.
  • X is selected from the group consisting of -N-, - CH- and -CR 4 -;
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, C 2 -C 6 alkenyl, halogen-substitutedCi-C 6 alkyl, -OH, Ci-C 6 alkylOH, -OCi-C 6 alkyl, - Ohalogen-substitutedCi-C 6 alkyl, -NH 2 , -S0 2 Ci-C 6 alkyl and -CN or when taken together R 2 and form a hetero cycle ring; and
  • R 4 is selected from the group consisting of halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halogen- substitutedCi-C 6 alkyl, -OH, Ci-C 6 alkylOH, -OCi-C 6 alkyl, -Ohalogen-substitutedCi-C 6 alkyl, - NH 2 , -S0 2 Ci-C 6 alkyl and -CN.
  • X is selected from the group consisting of -N-, -CH- and -CR 4 -. In some embodiments, X is -N-. In other embodiments, X is -CH-. In still other embodiments, X is -CR 4 -.
  • R 4 is selected from the group consisting of halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halogen-substitutedCi-C 6 alkyl, -OH, Ci-C 6 alkylOH, -OCi- C 6 alkyl, -Ohalogen-substitutedCi-C 6 alkyl, -NH 2 , -S0 2 Ci-C 6 alkyl and -CN.
  • R 4 is halogen. Suitable halogens include chlorine, fluorine and iodine.
  • R 4 is Ci-Cealkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • R 4 is C 2 -C 6 alkenyl. Suitable alkenyls include, but are not limited to, ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl.
  • R 4 is halogen-substitutedCi-Cealkyl. Suitable halogen-substituted alkyls include, but are not limited to, mono-, di- and trifluoromethyl. In another embodiment of the compounds described herein, R 4 is selected from -OH and Ci- CealkylOH. In still another embodiment, R 4 is OCi-Cealkyl. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy. In still another embodiment, R 4 is halogen-substitutedOCi-Cealkyl.
  • Suitable halogen-substituted alkoxys include, but are not limited to, mono-, di- and trifluoromethoxy.
  • R 4 is -NH 2 .
  • R 4 is -S0 2 Ci-C 6 alkyl.
  • Suitable -S0 2 Ci-C 6 alkyl include, but are not limited to, - SO 2 CH 3 .
  • R 4 is -CN.
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halogen- substitutedCi- Cealkyl, -OH, Ci-C 6 alkylOH, -OCi-C 6 alkyl, -Ohalogen-substitutedCi-C 6 alkyl, -NH 2 , -S0 2 Ci- Cealkyl and -CN or when taken together R 2 and R 3 form a heterocycle ring.
  • R 1 is hydrogen. In certain embodiments, R 1 is halogen. Suitable halogens include chlorine, fluorine, bromine and iodine. In other embodiments, R 1 is selected from the group consisting of hydrogen and halogen. In another embodiment, R 1 is Ci-C 6 alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl. In yet another embodiment, R 1 is C 2 -C 6 alkenyl.
  • Suitable alkenyls include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n- pentenyl.
  • R 1 is halogen-substitutedCi-Cealkyl. Suitable halogen- substituted alkyls include, but are not limited to, mono-, di- and trifluoromethyl.
  • R 1 is selected from -OH and Ci-C 6 alkylOH.
  • R 1 is OCi-Cealkyl.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy.
  • R 1 is halogen- substitutedOCi-Cealkyl. Suitable halogen-substituted alkoxys include, but are not limited to, mono-, di- and trifluoromethoxy. In yet another embodiment, R 1 is -NH 2 . In another
  • R 1 is -S0 2 Ci-C 6 alkyl. Suitable -S0 2 Ci-C 6 alkyl include, but are not limited to, - S0 2 CH 3 . In still another embodiment, R 1 is -CN.
