WO2014140241A1 - Dérivés de pyridine en tant qu'inhibiteurs de dgat-1 - Google Patents

Dérivés de pyridine en tant qu'inhibiteurs de dgat-1 Download PDF

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Publication number
WO2014140241A1
WO2014140241A1 PCT/EP2014/055056 EP2014055056W WO2014140241A1 WO 2014140241 A1 WO2014140241 A1 WO 2014140241A1 EP 2014055056 W EP2014055056 W EP 2014055056W WO 2014140241 A1 WO2014140241 A1 WO 2014140241A1
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mmol
compound
mixture
pharmaceutically acceptable
ethyl
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PCT/EP2014/055056
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English (en)
Inventor
Dong-Ming Shen
Thomas Graham
Min Shu
Wensheng Liu
Robert J. De Vita
Ravi P. Nargund
Tianying Jian
Ginger XU-QIANG YANG
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Intervet International B.V.
Intervet Inc.
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Publication of WO2014140241A1 publication Critical patent/WO2014140241A1/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
    • A61P3/08—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 pyridine 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
  • 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
  • patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
  • 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.
  • DGATs Diacylglycerol acyltransferases
  • EC 2.3.1.20 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. Lipid Res., 43, 134- 176, 2004 and Ann. Med., 36, 252-261 , 2004).
  • DGAT-1 DGAT-1
  • DGAT-2 There are two subtypes of DGATs.
  • 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 DGATl 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, cerebrovascular disorder, coronary artery disease and metabolic syndrome.
  • 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.
  • R 1 is selected from the group consisting of: hydrogen, Ci-Cio alkyl S0 2 , Ci-Cio alkyl S, Ci-Cio alkyl, and Ci-Cio alkoxy; wherein in the Ci-Cio alkyl may be unsubstituted or substituted with Ci-Cio alkyl, halogen, -OH, or N(R 2 ) 2 ; wherein each R 2 is independently selected from hydrogen, Ci-Cio alkyl, Ci-Cio alkoxy, or C(O) Ci-Cio alkyl;
  • R 3 is selected from the group consisting of: hydrogen and Ci-Cio alkyl; wherein in the Ci-Cio alkyl may be unsubstituted or substituted with Ci-Cio alkyl, halogen, -OH, or N(R 2 ) 2 ; wherein each R 2 is independently selected from hydrogen, Ci-Cio alkyl, Ci-Cio alkoxy, or C(O) Ci-Cio alkyl;
  • A is N or C, and means a single or a double bond ;
  • X is O or is not present.
  • Examples of the compounds described herein include, but are not limited to:
  • halogen includes “halogen”, fluorine, chlorine, bromine and iodine.
  • Ci-C l oalkyl encompasses straight alkyl having a carbon number of 5 to 10 and branched alkyl having a carbon number of 1 to 10.
  • Specific examples thereof include propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 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, l-ethyl-2-methylpropyl, 1 -ethyl- 1-methylpropyl, and the like.
  • halogen-substitutedCi-Cio alkyl encompasses Ci-Ci 0 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoropentyl, difluoropentyl, trifluoropentyl, 6-fluorohexyl, 6,6-difluorohexyl, 6,5-difluorohexyl and the like.
  • 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, 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, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine, choline
  • 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.
  • 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.
  • 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 (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.
  • DGAT1 -related diseases are also encompassed by the present invention.
  • the compounds described herein are effective in preventing or 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 chromatos
  • One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I.
  • 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. Moreover, if treatment is commenced in already obese subjects, 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 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 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 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.
  • the individual in need of treatment is a mammal. In another embodiment the individual is a human. In another embodiment, the individual is a dog or a cat. In another embodiment, the individual is a horse.
  • 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.
  • 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
  • compositions may further contain any other therapeutically-effective compounds.
  • the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect.
  • the dose when orally administered, may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times.
  • the dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day.
  • compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01 , 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein.
