US20090036425A1 - Substituted bicyclolactam compounds - Google Patents

Substituted bicyclolactam compounds Download PDF

Info

Publication number
US20090036425A1
US20090036425A1 US12/174,820 US17482008A US2009036425A1 US 20090036425 A1 US20090036425 A1 US 20090036425A1 US 17482008 A US17482008 A US 17482008A US 2009036425 A1 US2009036425 A1 US 2009036425A1
Authority
US
United States
Prior art keywords
compound
tautomer
alkyl
pharmaceutically acceptable
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/174,820
Other languages
English (en)
Inventor
Robert L. Dow
Michael J. Munchhof
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Priority to US12/174,820 priority Critical patent/US20090036425A1/en
Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MUNCHHOF, MICHAEL J., DOW, ROBERT L.
Priority to US12/357,544 priority patent/US7718645B2/en
Publication of US20090036425A1 publication Critical patent/US20090036425A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to substituted bicyclolactam derivatives, pharmaceutical formulations thereof, and uses thereof.
  • Obesity which is an excess of body fat relative to lean body mass, is a chronic disease that is highly prevalent in modern society. It is associated with decreased life span and numerous medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, Type 2 diabetes, hyperlipidemia, and some cancers.
  • a hallmark characteristic of obesity is an increase in white adipose tissue (WAT) mass that is largely due to accumulation of triacylglycerol. This increase in WAT mass is a key contributor to obesity-associated complications.
  • WAT white adipose tissue
  • DGAT-1 Diacylglycerol O-acyltransferase 1
  • DGAT-1 is a membrane-bound enzyme that catalyzes the terminal step of triacylglycerol biosynthesis.
  • DGAT-1 is expressed in the intestine and adipose tissue It has been found that DGAT-1 null mice do not become obese when challenged with a high fat diet in contrast to wild-type littermates (Smith, et al., Nature Genetics 25:87 90, 2000). DGAT-1 null mice display reduced postprandial plasma glucose levels and exhibit increased energy expenditure, but have normal levels of serum triglycerides.
  • DGAT-1 null mouse The phenotype of the DGAT-1 null mouse, along with the results of our studies with DGAT-1 inhibitors in diet-induced obese (DIO) mice, indicate that such mice are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes. (Subauste A, Burant C F, Curr Drug Targets Immune Endocr Metabol Disord. December 2003; 3(4):263-70.)
  • DGAT-1 inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, Type 2 diabetes and insulin resistance syndrome. Further, a need exists in the art for DGAT-1 inhibitors having IC 50 values of less than about 1000 nM and preferably below 100 nM.
  • the present invention relates to compounds having the structure of formula (1)
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
  • the present invention further relates to a method of treating Type 2 diabetes, insulin resistance syndrome or obesity, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt of the compound.
  • the present invention additionally relates to a method of inhibiting DGAT-1 in a mammal comprising administering to said mammal an inhibitory amount of a compound of the present invention, or a pharmaceutically acceptable salt of said compound.
  • the compounds, salts, and pharmaceutical compositions of the present invention are useful for the treatment of obesity, Type 2 diabetes and insulin resistance syndrome.
  • the compounds, salts and pharmaceutical compositions of the present invention are also useful for the treatment of impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer
  • the compounds and intermediates of the present invention may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems.
  • the carbon atom content of the various hydrocarbon-containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, for example, the prefixes (C a -C b )alkyl, and C a-b alkyl, indicate an alkyl moiety of the integer “a” to “b” carbon atoms, inclusive.
  • (C 1 -C 6 )alkyl and C 1-6 alkyl refer to an alkyl group of one to six carbon atoms inclusive.
  • alkyl denotes a straight or branched chain monovalent radical of an aliphatic chain of carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, isobutyl, and the like.
  • alkoxy refers to straight or branched, monovalent radical of a saturated aliphatic chain of carbon atoms bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups include methoxy, ethoxy and iso-propoxy.
  • cycloalkyl denotes a non-aromatic, monocyclic carbocyclic radical.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Cycloalkyl groups may be optionally fused to aromatic hydrocarbons such as benzene to form fused cycloalkyl groups, such as indanyl and the like.
  • cycloalkylene denotes a saturated, or partially saturated, monocyclic, bicyclic or tricyclic carbocyclic di-valent radical.
  • cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexen-di-yl octahydropentalene-di-yl and tricycloctylene-di-yl.
  • Cycloalkylene groups may be optionally fused to aromatic hydrocarbons such as benzene to form fused cycloalkylene groups, such as indanylene and the like.
  • perfluoroalkyl is defined herein as a monovalent alkyl radical wherein each hydrogen is substituted with a fluoro.
  • perfluoroalkyl groups include, but are not limited to, trifluoromethyl, perfluoroethyl, and the like.
  • perfluoroalkoxy is defined herein as an alkoxy group wherein each hydrogen is substituted with a fluoro.
  • perfluoroalkoxy groups include, but are not limited to, trifluoromethoxyl, perfluoroethoxy, and the like.
  • radical denotes a group of atoms that behaves as a single reactant in a chemical reaction, e. g., an organic radical is a group of atoms that imparts characteristic properties to a compound containing it, or which remains unchanged during a series of reactions, or transformations.
  • substituted means that a hydrogen atom on a molecule has been replaced with a different atom or molecule.
  • the atom or molecule replacing the hydrogen atom is denoted as a “substituent.”
  • tautomer refers to organic compounds that are interconvertible by a chemical reaction called tautomerization. Usually, the reaction involves the migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • treating includes preventing (e.g., prophylaxis), palliating, slowing progression and curing a disease, such as obesity, insulin resistance syndrome, Type 2 diabetes, or a disease-related condition such as a diabetic complication.
  • a disease such as obesity, insulin resistance syndrome, Type 2 diabetes, or a disease-related condition such as a diabetic complication.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • pharmaceutically acceptable indicates that the designated carrier, vehicle, diluent, excipient(s), and/or salt is generally chemically and/or physically compatible with the other ingredients comprising the formulation, and physiologically compatible with the recipient thereof.
  • mammal relates to an individual animal that is a member of the taxonomic class Mammalia.
  • mammals include, but are not limited to, humans, dogs, cats, horses and cattle.
  • the preferred mammals are humans, dogs and cats. More preferably, the mammal is a human.
  • R 1 , R 2 , R 3 and R 4 are each independently H or —CH 3 ;
  • R 5b and R 5c are each H;
  • R 5d is H, F or Cl;
  • R 5a is H, F, Cl or methyl;
  • R 5a is H, F, Cl or methyl;
  • R 7 is C(O)R 8 or cyano.
  • Q is a bond
  • A is a —(C 3 -C 10 )cycloalkylene group or a —(C 3 -C 10 )cycloalkenylene group.
  • R 1 , R 2 , R 3 and R 4 are each independently H or —CH 3 ;
  • R 5b and R 5c are each H;
  • R 5d is H, F or Cl;
  • R 5a is H, F, Cl or methyl;
  • Z is —CH 2 — or a bond, and
  • R 7 is C(O)R 8 or cyano.
  • R 5d is H; Q is a bond; A is a —(C 3 -C 10 )cycloalkylene group or a —(C 3 -C 10 )cycloalkenylene group; R 1 , R 2 , R 3 and R 4 are each independently H or —CH 3 ; R 5b and R 5c are each H; R 5a is H, F, Cl or methyl; Z is —CH 2 — or a bond, and R 7 is C(O)R 8 or cyano.
  • A is 1,4-cyclohexylene, cyclohex-3-en-1,4-di-yl, tricyclo[3.2.1.0 ⁇ 2,4 ⁇ ]octylene-1,3-di-yl or octahydropentalene-1,4-di-yl;
  • R 5d is H;
  • Q is a bond;
  • R 1 , R 2 , R 3 and R 4 are each independently H or —CH 3 ;
  • R 5b and R 5c are each H;
  • R 5a is H, F, Cl or methyl;
  • Z is —CH 2 — or a bond, and
  • R 7 is C(O)R 8 or cyano.
  • the compounds or formula (1), tautomers thereof, and salts of the compounds or tautomers include compounds having the structure of formula (2)
  • R 1 is H or —CH 3 ;
  • R 2 is H or —CH 3 ;
  • R is H or —CH 3 ;
  • R 4 is H or —CH 3 ;
  • R 5a is H, F, Cl or methyl;
  • Z is —C(R 6a )(R 6b )— or a bond wherein R 6a and R 6b are each independently —H or —(C 1 -C 4 )alkyl, or R 6a and R 6b , taken together with the carbon to which they are attached, is a —(C 3 -C 6 )cycloalkyl;
  • R 7 is C(O)R 8 , cyano, hydroxyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )-perfluoroalkoxy or a carboxylic acid mimic;
  • R 8 is —OR 9 or NHR 10 ;
  • R 9 is H or NHR 10 ;
  • Z is —CH 2 — and R 7 is —C(O)NHR 10 .