  • R 2 is hydrogen. In certain embodiments, R 2 is halogen. Suitable halogens include chlorine, fluorine, bromine and iodine. In other embodiments, R 2 is selected from the group consisting of hydrogen and halogen. In another embodiment, R 2 is Ci-C 6 alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl. In yet another embodiment, R 2 is C 2 -C 6 alkenyl.
  • Suitable alkenyls include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n- pentenyl.
  • R 2 is halogen-substitutedCi-Cealkyl. Suitable halogen- substituted alkyls include, but are not limited to, mono-, di- and trifluoromethyl.
  • R 2 is selected from -OH and Ci-C 6 alkylOH.
  • R 2 is OCi-Cealkyl.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy.
  • R 2 is halogen- substitutedOCi-Cealkyl. Suitable halogen-substituted alkoxys include, but are not limited to, mono-, di- and trifluoromethoxy. In yet another embodiment, R 2 is -NH 2 . In another
  • R 2 is -S0 2 Ci-C 6 alkyl. Suitable -S0 2 Ci-C 6 alkyl include, but are not limited to, - S0 2 CH 3 . In still another embodiment, R 2 is -CN. In some embodiments described herein, R 3 is hydrogen. In certain embodiments, R 3 is halogen. Suitable halogens include chlorine, fluorine and iodine. In another embodiment, R 3 is Ci-C 6 alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl.
  • R 3 is C 2 -C 6 alkenyl. Suitable alkenyls include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n- pentenyl. In still another embodiment, R 3 is halogen-substitutedCi-Cealkyl. Suitable halogen- substituted alkyls include, but are not limited to, mono-, di- and trifluoromethyl. In another embodiment of the compounds described herein, R 3 is selected from -OH and Ci-C 6 alkylOH. In still another embodiment, R 3 is OCi-Cealkyl.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy.
  • R 3 is halogen- substitutedOCi-Cealkyl. Suitable halogen-substituted alkoxys include, but are not limited to, mono-, di- and trifluoromethoxy.
  • R 3 is -NH 2 .
  • R 3 is -S0 2 Ci-C 6 alkyl. Suitable -S0 2 Ci-C 6 alkyl include, but are not limited to, - SO 2 CH 3 .
  • R 3 is -CN.
  • R 2 and R 3 when taken together form a heterocycle ring. In certain embodiments, when taken together R 2 and R 3 form a heterocycle ring, wherein the heterocyle is a 5-6 membered ring. In other embodiments, when taken together, R 2 and R 3 form a heterocyclic ring containing at least one oxygen. In still other embodiments, when taken together, R 2 and R 3 form at heterocyclic ring containing only oxygen.
  • Suitable heterocycles include, but are not limited to, 1 , 3-dioxolane or 3-morpholinone.
  • halogen examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Ci-C 6 alkyl encompasses straight alkyl 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, 1,1 ,2-trimethylpropyl, 1,2,2-trimethylprop
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and may be straight or branched and unless otherwise specified, contains from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. For example, C2-C 6 alkenyl is an alkenyl containing 2-6 carbon atoms.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • -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.
  • halogen-substitutedCi-C 6 alkyl encompasses Ci-C 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl and the like.
  • -Ohalogen-substitutedCi-Cealkyl means a -OCi-C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.
  • Ci-C 6 alkylOH means a Ci-C 6 alkyl substituted with an alcohol (-OH).
  • Examples include methanol, propanol, butanol and t-butanol.
  • S0 2 Ci-C 6 alkyl means a group having Ci-C 6 alkyl bonded to sulfonyl (-S0 2 -). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl,
  • heterocycle means mono- or bicyclic or bridged unsaturated, partially unsaturated and saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1 ,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthala
  • Examples also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-£)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l-3 ⁇ 4]thiazolyl,
  • tetrahydroquinolinyl morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, tetrahydropyran, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4- diones (TV-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 pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative 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, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
  • 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,
  • a “subject” is a human or non-human mammal. In one embodiment, a subject is a human.
  • a subject is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a subject is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a subject is a dog.
  • a subject is a cat.
