WO2013130370A2 - Composés en tant qu'inhibiteurs de dgat-1 - Google Patents

Composés en tant qu'inhibiteurs de dgat-1 Download PDF

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WO2013130370A2
WO2013130370A2 PCT/US2013/027548 US2013027548W WO2013130370A2 WO 2013130370 A2 WO2013130370 A2 WO 2013130370A2 US 2013027548 W US2013027548 W US 2013027548W WO 2013130370 A2 WO2013130370 A2 WO 2013130370A2
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alkyl
compound
pharmaceutically acceptable
mmol
acceptable salt
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PCT/US2013/027548
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WO2013130370A3 (fr
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Robert J. Devita
Yang Yu
Jian Liu
Shuwen He
Arto D. Krikorian
Daniel J. Miller
Zhicai Wu
Ginger Xu-Qiang Yang
Quingmei HONG
Zhong LAI
Nicolas Zorn
Pauline C. Ting
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Merck Sharp & Dohme Corp.
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Publication of WO2013130370A3 publication Critical patent/WO2013130370A3/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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • C07D401/10—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 linked by a carbon chain containing aromatic rings
    • 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
    • C07D403/10—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 linked by a carbon chain containing aromatic rings
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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

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.
  • acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways.
  • 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 acyltransferases
  • 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
  • mice with overexpression of DGAT-1 in adipose tissue have been reported to worsen in mice with overexpression of DGAT-1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).
  • 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.
  • V, U, W, X and Y are independently selected from the group consisting of -N- and -CH-;
  • R 1 , R 2 , R 3 and R 4 are each present at one of more at the ring carbons and are independently selected from the group consisting of hydrogen, halogen, -CN, halogen- substitutedCi-C 6 alkyl, Ci-C 6 alkyl, S0 2 Ci-C 6 alkyl and Ci-C 6 alkoxy, or taken together
  • R 4 and Z form a pyrole, C3-C 6 cycloalkyl, unsubstituted or substituted with -COOH, Ci-C 6 alkyl;
  • Z is selected from the group consisting of:
  • X is selected from the group consisting of -N- and -CH-.
  • X is -N-.
  • X is -CH-.
  • Y and V are not both -N- and W and U are not both -N-.
  • Y is selected from the group consisting of -N- and -CH-. In certain embodiments, Y is -N-. In other embodiments, Y is -CH-. Described herein are compounds wherein V is selected from the group consisting of -N- and -CH-. In other embodiments, V is -CH-. In certain embodiments, V is -N-. In certain embodiments, Y and V are both -CH-. In other embodiments, Y is -CH- and V is -N-. In yet other embodiments, Y is -N- and V is -CH-. In still other embodiments, Y and V are not simultaneously -N-.
  • W is selected from the group consisting of -N- and -CH-.
  • W is -N-.
  • W is -CH-.
  • U is -CH-.
  • U is -N-.
  • W and U are both -CH-.
  • W and U are both -N-.
  • W is -CH- and U is -N-.
  • W is -N- and U is -CH-.
  • R 1 , R 2 , R 3 and R 4 are present at one or more of the ring carbons and are independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy, or taken together R 4 and Z form a pyrole, C3-C 6 cycloalkyl, unsubstituted or substituted with -COOH, Ci- Cgalkyl.
  • R 1 is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl, S0 2 Ci-C 6 alkyl and Ci-C 6 alkoxy. In certain embodiments, R 1 is hydrogen. In other words,
  • R 1 is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine. In yet other embodiments, R 1 is -CN. In still other embodiments, R 1 is halogen- substitutedCi-C6alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, 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, 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- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl.
  • R 1 is S0 2 Ci-C 6 alkyl. Suitable S0 2 Ci-C 6 alkyls include, but are not limited to, SO 2 CH 3 . In still other embodiments, R 1 is Ci-C 6 alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.
  • R 2 is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl, S0 2 Ci-C 6 alkyl and Ci-C 6 alkoxy.
  • R 2 is hydrogen.
  • R 2 is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine.
  • R 2 is -CN.
  • R 2 is halogen- substitutedCi-C 6 alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl.
  • 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, 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- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -e
  • R 2 is S0 2 Ci-C 6 alkyl. Suitable include, but are not limited to, SO 2 CH 3 . In still other embodiments, R 2 is Ci-C 6 alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.