  • Z is —CH 2 — and R 7 is —CN.
  • a prefered compound of this embodiment is ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl ⁇ acetonitrile, or a tautomer thereof, or a salt of said compound or tautomer.
  • Z is —CH 2 — and R 7 is —C(O)OH.
  • One prefered compound of this embodiment is 2-(4-(4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-2-fluorophenyl)cyclohexyl)acetic acid, or a tautomer thereof, or a salt of said compound or tautomer.
  • Another prefered compound of this embodiment is ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]-oxazepin-6(5H)-yl)phenyl]cyclohexyl ⁇ acetic acid, or a tautomer thereof, or a salt of said compound or tautomer.
  • Z is —CH 2 — and R 2 is (R)-methyl.
  • R 7 is —C(O)NHR 10 , —CN, or —C(O)OH.
  • a prefered compound of this embodiment is (trans-4- ⁇ 4-[(8R)-4-amino-8-methyl-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl]phenyl ⁇ cyclohexyl)acetonitrile, or a tautomer thereof, or a salt of said compound or tautomer.
  • Another prefered compound of this embodiment is (trans-4- ⁇ 4-[(8R)-4-amino-8-methyl-5-oxo-7,8-dihydropyrimido-[5,4-f][1,4]oxazepin-6(5H)-yl]phenyl ⁇ cyclohexyl)acetic acid, or a tautomer thereof, or a salt of said compound or tautomer.
  • Yet another prefered compound of this embodiment is (R)-2-(4-(4-(4-amino-8-methyl-5-oxo-7,8-dihydro-pyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-2-fluorophenyl)cyclohexyl)acetic acid, or a tautomer thereof, or a salt of said compound or tautomer.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • stereoisomeric salts which may be separated, for example, by crystallization
  • stereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography
  • selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.
  • the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
  • Certain compounds of formula (1) may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the compounds of the present invention further include each conformational isomer of compounds of formula (1) and mixtures thereof.
  • a single compound may exhibit more than one type of isomerism.
  • Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • the compounds of the present invention, and the salts thereof, may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • solvents such as water, ethanol, and the like.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • hydrate is employed when said solvent is water.
  • solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • the compounds of the present invention may exist as clathrates or other complexes.
  • Certain compounds of formula (1) and their salts and solvates may exist in more than one crystal form.
  • Polymorphs of compounds represented by formula (1) form part of this invention and may be prepared by crystallization of a compound of formula (1) under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of formula (1) followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • This invention also includes isotopically-labeled compounds, which are identical to those described by formula (2), 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 include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 36 Cl, 125 I, 129 I, and 18 F respectively.
  • Compounds of the present invention, and pharmaceutically acceptable salts of the compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 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.
  • isotopically labeled compounds of formula (2) 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 labeled reagent for a non-isotopically labeled reagent.
  • Pharmaceutically acceptable salts include pharmaceutically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound or prodrug thereof, with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include, but are not limited to, the acetate, aspartate, benzoate, besylate, bicarbonate, dimesylate, diphosphate, bisulfate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, edisylate, esylate, fumarate, gluceptate, hemifumarate, hydrobromide, hydrochloride, isethionate, lactate, malate, maleate, mesylate, napsylate, nitrate, oxalate, palmitate, pamoate, phosphate, saccharate, stearate, succinate, sulfate, tartrate, tosylate, and trifluoroacetate salts.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, diethylamine and the like.
  • amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, diethylamine and the like.
  • the compounds of the present invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts.
  • compounds with multiple basic nitrogen atoms can form salts with varying number of equivalents (“eq.”) of acid. It will be understood by practitioners that all such salts are within the scope of the present invention.
  • the present invention further includes prodrugs of compounds of formula (1).
  • a prodrug of a compound of formula (1) may be one formed in a conventional manner with a functional group of the compound, such as with an amino, hydroxy or carboxy group.