  • 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 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 chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • 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. It will be understood that, as used herein, 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 (iH) and deuterium (3 ⁇ 4).
  • 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.
  • Also encompassed by the present invention are methods of treating DGATl -related diseases.
  • the compounds described herein are effective in preventing or treating various diseases.
  • 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 chromatosis.
  • the compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia
  • 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 subject 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 any of the formulas described herein.
  • 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 subjects 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.
  • the following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds described herein: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component.
  • Syndrome X also known as Metabolic Syndrome
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, hypertriglyceridemia, diabetes or insulin resistance in a mammalian subject in need of such treatment which comprises administering to said subject 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 subject 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 subject in need of such treatment comprising administering to the subject 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 any of the formulas described herein 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, 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 chromato
  • the present invention is directed to the use of a compound of any of the formulas described herein 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 any of the formulas described herein in the manufacture of a medicament for use in treating obesity.
  • DGAT-1 inhibitors may also serve as antiviral therapeutics that selectively suppresses HCV's (Hepatitis C virus) interation with lipid droplets without compromising the overall formation of lipid droplets in liver cells Nature Medicine, vol. 16, no. 11 pages 1295-1298, November 2010.
  • HCV's Hepatitis C virus
  • 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. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose,
  • carboxymethylcellulose corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate,
  • 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 in 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.
  • 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 subject 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 a time or in several times.
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day.
  • the compositions are preferably provided in the form of 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, 500, 750, 850 and 1,000 milligrams of a compound described herein. 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 any of the formulas described herein 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 any of the formulas described herein.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of any of the formulas described herein is preferred.
  • the combination therapy may also include therapies in which the compound of any of the formulas described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of any of the formulas described herein.
  • Examples of other active ingredients that may be administered in combination with a compound of any of the formulas described herein, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • (2) 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) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4)
  • 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 00/39088, and WO 00/69810;
  • incretin mimetics such as GLP-1, GLP-1 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) 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 CoA: cholesterol 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 ( SAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • 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
  • inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 such as those disclosed in U.S. 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 iso forms, such as SGLT-1; SGLT-2, such as PF-04971729, dapagliflozin and remogliflozin; and SGLT-3;
  • SGLT sodium-glucose transporter
  • MGAT-2 (31) agonists of the TG 5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR); and
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of any of the formulas described herein 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
  • DPP-4 dipeptidyl peptidase-IV
  • Antiobesity compounds that can be combined with compounds of any of the formulas described herein 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; CCK-1 agonists; melanin- concentrating hormone (MCH) receptor antagonists; neuropeptide Yl or Y5 antagonists (such as MK- 0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); ⁇ adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (
  • Glucagon receptor antagonists that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • SCD stearoyl-coenzyme A delta-9 desaturase
  • Glucokinase activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Selective PPARy modulators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: (2S)-2-( ⁇ 6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]- 1 ,2-benzisoxazol-5- yl ⁇ oxy)propanoic acid;
  • Inhibitors of 1 1 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
  • Inhibitors of acetyl-CoA carboxylase- 1 and 2 that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 3- ⁇ 1 '-[(1 -cyclopropyl-4-methoxy- lH-indol-6-yl)carbonyl]-4-oxospiro[chroman- 2,4'-piperidin]-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/ ⁇ Ddual agonists such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa 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 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, pitavastatin, 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 cholesterol 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 ( SAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • 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 and remoglifiozin; and SGLT-
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • the compounds described herein can be combined with a DPP-IV inhibitor, such as sitagliptin.
  • DPP 4 is responsible on the inactivation of incretin hormones GLP- 1 (glucagon- like peptide- 1) and GIP (glucose-dependent insulinotropic polypeptide).
  • GLP- 1 glucagon- like peptide- 1
  • GIP glycose-dependent insulinotropic polypeptide
  • 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).
  • Examples were assayed as follows: 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGAT1 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50s were calculated.
