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WO2013068439A1 - Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1 - Google Patents

Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1 Download PDF

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Publication number
WO2013068439A1
WO2013068439A1 PCT/EP2012/072093 EP2012072093W WO2013068439A1 WO 2013068439 A1 WO2013068439 A1 WO 2013068439A1 EP 2012072093 W EP2012072093 W EP 2012072093W WO 2013068439 A1 WO2013068439 A1 WO 2013068439A1
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group
compound
pharmaceutically acceptable
alkyl
compounds
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PCT/EP2012/072093
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English (en)
Inventor
Thomas Graham
Dong-Ming Shen
Wensheng Liu
Zhicai Wu
Ravi P. Nargund
Robert J. DE VITA
James M. Balkovec
Yang Yu
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Intervet International B.V.
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Publication of WO2013068439A1 publication Critical patent/WO2013068439A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to lactam derivative compounds.
  • the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1”), and can be useful in preventing, treating or acting as a remedial agent for
  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after meals. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type 1 diabetes or insulin- dependent diabetes mellitus (IDDM)
  • IDDM insulin- dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipo lysis in adipose tissue and of glucose production and secretion in the liver.
  • Type 2 diabetes which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat which results in the accumulation of triacylglycerol (TG) in adipose tissue.
  • TG triacylglycerol
  • TG synthesis pathways In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine.
  • Diacylglycerol acyltransferases DGATs, EC 2.3.1.20
  • DGATs diacylglycerol acyltransferases
  • the final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog.
  • DGAT-1 Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261 , 2004.
  • DGAT-2 There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001).
  • DGAT-1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005).
  • DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed.
  • DGAT1 KO mice show a lack of postprandial rise of plasma TG, suggesting an important role for DGAT1 in the regulation of fat absorption.
  • DGAT1- deficient mice are resistant to high fat diet-induced obesity and have increased sensitivity to insulin and leptin.
  • the KO mice are protected against hepatic steatosis and were shown to have decreased levels of tissue TG.
  • the DGAT1 KO mice have improved glucose metabolism, with lower plasma glucose levels after glucose load or insulin injection.
  • DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis,
  • DGAT-1 inhibitors which are useful in the treatment of type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.
  • X is selected from the group consisting of - NH-, -NR 2 -, -S-, -SO- and -SO 2 -;
  • R 1 is selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, C 3 -C 6 cycloalkyl, aryl, Ci- C 6 alkylaryl, heterocycle, Ci-C 6 alkyl-0-aryl and Ci-C 6 alkylheterocycle;
  • any alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 halogen-substitutedalkyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, - NH0 2 Ci-C 6 alkyl, -COOH, NHCOOCi-C 6 alkyl, NR 2 COOCi-C 6 alkyl, S0 2 N(Ci-C 6 alkyl) 2 and - OH,
  • any aryl or heterocycle are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 alkoxy and Ci-Cehalogen-substitutedalkyl; and
  • -R 2 is selected from the group consisting of Ci-Ci 0 alkyl.
  • formula I can have the following stereochemistry:
  • X is selected from the group consisting of-NH-, -NR 2 -, -S-, -SO- and -SO 2 -.
  • X is -NH- or -NR 2 -.
  • X is -S-, -SO- or -SO 2 -.
  • X is -NH-.
  • X is -NR 2 -.
  • X is -S-.
  • X is -SO-.
  • X is -SO 2 -.
  • R 1 is selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, C 3 -C 6 cycloalkyl, aryl, Ci-C 6 alkylaryl, heterocycle, Ci- C 6 alkyl-0-aryl and Ci-Cealkylheterocycle.
  • R 1 is hydrogen. In certain embodiments of the compounds described herein R 1 is Ci-Cioalkyl. In any of the embodiments described herein the alkyl can be branched or straight. Suitable alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1- ethylbutyl, 1,1,2-trimethyl
  • Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 1 is aryl. In other embodiments, R 1 is Ci-C 6 alkylaryl. In still other embodiments, R 1 is Ci-C 6 alkyl-0-aryl. Suitable aryls include, but are not limited to, phenyl and napthyl.
  • R 1 is heterocycle. In other embodiments, R 1 is Ci- C 6 alkylheterocycle. Suitable heterocylces include, but are not limited to, pyridine, pyrrolidinone, pyrrolidine, pyrimidine, pyrazole, pyrazine, oxolane, oxane and indazole.
  • the alkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 halogen- substitutedalkyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, -NH0 2 Ci-C 6 alkyl, -COOH, NR 2 COOCi-C 6 alkyl, S0 2 N(Ci-C 6 alkyl) 2 and -OH.
  • the alkyl is unsubstituted.
  • the alkyl is substituted with one or more halogens. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine and iodine. In other embodiments the alkyl is substituted with one or more Ci-C 6 halogen-substituted alkyls. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In other embodiments the alkyl is substituted with one or more cycloakyls. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments the alkyl is substituted with one or more Ci-C 6 alkoxys. Suitable alkoxys include methoxy, ethoxy, butoxy and propoxy.
  • the alkyl is substituted with one or more -OH groups. In other embodiments the alkyl is substituted with one or more -COOH groups.
  • the alkyl is substituted with one or more -NH0 2 Ci-C 6 alkyl groups. In still other embodiments, the alkyl is substituted with one or more, NR 2 COOCi-C 6 alkyl groups. In yet another embodiment, the alkyl can be substituted with one or more S0 2 N(Ci- C 6 alkyl) 2 groups.