  • the term “prodrug” means a compound that is transformed in vivo to yield a compound of formula (1) or a pharmaceutically acceptable salt of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, —C(OH)C(O)OY′ wherein Y′ is H, (C 1 -C 6 )alkyl or benzyl, —C(OY 0 )Y 1 wherein Y 0 is (C 1 -C 4 ) alkyl and Y 1 is (C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, amino(C 1 -
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxy-methyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1 -C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyl-oxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)-ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthali
  • the compounds of formula (1) of this invention may be prepared by methods that include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of formula (1) of this invention are illustrated by the following reaction schemes. Other processes are described in the experimental section. Some of the starting compounds for the reactions described in the schemes and Examples are prepared as illustrated herein.
  • aryl halide/sulfonates 1-1 can be prepared beginning with commercially available starting materials and using general synthetic techniques known to those skilled in the arts. Additional support for the preparation of intermediates such as 1-1, wherein X is a halide or OSO 2 R, are provided in U.S. Pat. No. 7,244,727, issued Jul. 17, 2007, the teachings of which are incorporated herein, by reference, in their entirety.
  • Compound 1-2 was prepared by the method of C. Palomo et al., Synthesis of ⁇ -Lactam Scaffolds for Ditopic Peptidomimetics, Organic Letters (2007), 9(1), pages 101-104.
  • Compounds 1-1 and 1-2 can be coupled using a metal catalyst, such as palladium or copper to form Compound 1-3. More specifically, 1-1 and 1-2 are heated to a temperature between 80° C. to 130° C. in a solvent, such as toluene, with cesium carbonate, palladium acetate and 2-dicyclohexyl phosphino-2′,4′,6′-triisopropylbiphenyl (X—PHOS) under nitrogen for about 15-20 hours to form Compound 1-3.
  • a metal catalyst such as palladium or copper
  • Compound 1-3 is acylated with 1-4 using conditions and reagents known to the skilled artisan (utilizing a mild base, such as triethylamine or pyridine) to afford compound 1-5.
  • Compound 1-4 is prepared by the method of Tarasov, Evgeniy V.; Henckens, Anja; Ceulemans, Erik; Dehaen, Wim. A short total synthesis of cerpegin by intramolecular hetero Diels-Alder cycloaddition reaction of an acetylene tethered pyrimidine. Synlett (2000), (5), 625-626.
  • the protecting group (Pg) present in compound 1-5 can be removed by one skilled in the art, utilizing conditions referenced in Greene's Protective Groups in Organic Synthesis, 4 th Ed., P. G. M Wuts and T. W. Greene, Wiley-Interscience to afford compound 1-6.
  • Cyclization of compound 1-6 to afford compound 1-7 can be accomplished utilizing a wide range of basic conditions, including organic (e.g. triethylamine) and inorganic (e.g. potassium carbonate) as the bases, in an aprotic solvent at 20° C. to 120° C. to provide the cyclic lactam structure 1-7.
  • Preferred conditions for this cyclization are triethylamine in acetonitrile at 40° C. to 120° C. for 4-16 hours.
  • Amination of compound 1-7 can be accomplished with ammonia in a range of aprotic or protic solvents at 0° C. to 100° C. for 4-20 hours.
  • Preferred conditions are ammonia in p-dioxane at ambient temperature for 4 to 24 hours.
  • Compounds of formula (1) which contain a carboxylic ester functionality, can be hydrolyzed to the corresponding carboxylic acid utilizing base or acid catalyzed hydrolysis conditions as known in the art.
  • a preferred method of hydrolysis is treating compound (1) with aqueous lithium hydroxide in an organic solvent at 20° C. to 100° C. for 1 to 10 hours.
  • Compound 1B may be formed through a peptide coupling reaction between Compound 1A and ammonia.
  • Compound 1B may be used to form Compound 1C by amide dehydration
  • the dehydration may be performed by treating the amide with SOCl 2 , POCl 3 , PCl 5 , p-TosCl/pyridine, Tf 2 O/pyridine or with the Vilsmeier reagent in combination with an organic or inorganic base.
  • the Vilsmeier reagent can be prepared by reacting dimethylformamide (DMF) with oxalylchloride in acetonitrile, dichloromethane, chloroform, dioxane, tetrahydrofuran (THF), or diethylether.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the Vilsmeier reagent is formed in the desired solvent for instance at a temperature between 0° C. and room temperature. The formation normally will be completed in 5-15 minutes.