  • R 3 is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl, S0 2 Ci-C 6 alkyl and Ci-C 6 alkoxy.
  • R 3 is hydrogen.
  • R 3 is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine.
  • R 3 is -CN.
  • R 3 is halogen- substitutedCi-C 6 alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl.
  • 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, 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- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -e
  • R 3 is S02Ci-C6alkyl. Suitable SC Ci-Cealkyls include, but are not limited to, SO2CH3. In still other embodiments, R 3 is Ci-C 6 alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.
  • R 4 is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy or taken together R 4 and Z form a pyrole, C 3 - C 6 cycloalkyl, unsubstituted or substituted with -COOH, Ci-C 6 alkyl.
  • R 4 is hydrogen.
  • R 4 is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine.
  • R 4 is -CN.
  • R 4 is halogen-substitutedCi-C 6 alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, R 4 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, 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- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl.
  • R 4 is SC Ci-Cealkyl. Suitable S02Ci-C6alkyls include, but are not limited to, SO2CH3. In still other embodiments, R 4 is Ci-C 6 alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy. In othe embodiments, taken together R 4 and Z form a pyrole, C 3 -C 6 cycloalkyl, unsubstituted or substituted with -COOH, Ci-C 6 alkyl;
  • Z is selected from the group consisting of: hydrogen, -OH, -COOH, COCi-C 6 alkyl, -Ci-C 6 alkylCOOH,-Ci-C 6 alkyl, halogen- substitutedCi-C 6 alkyl, -Ci-C 6 alkoxy, halogen-substitutedCi-C 6 alkoxy, -OCi-C 6 alkylCOOH, - OCi-C 6 alkylphenyl,-OphenylCi-C 6 alkylCOOH, -OCi-C 6 alkylphenylCi-C 6 alkylCOOH, -OCi- C 6 alkylphenylCOOH,-OphenylCOOH, -OnaphylCOOH, phenyl, piperidine, piperidineCOOCi- C 6 alkyl, -OCi-C 6 alkyl pyridineCOOH,-Obenzimidi
  • Z is hydrogen. In other embodiments, Z is -OH. In yet other embodiments, Z is -COOH. In still other embodiments, Z is COCi-C 6 alkyl. In certain embodiments, Z is -Ci-C 6 alkylCOOH. In some embodiments, Z is -Ci-C 6 alkyl. In other embodiments, Z is halogen-substitutedCi-C 6 alkyl. In yet other embodiments, Z is -Ci-C 6 alkoxy. In still other embodiments, Z is halogen-substitutedCi-C 6 alkoxy. In other embodiment of the compounds described herein, Z is -OCi-C6alkylCOOH.
  • Z is -(XV C 6 alkylphenyl. In still other embodiments, Z is -OphenylCi-C 6 alkylCOOH. In yet other embodiments, Z is -OCi-C 6 alkylphenylCi-C 6 alkylCOOH. In certain embodiments, Z is -(XV C 6 alkylphenylCOOH. In other embodiments, Z is -OphenylCOOH. In still other embodiments, Z is -OnaphylCOOH. In certain embodiments, Z is phenyl. In other embodiments, Z is piperidine. In still other embodiments, Z is piperidineCOOCi-C 6 alkyl. In yet other
  • Z is -OCi-C 6 alkylpyridineCOOH. In certain embodiments, Z is - ObenzimidizoleCOOH. In some embodiments, Z is -OCi-C 6 alkylthieneCOOH. In other embodiments, Z is pyridine. In yet other embodiments, Z is pyrollodiol. In yet other embodiments, Z is S0 2 HCi-C 6 alkylCOOH. In still other embodiments, Z is In certain embodiments, Z is S0 2 Ci-C 6 alkylphenylCOOH. In some embodiments, Z is SO 2 C 1 - C 6 alkylCOOH.
  • Z is S0 2 C 1 -C 6 alkylCOOC 1 -C 6 alkyl. In yet other embodiments, Z is -CN. In still other embodiments, Z is -OCi-C 6 alkylCN. In certain embodiments, Z is -NH 2 . In some embodiments, Z is -CONH 2 . In other embodiments, Z is - CONHCi-C 6 alkyl. In still other embodiments, Z is -OCi-C 6 alkylN(Ci-C 6 alkyl) 2 . In yet other embodiments, Z is CO (Ci-C 6 alkyl) 2 . In certain embodiments, Z is CONHCi-C 6 alkylOH.