  • This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of 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 compound of formula I is used
  • 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.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical 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
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestering agents, (iii) inhibitors of cholesterol absorption, and (iv) acyl
  • Co A cholesterol acyltransferase inhibitors, such as avasimibe
  • antihypertensive agents such as ACE, A-II receptor blockers, renin inhibitors, beta blockers and calcium channel blockers;
  • GKAs glucokinase activators
  • inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);
  • AMPK AMP-activated Protein Kinase
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR.
  • a pharmaceutical composition which comprises the above combinations of agents and a pharmaceutically acceptable carrier.
  • 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.
  • an effective dose of each will be used.
  • 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).
  • RP-HPLC reverse phase high performance liquid chromatography
  • RP-HPLC reverse phase high performance liquid chromatography
  • RT stands for room temperature
  • ACN is acetonitrile
  • aq is aqueous
  • Boc and BOC is tert-butoxycarbonyl
  • CeliteTM is diatomaceous earth
  • C0 2 is carbon dioxide
  • DCM or CH 2 C1 2 is dichloromethane
  • dppf is 1,1" - bis(diphenylphosphino)ferrocene
  • DBU is 1,8- diazabicyclo[5.4.0]undec-7-ene
  • DEA diethylamine
  • DIPEA or DIEA is N,N- diisopropylethylamine
  • DMAP is 4-N,N-dimethylaminopyridine
  • DME is 1 ,2-dimethoxyethane
  • DMF is N,N-dimethyl-formamide
  • DMA is N,N-dimethylacetamide
  • DMSO is dimethyl sulfoxide
  • EDC is N-ethyl-N'-
  • Step 1 Methyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-l-yl)acetate (1.2)
  • keto ester starting material methyl (4- oxocyclohexyl)acetate
  • methyl (4- hydroxyphenyl)acetate was obtained from commercially available methyl (4- hydroxyphenyl)acetate using a two-step sequence of hydrogenation (Rh/Al 2 0 3 ) and oxidation (NaOCl).
  • Step 2 Methyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)acetate (L3>
  • Method A Methyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (1.0 g, 3.57 mmol) from Step 2 above and 2-bromo-5-nitropyridine (0.80 g, 3.93 mmol) were mixed in DME (10 ml), ethanol (7 ml), and 2.0 M aqueous solution of sodium carbonate (3.6 ml). The mixture was bubbled with nitrogen, followed by addition of tetrakis(triphenylphosphine)palladium (0.41 g, 0.36 mmol). After heating at 80°C in a sealed tube for 15 h, the mixture was concentrated.
  • Step 5 Methyl 2-(4-(5-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pyridin-2- yl)cyclohexyl)acetate (1)
  • Methyl 2-(4-(5-aminopyridin-2-yl)cyclohexyl)acetate 9.3 g, 37.5 mmol
  • (t- butyldimethylsilyloxy)acetaldehyde 7.43 g, 38.4 mmol
  • the mixture was stirred at RT for 1 h, then cooled to 0°C and followed by addition of sodium triacetoxyborohydride (10.32 g, 48.7 mmol) in several portions.
  • Step 2 Methyl 2-(4-(5-(N-(2-((tert-butyldimethylsilyl oxy ethyl -4,6-dichloro-2- (methylthio)pyrimidine-5 -carboxamido)pyridin-2-yl)cyclohexyl)acetate (2.3)
  • Step 4 Methyl (4- ⁇ 5-[4-chloro-2-(methylthio)-5-oxo-7,8-dihydropyrimido[5,4- /][l ⁇ ]oxazepin-6(5H)-yl]pyridin-2-yl ⁇ cyclohexyl)acetate (2.5)
  • Step 5 Methyl 2-(4-(5-(4-amino-2-(methylthio)-5-oxo-7,8-dihydropyrimido[5,4- f][l,4]oxazepin-6(5H)-yl)pyridin-2-yl)cyclohexyl)acetate (2.6)
  • Step 6 2-(4-(5-(4-Amino-2-(methylthio)-5-oxo-7,8-dihydropyrimido[5 ⁇ -f][l,4]oxazepin- 6(5H)-yl)pyridin-2-yl)cyclohexyl)acetic acid (2)
  • trans- and cis- mixture was then separated on SFC using a ChiralPak OJ column eluting with 40-60% MeOH in CO 2 containing 0.2% DEA to give trans-isomer and czs-isomer respectively as diethylamine salts.