  • a solution of the amide in the desired solvent is added dropwise to the Vilsmeier reagent at a temperature between 0° C. and room temperature. The addition normally will be completed in 10-20 minutes.
  • two equivalents of a base are added.
  • an organic base for instance pyridine or triethylamine (TEA) is used.
  • Inorganic bases may also be effective.
  • the ketones (2-5) which are the equivalent of compound 1-1 of Scheme 1, wherein m and n are each independently 1, 2 or 3, can be prepared utilizing the procedure of Zang, Y.; Schuster, G., J. Org. Chem. 1994, 59, 1855-62.
  • the monoprotected diones (2-2) can be prepared using the procedures of Alonso, F.; et al., Tetrahedron, 1995, 51(37), 10259-80, Crich, D.; Fortt, S. Tetrahedron, 1989, 45(20), 6581-98, or Lee, S.; Fuchs, P., J. Amer. Chem. Soc., 2002, 124, 13978-9.
  • compounds of formula (1) may also be prepared from compound 4-7, which is prepared by the method of Scheme 3 above, through methods known in the art.
  • a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
  • a preferred pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formula (2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
  • the pharmaceutical composition contains ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl ⁇ -acetonitrile or a pharmaceutically acceptable salt thereof, 2-(4-(4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-2-fluorophenyl)-cyclohexyl)acetic acid or a pharmaceutically acceptable salt thereof, ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]-oxazepin-6(5H)-yl)phenyl]-cyclohexyl ⁇ acetic acid or a pharmaceutically acceptable salt thereof, (trans-4-[4
  • compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate
  • various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
  • solutions of the compounds or compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the compounds or compositions of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of a compound of this invention.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
  • the invention is directed to a pharmaceutical composition, which comprises a therapeutically effective amount of a first compound of formula (1), or a pharmaceutically acceptable salt of the compound; a second compound that is an antidiabetic agent selected from insulin and insulin analogs; insulinotropin; biguanides; ⁇ 2 -antagonists and imidazolines; glitazones; aldose reductase inhibitors; glycogen phosphorylase inhibitors; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors; ⁇ -glucosidase inhibitors; ⁇ -agonists; phosphodiesterase inhibitors; lipid-lowering agents; antiobesity agents; vanadate and vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents; a prodrug of the antidiabetic agents, or
  • the invention is directed to a kit comprising: a first dosage form comprising a compound of formula (1), or a pharmaceutically acceptable salt of the compound; and a second dosage form comprising an antidiabetic agent selected from insulin and insulin analogs; insulinotropin; biguanides; ⁇ 2 -antagonists and imidazolines; glitazones; aldose reductase inhibitors; glycogen phosphorylase inhibitors; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors; ⁇ -glucosidase inhibitors; ⁇ -agonists; phosphodiesterase inhibitors; lipid-lowering agents; antiobesity agents; vanadate and vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents; prodrugs of the antidiabetic agents, or a pharmaceutical
  • the invention is directed to a method of inhibiting DGAT-I comprising administering to a mammal an inhibitory amount of a compound of formula (1), or a pharmaceutically acceptable salt of the compound, either alone or in combination with an antidiabetic agent as described above.
  • the invention is directed to a method of treating a condition mediated by DGAT-1 inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt of the compound, either alone or in combination with an antidiabetic agent as described above.
  • the condition treated is Type 2 diabetes, insulin resistance syndrome or obesity.
  • the condition is treated by administering a compound of formula (2), or a pharmaceutically acceptable salt thereof.
  • the condition is treated by administering one of the following compounds, or pharmaceutically acceptable salts thereof: ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl ⁇ -acetonitrile, 2-(4-(4-(4-amino-5-oxo-7,8-dihydro-pyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-2-fluorophenyl)-cyclohexyl)acetic acid, ⁇ trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,
  • the mammal treated is a human.
  • the condition treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer
  • the present invention also relates to therapeutic methods for treating the above described conditions in a mammal, including a human, wherein a compound of formula (1) of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy.
  • the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (1) of this invention being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions.
  • an effective dosage for the compounds of the present invention is in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 mg/kg/day of active compound in single or divided doses. Some variation in dosage will necessarily occur, however, depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject. Practitioners will appreciate that “kg” refers to the weight of the patient measured in kilograms.