  • Step 1 Methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-l-carboxylate (10 g, 50.4 mmol, 1 equiv) from the previous step was dissolved in THF (100 mL) and triethylamine (7.73 mL, 55.5 mmol, 1.1 equiv) and chilled to 0 °C in an ice bath. Trimethylchlorosilane (6.77 mL, 53.0 mmol, 1.05 equiv) was then added dropwise during which time copious white solid formed.
  • triethylsilane (8.06 mL, 50.4 mmol, 1 equiv) and fitted with a pressure equalized dropping funnel, a mechanical stirrer and a Claisen adaptor fitted with a nitrogen inlet and an internal temperature probe and cooled to -78 °C in an ice bath.
  • Trimethylsilyl trifluoromethanesulfonate (4.56 mL, 25.2 mmol, 0.5 equiv) was added dropwise from the dropping funnel over ⁇ 3 minutes ensuring that the internal temperature did not rise above -60 °C. After 5 minutes, the reaction was warmed to 0 °C and held there with stirring for 1 hour then warmed to room temperature.
  • the reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo and left on a high- vacuum pump overnight.
  • the resulting orange oil contained -30% triethylsilyl-containing impurities as indicated by 1H NMR which were removed by trituration with hexanes (3 x 10 mL) to give an orange oil which was carried forward without further purification.
  • Step 3 A 500 mL thick- walled glass Parr Shaker flask was charged with 30 % (w/w) palladium on carbon (2.1 g, 5.92 mmol, 16 mol%) and a solution of the orange oil from Step 2 (17.4 g, 37.7 mmol, 1 equiv) in methanol (100 mL) and pressurized to 48 psi with hydrogen. Agitation on a Parr shaker for 90 minutes at room temperature led to complete removal of the carbamate as indicated by LCMS analysis of an aliquot. Solids were removed by filtration through a pad of Celite and the filtrate was concentrated in vacuo.
  • Step 1 Methyl 4-((piperidin-4-yloxy)methyl)bicyclo[2.2.2]octane-l-carboxylate (2 g, 7.11 mmol, 1 equiv) was dissolved in methanol (14 mL) and THF (14 mL) and a 2.5 M aqueous solution of lithium hydroxide (15 mL, 37.5 mmol, 5.3 equiv) was added and the mixture stirred under an atmosphere of nitrogen at 65 °C for 1 hour at which point LCMS analysis of an aliquot indicated complete saponification had occurred. The mixture was acidified with glacial acetic acid (2 mL, 34.9 mmol, 4.9 equiv) and concentrated in vacuo. Residual water was removed by addition of toluene (40 mL) to the residue and concentration first by rotary evaporation and then by evacuation on a high- vacuum pump for 15 minutes. The resulting white solid was carried forward crude.
  • Step 2 To the white solid from Step 1 was added solid sodium bicarbonate (2.99 g, 35.5 mmol, 5 equiv) and 2-fluoronicotinaldehyde (0.889 g, 7.11 mmol, 1 equiv) and N-methyl pyrrolidinone (12 mL) and the mixture stirred vigorously with heating at 90 °C for 3 hours at which point LCMS analysis of an aliquot indicated complete conversion to the desired product. The mixture was poured into water and carefully brought to pH 7 with 1 M hydrochloric acid ( ⁇ 50 mL) and then to pH 4 with concentrated hydrochloric acid.

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Abstract

La présente invention concerne des composés de formule (I), Formule (I). Les composés de formule (I) agissent comme inhibiteurs de la DGAT1 et peuvent être utiles pour prévenir, traiter ou agir comme agent curatif de l'hyperlipidémie, du diabète sucré et de l'obésité.