  • Z is NHCOCi-C6alkylCOOH. In other embodiments, Z is NHCi- C 6 alkylCOOH. In still other embodiments, Z is NHCi-C 6 alkylphenylCOOH. In yet other embodiments, Z is -NHCi-C 6 alkylphenylCi-C 6 alkylCOOH. In certain embodiments, Z is NHCV C 6 alkylphenylCOOH. In other embodiments, Z is NHS0 2 C 1 -C 6 alkyl. In still other
  • Z is -SCi-C 6 alkylCOOCi-C 6 alkyl. In yet other embodiments, Z is -SCV
  • 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 IC50 values were calculated.
  • 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, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-eth
  • C3-C 6 cycloalkyl encompasses cycloalkyls having 3 to 6 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. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • -Ci-C 6 alkoxy refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.
  • halogen-substitutedCi-C6 alkyl encompasses C1-C6 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.
  • -halogen-substitutedCi-C 6 alkoxy means a -Ci-C 6 alkoxy 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.
  • pharmaceutically acceptable salt refers to salts prepared from
  • “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, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine,
  • a "subject” is a human or non-human mammal.
  • 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
  • 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.
  • Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well.
  • 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 (IF!) and deuterium (2H).
  • IF protium
  • 2H deuterium
  • 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.
  • DGAT 1 -related diseases are also encompassed by the present invention.
  • the compounds described herein are effective in preventing or treating various DGAT 1 -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 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
  • obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk. Therefore, DGAT-1 inhibitors may also be useful to treat hypertension associated with this condition.
  • 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 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 type 2 diabetes.
  • 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 DGAT 1 -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. 1 1 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.
  • 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, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, 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 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
  • compositions are preferably
  • tablets or capsules containing from 0.01 mg to 1,000 mg, preferably
  • This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of formula I 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.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred.
  • the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I.
  • Examples of other active ingredients that may be administered separately or in the same pharmaceutical composition in combination with a compound of the formulas described herein include, but are not limited to:
  • dipeptidyl peptidase-IV (DPP-4) inhibitors e.g., sitagliptin, alogliptin, MK-3102, linagliptin, vildagliptin;
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ dual agonists e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate)
  • SPPARyM's selective PPARy modulators
  • amylin and amylin analogs e.g., pramlintide
  • sulfonylurea and non-sulfonylurea insulin secretagogues e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide
  • insulin secretagogues e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide
  • a-glucosidase inhibitors e.g., acarbose, voglibose and miglitol
  • glucagon receptor antagonists e.g., 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 e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1 131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acyl
  • HMG-CoA reductase inhibitors e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin
  • CoA:cholesterol acyltransferase inhibitors (e.g., avasimibe);
  • HDL-raising drugs e.g., niacin and nicotinic acid receptor agonists, and extended- release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP- 1 antagonist MK-524);
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;
  • antihypertensive agents such as ACE inhibitors (e.g.,lisinopril, enalapril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers, and calcium channel blockers;
  • ACE inhibitors e.g.,lisinopril, enalapril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisart
  • GKAs glucokinase activators
  • inhibitors of 1 1 ⁇ -hydroxysteroid dehydrogenase type 1, e.g., such as those disclosed in U.S. Patent No. 6,730,690, and LY-2523199;
  • CETP inhibitors e.g., anacetrapib, and torcetrapib
  • inhibitors of fructose 1,6-bisphosphatase e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6,1 10,903; 6,284,748; 6,399,782; and 6,489,476);
  • inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • GPR-109 e.g., GPR-109
  • GPR-119 e.g., MBX2982 and PSN821
  • GPR-40 e.g., TAK875, 5-[4-[[(lR)-4-[6-(3-hydroxy-3- methylbutoxy)-2-methylpyridine-3 -yl] -2,3 -dihydro- 1 H-indene- 1 -yl] oxy]phenyl] isothiazole-3 -ol 1-oxide, 5-(4-((3-(2,6-dimethyl-4-(3-
