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WO2014081995A1 - Nouveaux composés utilisés comme inhibiteurs de diacylglycérol acyltransférase - Google Patents

Nouveaux composés utilisés comme inhibiteurs de diacylglycérol acyltransférase Download PDF

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Publication number
WO2014081995A1
WO2014081995A1 PCT/US2013/071378 US2013071378W WO2014081995A1 WO 2014081995 A1 WO2014081995 A1 WO 2014081995A1 US 2013071378 W US2013071378 W US 2013071378W WO 2014081995 A1 WO2014081995 A1 WO 2014081995A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
acid
alkyl
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Inventor
Mui Cheung
Raghuram S. TANGIRALA
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which are inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination with weight management therapies or other triglyceride lowering therapy, for the prevention or treatment of diseases related to DGAT- 1 dysfunction or where modulation of DGAT- 1 activity may have therapeutic benefit including but not limited to obesity, obesity related disorders, genetic (Type 1 , Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia- related disorders, caused by but not limited to lipodystrophy, hypothyroidism, medications (beta blockers, thiazides, estrogen, glucocorticoids, transplant) and other factors (pregnancy, alcohol intake), hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess
  • Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness.
  • DGAT-1 diacylglycerol acyltransferase 1
  • DGAT-1 is an enzyme that is implicated in the development of both diabetes and insulin resistance.
  • Studies of DGAT-1 deficient mice show that DGAT- 1 deficiency protects against insulin resistance and obesity, see Chen, H.C. et al., J Clin Invest., 109(8), 1049-1055 (2002). Therefore, inhibitors of DGAT-1 should be useful for the treatment of metabolic disorders, e.g. obesity, Type 2 diabetes, and insulin resistance syndrome (or metabolic syndrome) and other associated or related diseases and conditions.
  • metabolic disorders e.g. obesity, Type 2 diabetes, and insulin resistance syndrome (or metabolic syndrome) and other associated or related diseases and conditions.
  • This invention relates to compounds of Formula (I):
  • R 1 is hydrogen or (Ci-C 4 )alkyl
  • R 2 is hydrogen or -C(R 5 ) 2 R 4 ;
  • R 3 is hydrogen, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, hydroxyl, or (Ci-C 4 )alkoxy;
  • R 4 is -CH 2 C(0)OH or -C(0)OR 6 ;
  • each R 5 is independently hydrogen or -CH 3 ;
  • R 6 is hydrogen, (C C 4 )alkyl, halo(Ci-C 4 )alkyl, phenyl, or 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.
  • This invention also relates to a method of treating obesity comprising administering to a human in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention relates to compounds of the Formula (I) as defined above.
  • this invention also relates to compounds of Formula (II):
  • R 3 is hydrogen, (C C 4 )alkyl, halo(Ci-C 4 )alkyl, hydroxyl, or (C C 4 )alkoxy; or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, (Ci-Cz alkyl, halo(Ci-C4)alkyl, hydroxyl, or (Ci-Cz alkoxy; or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, (Ci-Cz alkyl, halo(Ci-C4)alkyl, hydroxyl, or (Ci-Cz alkoxy; or a pharmaceutically acceptable salt thereof.
  • this invention relates to compounds of Formula (I), (II), (III), or
  • R 3 is hydrogen, (Ci-Cz alkyl, or halo(Ci-C4)alkyl.
  • this invention relates to compounds of Formula (I), (II), (III), or (IV), wherein R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , or -OCH 3 .
  • This invention also relates to compounds that are exemplified in the Experimental section.
  • This invention also relates to compounds of Formula (I), (II), (III), (IV) or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use in therapy.
  • diseases mediated by Acyl coenzyme A diacylglycerol acyltransferase 1 (DGAT- 1 ), such as obesity, obesity related disorders, genetic (Type 1 , Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia-related disorders, hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess hair growth (including syndromes associated with hirsutism), nephrotic syndrome, fibrosis such as mycocardial, renal and liver fibrosis, hepatitis C virus infection and acne or other skin disorders.
  • this invention relates to compounds of Formula (I), (II), (III), (DGAT- 1 ), such as
  • This invention also relates to compounds of Formula (I), (II), (III), (IV) or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use as a medicament.
  • This invention also relates to compounds of Formula (I), (II), (III), (IV), or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of obesity.
  • salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as be
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne- l,4-dioates, hexyne- 1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,
  • methoxybenzoates phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ -hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as
  • xylenesulfonates methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthalene-2-sulfonates.
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
  • dehydroabietylamine N,N-bisdehydroabietylamine
  • glucamine N-methylglucamine
  • collidine choline, quinine, quinoline, and basic amino acid such as lysine and arginine.
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • a compound of Formula (I) or “the compound of Formula (I)” refers to one or more compounds according to Formula (I).
  • the compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the compound of Formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • stereoisomeric forms e.g., it contains one or more asymmetric carbon atoms.
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • a compound or salt of Formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • U C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • alkyl represents a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms.
  • (Ci-C6)alkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, ?-butyl, «-pentyl, isopentyl, «-hexyl and branched analogs thereof.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as "halo(Ci-C 4 )alkyl", the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • halo(Ci-C 4 )alkyl is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical.
  • halo(Ci-C4)alkyl groups useful in the present invention include, but are not limited to, -CF 3 (trifluoromethyl), -CCI 3 (trichloromethyl), 1 , 1 -difluoroethyl, 2,2,2-trifluoroethyl, and
  • Alkoxy refers to a group containing an alkyl radical, defined hereinabove, attached through an oxygen linking atom.
  • the term "(Ci-C 4 )alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(Ci-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and ?-butoxy.
  • halogen or “halo” refers to F, CI, Br, or I.
  • Halogen or “hydroxyl” is intended to mean the radical -OH.
  • 5- or 6-membered heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms.
  • 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • a pharmaceutical composition also referred to as pharmaceutical formulation
  • excipients are pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, with at least one excipient.
  • compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual, or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules, powders or granules, solutions or suspensions in aqueous or nonaqueous liquids, edible foams or whips, oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as a syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as a syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through a tablet machine, resulting in imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be any suitable dosage unit formulations for oral administration.
  • microencapsulated The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • tablets and capsules are preferred for delivery of the
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • the present invention provides a method of treatment in a mammal, especially a human, suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof.
  • Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a
  • Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, to said mammal, particularly a human.
  • the term "effective amount” means that amount of a drug or
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • therapeutically effective amounts of a compound of Formula (I), (II), (III), or (IV), as well as salts thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a
  • a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian.
  • a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 0.1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I), (II), (III), or (IV) per se. Similar dosages should be appropriate for treatment of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
  • the present invention provides the use of a compound of the invention in combination with weight management therapies or other triglyceride lowering therapy.
  • the present invention provides a combination of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof with at least one other therapeutically active agent, including another anti-obesity drug and/or an anti- diabetes drug.
  • Such other therapeutically active agent can include, for example, metformin (Glucophage ® ), CB 1 receptor antagonists, GLP- 1 agonists, opioid antagonists, and
  • the compounds of this invention may be made by a variety of methods, including well- known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M.
  • the cyano group in I is then selectively reduced to the corresponding aldehyde in the presence of the methyl ester by treatment with Raney nickel in the presence of sodium
  • HBr 100 °C; f) MeOH, H 2 S0 4 , 65 °C; g) Tf 2 0, CH 2 C1 2 , Py, RT; h) Pd(PPh 3 ) 4 , Zn(CN) 2 , DMF, 140 °C; i) Raney Ni, NaH 2 P0 2 .H 2 0, Py-AcOH, 45 °C; j) NaBH 4 , MeOH, RT; k) Ph 3 P, CBr 4 , DCM, RT; 1) NaCN, CH 3 CN-H 2 0, 60 °C; m) Bredereck's reagent, toluene, 80 °C, then 3-aminopyrazole, AcOH, CH 3 CN, 80 °C; n) LiOH, EtOH-H 2 0, RT.
  • Reagents and conditions a) Glyoxalic acid, H 2 S0 4 , diglyme, 1 10 °C, 12 h; b) Zn, AcOH, 100 °C, 3 h; c) MeS0 3 H, EtOH, RT, 16 h; d) CF 3 CH 2 I, NaH, DMF, RT, 3 h; e) Aq.
  • Zinc (493 g, 7.54 mol) was added to a solution of 1A (350 g, 1.51 mol) in acetic acid - water mixture (1 L + 420 mL), and stirred at 100 °C for 3 h. The reaction mixture was then filtered over celite bed, and the organic layer was removed under reduced pressure. Water (5 L) was added to the residue. The resulting solids were filtered off and dried under vacuum to afford the title compound (280 g, 77%) as a solid.
  • Methanesulfonic acid 450 mL was added to a solution of IB (250 g, 1.07 mol) in ethanol (1.5 L) and stirred at room temperature for 16 h. Ethanol was removed from the reaction mixture under reduced pressure and the residue diluted with ethyl acetate and extracted with brine solution. The organic layer dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford the title compound (241 g, 81%) as a solid.
  • Trifluoromethanesulfonic anhydride (6.02 g, 21.34 mmol) was added to an ice cold solution of IF (4.5 g, 14.23 mmol) and pyridine (1.68 mL, 21.3 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (5 g, 64%) as a syrup.
  • reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water.
  • Triphenylphosphine (0.476 g, 1.81 mmol) and CBr 4 (0.6 g, 1.81 mmol) were added to an ice cold solution of 1J (0.4 g, 1.21 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was diluted with dichloromethane (100 mL) and washed with water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and triturated with diethyl ether and n-pentane to afford the title compound (0.3 g, 54%) as a yellow solid.
  • Lithium hydroxide (0.015 g, 0.63 mmol) was added to a solution of 1M (0.055 g, 0.127 mmol) in 4 mL ethanol - water (3: 1) mixture and stirred at room temperature overnight. After the solvent was removed in vacuo the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified by addition of saturated citric acid solution until pH 5 was attained. The resulting solution was cooled to 0 °C and solids obtained were filtered off and dried under vacuum to afford the title compound (0.03 g, 55%) as a pale yellow solid.
  • Human DGAT1 was expressed in Sf9 insect cells using a baculovirus expression system. Microsomes were prepared and used as enzyme for in vitro inhibition testing in either of two formats measuring production of coenzyme A or tridecanoylglycerol product, respectively. All steps were performed at 21-23°C. All data for DGAT1 inhibition by test compounds were collected under conditions where product formation was linear with reaction time.
  • CPM assay For inhibition of CoA product formation, test compounds were prepared in 100% DMSO, diluted 100-fold into assay buffer, and 10 uL added to 96-well half-area plates (Greiner 675076). An equal volume (10 uL) of 3X enzyme in buffer was added and the components incubated for 30 minutes pre -reaction incubation to allow enzyme and test compounds to attain binding equilibrium.
  • the 3X enzyme mixture contained 30 uM ⁇ 4-[4-(4-amino-7,7- dimethyl-7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl ⁇ acetic acid for fully inhibited control wells.
  • DGAT reactions (30 uL) were initiated upon addition of 10 uL of 3X substrate solution.
  • Final reaction conditions consisted of 20 mM HEPES pH 7.5, 2 mM MgCl 2 , 1 mM CHAPS, 50 uM didecanoylglycerol, 3 uM decanoyl-CoA, 1 ug/mL microsomal protein, and 1% DMSO.
  • Inhibition was normalized to controls containing DMSO or 10 uM ⁇ 4-[4-(4-amino-7,7-dimethyl- 7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl ⁇ acetic acid.
  • IC 5 oS were fitted using GraphPad Prism to a sigmoidal dose response.
  • Reactions were initiated after 30 minute pre-reaction incubation via addition of 5 uL of 2.2X substrate.
  • Final reaction conditions consisted of 50 mM HEPES pH 7.5, 2 mM MgCl 2 , 1 mM CHAPS, 25 uM didecanoylglycerol, 0.5 uM decanoyl-CoA, 0.3 nCi/uL [ 14 C]-decanoyl-CoA or 0.5 nCi/uL [ 3 H]-decanoyl-CoA, 0.05-4 ug/mL microsomal protein, and 1% DMSO.
  • Exemplified compounds of the present invention were tested in one or more DGAT assays described above and were found to be inhibitors of DGAT 1 with IC 5 o ⁇ 10 ⁇ .
  • the compound of Example 1 exhibited an IC 5 o of approximately 49 nM in the human DGAT1 lipid extraction (LE) assay.