PCT/EP2012/071894 2011-11-07 2012-11-06 Composés d'acide bicyclo[2.2.2]octan-1-ylcarboxylique comme inhibiteurs de la dgat-1 WO2013068328A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159802A1 (fr) * 2013-03-14 2014-10-02 Bristol-Myers Squibb Company Modulateurs de récepteurs gpr120 à base d'acide bicyclo [2.2.2]
WO2015140658A1 (fr) * 2014-03-17 2015-09-24 Pfizer Inc. Inhibiteurs de diacylglycérol acyltransférase pour le traitement de troubles métaboliques ou analogues
WO2021133035A1 (fr) * 2019-12-23 2021-07-01 주식회사 엘지화학 Nouveau dérivé amino-aryle utile en tant qu'inhibiteur de diacylglycérol acyltransférase 2 et son utilisation
RU2799819C1 (ru) * 2019-12-23 2023-07-12 ЭлДжи КЕМ, ЛТД. Новое аминоарильное производное, пригодное в качестве ингибитора диацилглицеролацилтрансферазы 2, и его применение

Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004528A2 (fr) 1996-07-31 1998-02-05 Bayer Corporation Pyridines et diphenyles substitues utilises comme agents antihypocholesterolemiques, et antihyperlipoproteinemiques et antihyperglycemiques
WO1999001423A1 (fr) 1997-07-01 1999-01-14 Novo Nordisk A/S Antagonistes/agonistes inverses du glucagon
US6054587A (en) 1997-03-07 2000-04-25 Metabasis Therapeutics, Inc. Indole and azaindole inhibitors of fructose-1,6-bisphosphatase
WO2000039088A1 (fr) 1998-12-23 2000-07-06 Novo Nordisk A/S Antagonistes de glucagon/agonistes inverses
US6110903A (en) 1997-03-07 2000-08-29 Sankyo Company Ltd. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
WO2000069810A1 (fr) 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
US6284748B1 (en) 1997-03-07 2001-09-04 Metabasis Therapeutics, Inc. Purine inhibitors of fructose 1,6-bisphosphatase
WO2002008188A1 (fr) 2000-07-25 2002-01-31 Merck & Co., Inc. Indoles n-substitues utiles pour le traitement du diabete
WO2002060388A2 (fr) 2001-01-30 2002-08-08 Merck & Co., Inc. Acyl-sulfamides pour le traitement de l'obesite, du diabete et des troubles lipidiques
US6489476B1 (en) 1998-09-09 2002-12-03 Metabasis Therapeutics, Inc. Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase
WO2003104207A2 (fr) 2002-06-10 2003-12-18 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase 1 utilisables pour le traitement du diabete, de l'obesite et de la dyslipidemie
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004020409A1 (fr) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles a activite antidiabetique
WO2004019869A2 (fr) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles presentant un effet antidiabetique
WO2004058741A1 (fr) 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de triazole en tant qu'inhibiteurs de la 11-beta-hydroxysteroide dehydrogenase 1
WO2004066963A2 (fr) 2003-01-17 2004-08-12 Merck & Co., Inc. Derives de n-cyclohexylaminocarbonyl benzenesulfonamide
WO2007071966A1 (fr) * 2005-12-22 2007-06-28 Astrazeneca Ab Pyrimido-[4,5-b]-oxazines pour utilisation en tant qu'inhibiteurs de dgat
WO2009000087A1 (fr) 2007-06-28 2008-12-31 Merck Frosst Canada Ltd. Pyrimidines fusionnées substituées en tant qu'antagonistes de l'activité de gpr105
WO2009011836A1 (fr) 2007-07-19 2009-01-22 Merck & Co., Inc. Dérivés de bêta-carboline en tant que composés antidiabétiques
WO2009042053A2 (fr) 2007-09-21 2009-04-02 Merck & Co., Inc. Agonistes du récepteur de la neuromédine u et leurs utilisations