  • any aryl and heterocycle are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-Cealkoxy and Ci-Cehalogen-substitutedalkyl.
  • any aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 alkoxy and Ci-Cehalogen-substitutedalkyl. Suitable halogens, Ci-C 6 alkoxys and Ci-C 6 halogen-substituted alkyls are described above.
  • any heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 alkoxy and Ci-C 6 halogen-substitutedalkyl.
  • substituents selected from the group consisting of halogen, Ci-C 6 alkoxy and Ci-C 6 halogen-substitutedalkyl. Suitable halogens, Ci-C 6 alkoxys and Ci-C 6 halogen-substituted alkyls are described above.
  • the aryl is substituted with one or more halogens. In other embodiments, the aryl is substituted with one or more halogen-substituted alkyls. In yet another embodiment, the aryl is substituted with one or more alkoxys. In some embodiments, the heterocycle is substituted with one or more halogens. In other embodiments, the heterocycle is substituted with one or more halogen-substituted alkyls. In yet another embodiment, the heterocycle is substituted with one or more alkoxys.
  • R 2 is Ci-C 6 alkyl.
  • Suitable alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1 , 1- dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1-ethylbutyl, 1,1 ,2- trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl and 1
  • halogen includes "halogen", fluorine, chlorine, bromine and iodine.
  • Ci-C l oalkyl encompasses straight alkyl having a carbon number of 1 to 10 and branched alkyl having a carbon number of 3 to 10. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2- dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1 , 1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2- ethylbutyl, 1-ethylbutyl, 1,1 ,2-trimethylpropyl, 1,2,2-trimethylpropyl,
  • halogen-substitutedCi-C 6 alkyl encompasses Ci-C 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl and the like.
  • aryl include phenyl, naphthyl, tolyl, and the like.
  • heterocycles includes heteroaryls and hetercycloalkyls.
  • Heteroaryls are 5- or 6-membered monocyclic or 8- to 14-membered polycyclic hetero aromatic cyclic group containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring-constitutive members; and concretely, for example, it includes a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a t
  • Heterocycloalkyls are 5- or 6-membered monocyclic or 8- to 14-membered polycyclic heteronon-aromatic cyclic group containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring-constitutive members.
  • Cycloheteroalkyls include an aziridine ring, pyrrolidine ring, piperidine ring, tetrahydropyran ring (or xane), tetrahydrofuran ring (or oxolane ring), dioxane ring, morpholine ring and the like.
  • cycloalkyl includes a monocyclic or polycyclic, saturated or partially- unsaturated carbocyclic group having from 3 to 10, preferably from 3 to 8 carbon atoms, concretely, for example, a cyclopropyl group, a cyclobutenyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a bicyclohexyl group, an adamantyl group and the like.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-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,
  • the compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of these compounds.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. It will be understood that, as used herein, references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein.
  • different isotopic forms of hydrogen (H) include protium (iH) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Also encompassed by the present invention are methods of treating DGAT1 -related diseases.
  • the compounds described herein are effective in preventing or treating various diseases.
  • DGAT1 -related diseases such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis.
  • the compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia
  • One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I.
  • Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of treatment may be preventing body weight, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • arteriosclerosis such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
  • Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising
  • Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.
  • the present invention is also directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis.
  • the compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
  • the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.
  • the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating diabetes.
  • Compounds of the invention may be administered orally or parenterally.
  • the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.
  • the compound of the invention In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered.
  • pharmaceutically acceptable it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • additives various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose,
  • carboxymethylcellulose corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate,
  • Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations.
  • the liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use.
  • the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.
  • the pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition.
  • the compositions may further contain any other therapeutically-effective compounds.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the
  • the dose when orally administered, may be from
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day.
  • the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01 , 0.05, 0.1, 0.2,
  • 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 in combination with a compound of formula I and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • (2) insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/ ⁇ Ddual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and