  • the trans-isomer DEA salt was then converted to free form 2a by stirring in acetonitrile at RT overnight while the czs-isomer salt was dissolved in a minimum amount of 1 ,4-dioxane and water mixture (1 :2) and acidified with 1 N HCl to pH 5 to precipitate neutral czs-isomer 2b.
  • reaction mixture was stirred at 0°C for 30 minutes, then treated with a solution of 5-hexen-l-ol (20.5 mL, 171 mmol) in CH 2 CI 2 .
  • the reaction mixture was allowed to warm up and stirred at RT and the progress of the reaction was monitored by NMR.
  • the reaction was complete within 1.5 hr.
  • the suspension turned clear and it was quenched with 6 N HC1.
  • the mixture was extracted with MTBE and hexanes.
  • the combined organic phase was washed with 2 N NaOH and brine, then dried over MgSC"4 and concentrated.
  • Step 1 N-(2-((ter ⁇ butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3 -amine (6.3) 6-Chloropyridine-3 -amine (22.0 g, 171 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (49.1 g, 205 mmol) were dissolved in THF (500 ml), then treated with a suspension of NaH (8.21 g, 205 mmol, 60% oil dispersion) in hexanes. After stirring at 50 °C for 2 hours, the reaction mixture was quenched with water (100 ml) and extracted with MTBE (2x100 mL).
  • Step 2 N-(2-((ter ⁇ butyldimethylsilyl)oxy)ethyl)-4,6-dichloro-N-(5-chloropyridin- (methylthio)pyrimidine-5 -carboxamide (6.4)
  • Step 6 4-(Di-tert-butoxycarbonyl)amino-6-(6-chloropyridin-3-yl)-2-(methylthio)-7,8- dihydropyrimido[5,4-f][l,4]oxazepin-5(6H)-one (6.8)
  • Step 7 Ethyl 2-(l-(5-(4-((tert-butoxycarbonyl)amino)-2-(methylthio)-5-oxo-7,8- dihydropyrimido[5 ⁇ -f][l ⁇ ]oxazepin-6(5H)-yl)pyridin-2-yl)piperi (6.10)
  • a mixture of intermediate 6.8 (0.30 g, 0.56 mmol) and commercially available ethyl 2- (piperidin-4-yl)acetate (0.14 g, 0.84 mmol) in 1,4-dioxane (2.6 ml) was treated with 2- dicyclohexylphosphino-2',6'-di-isopropoxy-l, -biphenyl (0.013 g, 0.028 mmol) and RuPhos indoline precatalyst (0.020 g, 0.028 mmol, ⁇ 2-[2-(azanidyl-KN
  • Step 8 Ethyl 2-(l-(5-(4-amino-2-(methylthio)-5-oxo-7,8-dihydropyrimido[5,4-f][l,4]oxazepin- 6(5H)-yl)pyridin-2-yl)piperidin-4-yl)acetate (6.11)
  • Step 9 Ethyl 2-(l-(5-(4-amino-2-(methylsulfonyl)-5-oxo-7,8-dihydropyrimido[5,4- f] [ 1 ⁇ ]oxazepin-6(5H)-yl)pyridin-2-yl)piperidin-4-yl)acetate (6)
  • Step 3 -A 2- ⁇ [ rert-butyKdimethyDsilyljoxylethyl trifluoromethanesulfonate
  • Step 3-B N-(2- ⁇ [ter ⁇ butyl(dimethyl)silyl]oxy ⁇ ethyl)-4,6-dichloro-N-(6-iodopyridin-3- yl)pyrimidine-5 -carboxamide
  • Step 7 Methyl ⁇ 4-[5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4 ][l ,4]oxazepin-6(5H)- yl)pyridin-2-yl] cyclohex-3 -en- 1 -yl ⁇ acetate
  • Example 1 Step 2 (36.8 mg, 0.131 mmol), and cesium carbonate (53.4 mg, 0.164 mmol) in 1.0 mL THF. Purge with nitrogen and add tetrakis(triphenylphosphine)palladium (12.6 mg, 0.011 mmol). Purge with nitrogen for 2 minutes. This mixture was heated in a capped vial at 80 C for 15 hr. Following aqueous work-up using EtOAc, the residue was purified on silica gel using 0-90% EtOAc gradient in hexanes to give the title compound. LC-MS: 1.90 min. (LC4, m/Z 610.3). Step 3.