WO2009081195A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Composés carbamoyles comme inhibiteurs de dgat1 190
WO2012009217A1 (fr) * 2010-07-13 2012-01-19 Merck Sharp & Dohme Corp. Composés spirocycliques

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004528A2 (fr) 1996-07-31 1998-02-05 Bayer Corporation Pyridines et diphenyles substitues utilises comme agents antihypocholesterolemiques, et antihyperlipoproteinemiques et antihyperglycemiques
US6054587A (en) 1997-03-07 2000-04-25 Metabasis Therapeutics, Inc. Indole and azaindole inhibitors of fructose-1,6-bisphosphatase
US6110903A (en) 1997-03-07 2000-08-29 Sankyo Company Ltd. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
US6284748B1 (en) 1997-03-07 2001-09-04 Metabasis Therapeutics, Inc. Purine inhibitors of fructose 1,6-bisphosphatase
US6399782B1 (en) 1997-03-07 2002-06-04 Metabasis Therapeutics, Inc. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
WO1999001423A1 (fr) 1997-07-01 1999-01-14 Novo Nordisk A/S Antagonistes/agonistes inverses du glucagon
US6489476B1 (en) 1998-09-09 2002-12-03 Metabasis Therapeutics, Inc. Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase
WO2000039088A1 (fr) 1998-12-23 2000-07-06 Novo Nordisk A/S Antagonistes de glucagon/agonistes inverses
WO2000069810A1 (fr) 1999-05-17 2000-11-23 Novo Nordisk A/S Antagonistes/agonistes inverses de glucagon
WO2002008188A1 (fr) 2000-07-25 2002-01-31 Merck & Co., Inc. Indoles n-substitues utiles pour le traitement du diabete
WO2002060388A2 (fr) 2001-01-30 2002-08-08 Merck & Co., Inc. Acyl-sulfamides pour le traitement de l'obesite, du diabete et des troubles lipidiques
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2003104207A2 (fr) 2002-06-10 2003-12-18 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase 1 utilisables pour le traitement du diabete, de l'obesite et de la dyslipidemie
US6730690B2 (en) 2002-06-10 2004-05-04 Merck & Co., Inc. 11-β-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
WO2004020409A1 (fr) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles a activite antidiabetique
WO2004019869A2 (fr) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles presentant un effet antidiabetique
WO2004020408A1 (fr) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles a activite antidiabetique
WO2004058741A1 (fr) 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de triazole en tant qu'inhibiteurs de la 11-beta-hydroxysteroide dehydrogenase 1
WO2004066963A2 (fr) 2003-01-17 2004-08-12 Merck & Co., Inc. Derives de n-cyclohexylaminocarbonyl benzenesulfonamide
WO2007071966A1 (fr) * 2005-12-22 2007-06-28 Astrazeneca Ab Pyrimido-[4,5-b]-oxazines pour utilisation en tant qu'inhibiteurs de dgat
WO2009000087A1 (fr) 2007-06-28 2008-12-31 Merck Frosst Canada Ltd. Pyrimidines fusionnées substituées en tant qu'antagonistes de l'activité de gpr105
WO2009011836A1 (fr) 2007-07-19 2009-01-22 Merck & Co., Inc. Dérivés de bêta-carboline en tant que composés antidiabétiques
WO2009042053A2 (fr) 2007-09-21 2009-04-02 Merck & Co., Inc. Agonistes du récepteur de la neuromédine u et leurs utilisations
WO2009081195A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Composés carbamoyles comme inhibiteurs de dgat1 190
WO2012009217A1 (fr) * 2010-07-13 2012-01-19 Merck Sharp & Dohme Corp. Composés spirocycliques