  • insulin or insulin analogs such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;
  • amylin and amylin analogs such as pramlintide
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO
  • incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl Co A: cholesterol acyltransferase inhibitors, such as avasimibe;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof;
  • MK-524A which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal 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 (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • LY2599506 LY2599506
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS);
  • GPR-105 antagonists such as those disclosed in WO 2009/000087;
  • inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various iso forms, such as SGLT-1; SGLT-2, such as dapagliflozin, canagliflozin and remogliflozin and those described in WO2010/023594 such as PF-04971729; and SGLT-3;
  • SGLT sodium-glucose transporter
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR.
  • Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
  • DPP-4 dipeptidyl peptidase-IV
  • DPP-4 dipeptidyl peptidase-IV
  • Antiobesity compounds that can be combined with compounds of 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; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); ⁇ 3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3
  • Glucagon receptor antagonists that can be used in combination with the compounds of formula I include, but are not limited to:
  • Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I include, but are not limited to:
  • 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:
  • AMP-activated Protein Kinase (AMPK) activators 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
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • PPARa/ ⁇ Ddual agonists such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar
  • PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate)
  • SPPARyM's selective PPARy modulators
  • PPARy partial agonists include (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and
  • GlucophageXR® (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
  • sulfonylurea and non-sulfonylurea insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose, voglibose and miglitol
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
  • lovastatin simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin
  • bile acid sequestering agents such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran
  • inhibitors of cholesterol absorption such as ezetimibe
  • acyl CoA cholesterol acyltransferase inhibitors, such as avasimibe
  • HDL-raising drugs such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;
  • antiobesity compounds (8) antiobesity compounds; (9) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;
  • ACE inhibitors such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril
  • A-II receptor blockers such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan
  • GKAs glucokinase activators
  • CETP cholesteryl ester transfer protein
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • neuromedin U receptor agonists including, but not limited to, neuromedin S (NMS);
  • (22) inhibitors of glucose uptake such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT- 3;
  • SGLT sodium-glucose transporter
  • TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • DGAT1 CPM Assay 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGAT1 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50s were calculated.
  • the compounds exemplified herein are believed to have a lower Cmax to trough ratio as compared to the Reference Examples. High Cmax to trough ratio is not a desirable feature of a drug. A higher ratio may lead to low therapeutic index due to potential Cmax related adverse events. It is also believed that the compounds exemplified herein show moderate metabolism in vitro in hepatocyte incubations, which may impart multiple mechanism of excretion in vivo.
  • liver microsome or hepatocytes may indicate that they might be eliminated in vivo via excretion as intact drug, which may contribute to undesirably long pharmacodynamic half- life in vivo.
  • Step A methyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate.
  • Step B methyl [trans-4-(4-hydroxyphenyl)cyclohexyl]acetate.
  • the product from step A 200 g, 812 mmol, 1.00 equiv) and Pd/C (20 g) in ethyl acetate (2500 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was re-crystallized from ethyl acetate/hexane in the ratio of 1 : 1 to afford the title compound as a white solid.
  • Step C methyl [tra/? -4-(4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)cyclohexyl]acetate.
  • Step A (tra -4- ⁇ 4-[4-amino-2-(methylsulfanyl)-5-oxo-7,8-dihydropyrimido[5,4- ] [ 1 ,4]oxazepin-6(5H)-yl]phenyl ⁇ cyclohexyPacetic acid.
  • a 250 mL single neck round bottom flask was charged with Intermediate 6 (5.45 g, 1 1.9 mmol) and THF (60 ml). The mixture was treated with a 2 M aqueous lithium hydroxide solution (29.8 ml, 59.7 mmol), warmed to 55 °C for
  • Example 79 was prepared in a manner similar to the preparation of Intermediate 7 (Step B) with the use of 1.2 equiv of MMPP and purification of the crude reaction mixture by preparative RP-HPLC (25% to 65% ACN/ water+0.05% TFA over 10 min).
  • Examples 80 and 81 were prepared from Example 59 in a similar manner to Intermediate 7 and Example 79.

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Abstract

La présente invention concerne des composés de formule I. Les composés de formule I agissent comme des inhibiteurs de DGAT1 et peuvent être utiles dans la prévention, le traitement ou comme agent thérapeutique pour l'hyperlipidémie, le diabète sucré et l'obésité.
PCT/EP2012/072093 2011-11-09 2012-11-08 Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1 WO2013068439A1 (fr)

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