  • the title compound was isolated as the fast-eluting isomer from SCF separation of the cis- and trans- mixture from Example 3 on a ChiralPak AS column using 25% MeOH (0.2% triethylamine) in CO 2 .
  • the triethylamine can be removed by re-purifying the separated isomer on RP-HPLC.
  • LC-MS 0.25 min. (LC4, m/Z 398.1).
  • the title compound was isolated as the slower-eluting isomer from SCF separation of the cis- and trans- mixture from Example 3 on a ChiralPak AS column using 25% MeOH (0.2% triethylamine) in CO 2 .
  • the triethylamine can be removed by re-purifying the separated isomer on RP-HPLC.
  • LC-MS 0.45 min. (LC4, m/Z 398.1).
  • Example 18 was prepared according to the methods described in Examples 18 and 19, starting from the appropriate sulfone and alcohol, except Examples 20 and Example 29 were obtained according to the methods described in Example 11 starting from the appropriate sulfone and Grignard reagent.
  • Example 24 was prepared as described for Example 18 starting from the cis- and trans-sulfone mixture derived from Compound 2 of Preparative Example 2.
  • Step 1 Ethyl 2-(l-(5-(4-amino-2-(4-cyclopropylbutoxy)-5-oxo-7,8-dihydropyrimido[5,4- f] [ 1 ⁇ ]oxazepin-6(5H)-yl)pyridin-2-yl)piperidin-4-yl)acetate
  • Step 2 2-(l-(5-(4-Amino-2-(4-cyclopropylbutoxy)-5-oxo-7,8-dihydropyrimido[5,4- f] [ 1 ⁇ ]oxazepin-6(5H)-yl)pyridin-2-yl)piperidin-4-yl)acetic acid
  • 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. Compounds found not to be metabolized by 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.

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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 correcteur pour l'hyperlipidémie, le diabète sucré et l'obésité.
PCT/EP2014/055056 2013-03-15 2014-03-14 Dérivés de pyridine en tant qu'inhibiteurs de dgat-1 WO2014140241A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016462A2 (fr) * 2007-08-02 2009-02-05 Pfizer Products Inc. Bicyclolactames substitués
WO2012009217A1 (fr) * 2010-07-13 2012-01-19 Merck Sharp & Dohme Corp. Composés spirocycliques
WO2012015693A1 (fr) * 2010-07-28 2012-02-02 Merck Sharp & Dohme Corp. Dérivés d'imidazole
WO2012112364A1 (fr) * 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1
WO2012122075A1 (fr) * 2011-03-08 2012-09-13 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016462A2 (fr) * 2007-08-02 2009-02-05 Pfizer Products Inc. Bicyclolactames substitués
WO2012009217A1 (fr) * 2010-07-13 2012-01-19 Merck Sharp & Dohme Corp. Composés spirocycliques
WO2012015693A1 (fr) * 2010-07-28 2012-02-02 Merck Sharp & Dohme Corp. Dérivés d'imidazole
WO2012112364A1 (fr) * 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1
WO2012122075A1 (fr) * 2011-03-08 2012-09-13 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1

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