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Abstract

L'invention concerne de nouveaux composés qui sont des inhibiteurs d'acyl-coenzyme A: diacylglycérol transférase 1 (DGAT1), des compositions pharmaceutiques les contenant, des procédés pour leur préparation, ainsi que leur utilisation en thérapie, seuls ou en combinaison avec des thérapies de gestion du poids ou autre thérapie de diminution des triglycérides pour la prévention ou le traitement de maladies liées à un dysfonctionnement de DGAT1 ou dans lesquelles une modulation de l'activité de DGAT1 peut avoir un bénéfice thérapeutique.
PCT/US2013/071378 2012-11-23 2013-11-22 Nouveaux composés utilisés comme inhibiteurs de diacylglycérol acyltransférase Ceased WO2014081995A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
US20040209871A1 (en) * 2002-11-22 2004-10-21 Tularik Inc. Fused bicyclic nitrogen-containing heterocycles
US20050070545A1 (en) * 2003-08-07 2005-03-31 Tularik Inc. Pyrrolo[1,2-b]pyridazine derivatives
US20120238581A1 (en) * 2006-11-29 2012-09-20 Souers Andrew J Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
US20120289505A1 (en) * 2009-12-31 2012-11-15 Ravindra Dnyandev Jadhav Inhibitors of diacylglycerol acyl transferase
WO2012162127A1 (fr) * 2011-05-20 2012-11-29 Glaxosmithkline Llc Composés inédits utilisables en tant qu'inhibiteurs de la diacylglycérol acyltransférase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040209871A1 (en) * 2002-11-22 2004-10-21 Tularik Inc. Fused bicyclic nitrogen-containing heterocycles
US20050070545A1 (en) * 2003-08-07 2005-03-31 Tularik Inc. Pyrrolo[1,2-b]pyridazine derivatives
US20120238581A1 (en) * 2006-11-29 2012-09-20 Souers Andrew J Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
US20120289505A1 (en) * 2009-12-31 2012-11-15 Ravindra Dnyandev Jadhav Inhibitors of diacylglycerol acyl transferase
WO2012162127A1 (fr) * 2011-05-20 2012-11-29 Glaxosmithkline Llc Composés inédits utilisables en tant qu'inhibiteurs de la diacylglycérol acyltransférase

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Title
YEH ET AL.: "Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA: diacylglycerol acyltransferase 1.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, 20 January 2012 (2012-01-20), pages 1751 - 1757 *

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