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Journal of Japan Society for the Study of Obesity", vol. 12, 2006
ANN. MED., vol. 36, 2004, pages 252 - 261
D. SPANSWICK; K. LEE: "Emerging antiobesity drugs", EXPERT OPIN. EMERGING DRUGS, vol. 8, 2003, pages 217 - 237, XP008028338, DOI: doi:10.1517/eoed.8.1.217.21037
DIABETES, vol. 51, 2002, pages 3189 - 3195
DIABETES, vol. 53, 2004, pages 1445 - 1451
DIABETES, vol. 54, 2005, pages 3379 - 3386
J.A. FERNANDEZ-LOPEZ ET AL.: "Pharmacological Approaches for the Treatment of Obesity", DRUGS, vol. 62, 2002, pages 915 - 944, XP009001892, DOI: doi:10.2165/00003495-200262060-00005
JBC, vol. 276, 2001, pages 38870 - 38876
JBC, vol. 280, 2005, pages 21506 - 21514
JCI, vol. 109, 2002, pages 1049 - 1055
JCI, vol. 111, 2003, pages 1715 - 1722
K.M. GADDE ET AL.: "Combination pharmaceutical therapies for obesity", EXP. OPIN. PHARMACOTHER., vol. 10, 2009, pages 921 - 925
NATURE GENETICS, vol. 25, 2000, pages 87 - 90
NATURE MEDICINE, vol. 16, no. 11, November 2010 (2010-11-01), pages 1295 - 1298
PROC. NATL. ACAD. SCI. USA., vol. 95, 1998, pages 13018 - 13023
PROG. LIPID RES., vol. 43, 2004, pages 134 - 176
S. CHAKI ET AL.: "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity", EXPERT OPIN. THER. PATENTS, vol. 11, 2001, pages 1677 - 1692, XP002438303, DOI: doi:10.1517/13543776.11.11.1677

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* Cited by examiner, † Cited by third party
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WO2014159802A1 (fr) * 2013-03-14 2014-10-02 Bristol-Myers Squibb Company Modulateurs de récepteurs gpr120 à base d'acide bicyclo [2.2.2]
US9598390B2 (en) 2013-03-14 2017-03-21 Bristol-Myers Squibb Company Bicyclo[2.2.2]acid GPR120 modulators
US20160039780A1 (en) * 2013-03-14 2016-02-11 Bristol-Myers Squibb Company Bicyclo [2.2.2] acid gpr120 modulators
US9440949B2 (en) 2014-03-17 2016-09-13 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
TWI551596B (zh) * 2014-03-17 2016-10-01 輝瑞大藥廠 二醯甘油醯基轉移酶２抑制劑
CN106103425A (zh) * 2014-03-17 2016-11-09 辉瑞公司 用于治疗代谢及相关病症的二酰甘油酰基转移酶2抑制剂
WO2015140658A1 (fr) * 2014-03-17 2015-09-24 Pfizer Inc. Inhibiteurs de diacylglycérol acyltransférase pour le traitement de troubles métaboliques ou analogues
JP2017507979A (ja) * 2014-03-17 2017-03-23 ファイザー・インク 代謝性および関連障害の処置において使用するためのジアシルグリセロールアシルトランスフェラーゼ２阻害剤
KR101772836B1 (ko) 2014-03-17 2017-08-29 화이자 인코포레이티드 대사 및 관련 장애의 치료에 사용하기 위한 디아실글리세롤 아실트랜스퍼라제 2 억제제
US9789110B2 (en) 2014-03-17 2017-10-17 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
US10188653B2 (en) 2014-03-17 2019-01-29 Pfizer Inc. Diacylglycerol acyltransferase 2 inhibitors
EA032356B1 (ru) * 2014-03-17 2019-05-31 Пфайзер Инк. Ингибиторы диацилглицеринацилтрансферазы 2 для применения в лечении метаболических и связанных с метаболизмом расстройств
WO2021133035A1 (fr) * 2019-12-23 2021-07-01 주식회사 엘지화학 Nouveau dérivé amino-aryle utile en tant qu'inhibiteur de diacylglycérol acyltransférase 2 et son utilisation
RU2799819C1 (ru) * 2019-12-23 2023-07-12 ЭлДжи КЕМ, ЛТД. Новое аминоарильное производное, пригодное в качестве ингибитора диацилглицеролацилтрансферазы 2, и его применение
AU2020414202B2 (en) * 2019-12-23 2024-01-04 Lg Chem, Ltd. Novel amino aryl derivative useful as diacylglycerol acyltransferase 2 inhibitor and use thereof

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