  • neuromedin U receptor agonists e.g., such as those disclosed in WO 2009/042053, including, but not limited to, neuromedin S (NMS)
  • NMS neuromedin S
  • GPR-105 antagonists e.g., such as those disclosed in WO 2009/000087;
  • SGLT inhibitors e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211
  • SGLT inhibitors e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211
  • acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 DGAT-1 and DGAT-2
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR
  • PACAP PACAP
  • PACAP mimetics PACAP
  • PACAP receptor 3 agonists PACAP, PACAP mimetics, and PACAP receptor 3 agonists
  • PTP-1B protein tyrosine phosphatase- IB
  • IL-lb antibodies e.g., XOMA052 and canakinumab
  • DPP-4 dipeptidyl peptidase-rv
  • Such inhibitors include, without
  • sitagliptin (disclosed in US Patent No. 6,699,871), MK-3102, SYR-472, teneligliptin, KRP104, TS021, AMG222, SK0403, LC15-0444, vildagliptin, saxagliptin, alogliptin,
  • melogliptin melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose
  • DPP-4 dipeptidyl peptidase-IV
  • DPP-4 dipeptidyl peptidase-IV
  • Antiobesity compounds that can be combined with compounds of formula I 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; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat;
  • melanocortin receptor agonists in particular, melanocortin-4 receptor agonists; CC -1 agonists;
  • MCH melanin-concentrating hormone
  • neuropeptide Yi or Y5 antagonists such as MK-0557
  • CB 1 receptor inverse agonists and antagonists such as rimonabant and taranabant
  • ⁇ 3 adrenergic receptor agonists such as ghrelin antagonists
  • bombesin receptor agonists such as bombesin receptor subtype-3 agonists
  • 5-hydroxytryptamine-2c (5-HT2c) agonists such as lorcaserin.
  • Patents. 11 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs,” Expert Opin. Emerging Drugs. 8: 217-237 (2003); J.A. Fernandez-Lopez, et al., “Pharmacological Approaches for the Treatment of Obesity,” Drugs. 62: 915-944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother., 10: 921-925 (2009).
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula I 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 formula I, but are not limited to:
  • Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I include, but are not limited to:
  • Selective PPARy modulators that can be used in combination with the compounds of formula I include, but are not limited to:
  • Inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I include, but are not limited to:
  • Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I 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 I include, but are not limited to:
  • composition which comprises one or more of the following agents:
  • DPP-4 dipeptidyl peptidase-IV
  • (2) insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, pioglitazone, rosiglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/ ⁇ dual agonists, such as ZYH1, YYH2, chiglitazar, GFT505, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) big
  • sulfonylurea and non-sulfonylurea insulin secretagogues e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide
  • insulin secretagogues e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide
  • a-glucosidase inhibitors e.g., acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (e.g., colestilan, cholestyramine, colestimide, colesevelam
  • HMG-CoA reductase inhibitors e.g., lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • bile acid sequestering agents e.g., colestilan, cholestyramine, colestimide, colesevelam
  • 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 anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (e.g., enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers (e.g., calcium channel blockers);
  • ACE inhibitors e.g., enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan
  • GKAs glucokinase activators
  • inhibitors of 1 1 ⁇ -hydroxysteroid dehydrogenase type 1 e.g., 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 fructose 1,6-bisphosphatase e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6, 1 10,903; 6,284,748; 6,399,782; and 6,489,476);
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • agonists of the G-protein-coupled receptors (i) GPR-109, (ii) GPR-119 (e.g., MBX2982, and PSN821), and (iii) GPR-40 (e.g., TAK875, 5-[4-[[(lR)-4-[6-(3-hydroxy-3- methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-lH-indene-l-yl]oxy]phenyl]isothiazole-3-ol 1- oxide, 5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)iso, 5-(4- ((3-(2-methyl-6-(3-hydroxypropoxy)pyridine-3-yl)-2-methylphenyl)methoxy)phenyl)isothiazole-3-ol 1- oxide, and 5-[4-[4-
  • SSTR3 antagonists e.g., such as those disclosed in WO 2009/011836
  • neuromedin U receptor agonists e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS)
  • NMS neuromedin S
  • GPR-105 antagonists e.g., such as those disclosed in WO 2009/000087;
  • (22) inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2 (e.g., ASP1941, TS071, BI10773, tofogliflozin, LX421 1, canagliflozin, dapagliflozin and remogliflozin; and SGLT-3);
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR
  • IL-lb antibodies e.g., XOMA052, and canakinumab
  • 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. 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).
  • 2,3'-bipyridine-5-carbaldehyde (19.8 g, 98 mmol) was dissolved in DMA (350 ml) and the solution was cooled to 0°C. 4-Chloro-l,2-phenylenediamine (14.40 g, 98 mmol) was added. Water (315 ml) was added followed by slow addition of potassium peroxymonosulfate (39.1 g, 63.7 mmol). The reaction mixture became thick. 3 mL of DMAc and 2mL of water were added to facilite stirring. The dark brown slurry was allowed to age at RT. After 3h, the reaction mixture was diluted with water and the remaining slurry was allowed to age overnight at RT.
  • the vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW irridiation at 120 °C for 1 hr.
  • the reaction mixture was filtered and washed with ethyl acetate.
  • the filtrate was concentrated and partitioned between water (20 mL) and ethyl actate (50 mL), and worked up by extraction.
  • the combined organic phases were dried over MgS0 4 , filtered and concentrated.
  • the residue was dissolved in small amount of ethyl acetate (10 mL) by heating and then slowly cooled to room temperature and 0 °C.
  • the precipitated solid was filtered and washed with ethyl actate to afford crop of product.
  • Triphenylphosphine (18.8 g, 71.8 mmol) was then added followed by dropwise addition of diisopropyl azodicarboxylate (14.1 ml, 71.8 mmol) at OoC. The reaction was then heated to 55 °C and allowed to stir at this temperature over night. The reaction mixture was concentrated. The residue was treated with EtOAc (70 ml) and then Hexane (70 ml), the solid was filtered off. The filtrate was concentrated, separated by MPLC (10-100% EtoAC in hexane) to give methyl 3-(5- bromopyridin-2-yloxy)-2,2-dimethylpropanoate (9.94 g). LC-MS (ES, m/z) C u H 14 BrN0 3 : 287; Found: 288 [M+H]+.
  • Methyl 3-(5-bromo-3-methylpyridin-2-yloxy)-2,2-dimethylpropanoate Prepared following the procedure described above for Methyl 3-(5-bromopyridin-2- yloxy)-2,2-dimethylpropanoate, but starting with 5-bromo-3-methylpyridin-2-ol.
  • Methyl 3-(5-formyl-2,3'-bipyridin-6'-yloxy)-2,2-dimethylpropanoate A mixture of methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yloxy)propanoate (1.5 g, 4.47 mmol), 6-Bromonicotinaldehyde (0.832 g, 4.47 mmol), [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.164 g, 0.224 mmol) and sodium carbonate (0.949 g, 8.95 mmol) are suspended in DMF / H 2 0, and stirrred at 80°C under 2 over night.
  • Examples 72 - 74 Prepared following the proceure described above for methyl 4-(4'-(5-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)biphenyl-4-ylthio)butanoate and 4-(4'-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)biphenyl-4-ylthio)butanoic acid.
  • Examples 107-115 Prepared following the procedure described for Methold 1 of 3-(5-(4-(5-cyano-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid, starting from the appropriate aldehyde and diamines.
  • Step B 5-r4'-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-yl1-oxazolidine-2,4-dione

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Abstract

La présente invention concerne des composés de formule I. Les composés de formule I agissent en tant qu'inhibiteurs de DGAT-1 et peuvent être utiles dans la prévention, le traitement ou l'action en tant qu'agent curatif pour une hyperlipidémie, un diabète sucré et l'obésité.
PCT/US2013/027548 2012-03-01 2013-02-25 Composés en tant qu'inhibiteurs de dgat-1 WO2013130370A2 (fr)

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US10519115B2 (en) 2013-11-15 2019-12-31 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CN111936137A (zh) * 2018-03-16 2020-11-13 安济药业公司 用于治疗严重便秘的组合物和方法

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US10519115B2 (en) 2013-11-15 2019-12-31 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CN111936137A (zh) * 2018-03-16 2020-11-13 安济药业公司 用于治疗严重便秘的组合物和方法
EP3765012A4 (fr) * 2018-03-16 2021-12-15 Anji Pharmaceuticals Inc. Compositions et méthodes de traitement de la constipation sévère
US11224590B2 (en) 2018-03-16 2022-01-18 Anji Pharmaceuticals Inc. Compositions and methods for treating severe constipation
CN111936137B (zh) * 2018-03-16 2023-09-08 安济药业公司 用于治疗严重便秘的组合物和方法
US11819495B2 (en) 2018-03-16 2023-11-21 Anji Pharmaceuticals Inc. Compositions and methods for treating severe constipation

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