  • the compounds or compositions of this invention may be administered in single (e.g., once daily) or multiple doses or via constant infusion.
  • the compounds of this invention may also be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • compositions of the present invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a “flash” formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
  • Mass Spectra were recorded on a Waters® (Waters Corp.; Milford, Mass.) Micromass® Platform II spectrometer. Unless otherwise specified, mass spectra were recorded on a Waters® (Milford, Mass.) Micromass® Platform II spectrometer.
  • Step 1 Methyl(trans-4- ⁇ 4-[(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)amino]-phenyl ⁇ cyclohexyl)acetate, shown above, was prepared as follows.
  • Methyl[trans-4-[4-[[(trifluoromethyl)sulfonyl]oxy]phenyl]cyclohexyl]acetate shown above, which is identified as Compound 55 in U.S. Pat. No. 7,244,727, issued Jul. 17, 2007, was prepared according to the method described therein.
  • Step 4 The title compound of Preparation 1 was prepared as follows. A slurry of methyl (trans-4- ⁇ 4-[[4,6-dichloropyrimidin-5-yl)carbonyl](2-hydroxy-ethyl)amino]phenyl ⁇ cyclohexyl)acetate (4.78 g, 10.2 mmol, unpurified material from Step 3) and TEA (4.15 g, 41 mmol) in acetonitrile was stirred at 80° C. for 6 hours. The reaction was cooled, concentrated in vacuo, diluted into EtOAc, washed with water (3 ⁇ ), saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford a yellow solid.
  • Step 3 The title compound of Preparation 2 was prepared as follows. 4M HCl in dioxane (25 mL) was added to a solution of methyl [trans-4-(4- ⁇ [(2R)-2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propyl][(4,6-dichloropyrimidin-5-yl)carbonyl]amino ⁇ phenyl)cyclohexyl]acetate (3.95 g, 6.72 mmol), from Step 2, in methanol (50 mL). The mixture was stirred at 23° C. for 30 minutes. The reaction mixture was concentrated to remove the solvent.
  • Step 5 The title compound of Preparation 3 was prepared as follows. Methyl[trans-4-(4- ⁇ [(3S)-2- ⁇ oxy ⁇ propyl][(4,6-dichloropyrimidin-5-yl)carbonyl]-amino ⁇ phenyl)cyclohexyl]acetate (0.8 g, 1.66 mmol), potassium carbonate (0.46 g, 3.33 mmol) and 200 mg of molecular sieves were mixed into 41.6 ml of acetonitrile. The mixture was added to sealed tube and heated at 80° C. overnight. The reaction mixture was concentrated and then diluted with EtOAc and water. Separated layers and washed organic layer with brine, then dried and concentrated.
  • Step 1 1-(Bromomethyl)benzene (4.92 g, 28.8 mmol) and K 2 CO 3 (3.98 g, 28.8 mmol) were added to a solution of 4-bromo-2-fluorophenol (5.0 g, 26 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 hours. Water (100 mL) and EtOAc (100 mL) were added, the organic layer was separated and dried over MgSO 4 and concentrated to give 1-(benzyloxy)-4-bromo-2-fluorobenzene as a yellow solid 7.06 g. 1 H NMR (400 MHz, CDCl 3 ): ⁇ 7.24-7.41 (m, 5H), 7.20 (m, 1H), 7.16 (m, 1H), 6.82 (m, 1H), 5.10 (m, 2H).
  • Step 4 Methyl 2-(4-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate, shown below, was prepared as follows.
  • Step 7 The title compound of Preparation 4 was prepared as follows. 4M HCl in dioxane (0.5 mL) was added to a solution of methyl 2-(4-(4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)-3-fluorophenyl)cyclohexyl)acetate (30 mg, 0.05 mmol) in methanol (1 mL). The mixture was stirred at 23° C. for 30 minutes. The reaction mixture was concentrated to remove solvent. The residue was dissolved in acetonitrile (1 mL) and NEt 3 (0.05 mL) was added to it.
  • Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate was prepared as follows.
  • Methyl 2-(4-(trifluoromethyl-sulfonyloxy)cyclohex-3-enyl)acetate (21.9 g, 72.4 mmol, 1.0 eq), bis(pinacolato)diboron (16.7 g, 65.8 mmol, 0.9 eq), KOAc (21.5 g, 219 mmol, 3.0 eq) and PdCl 2 (dppf) (1.6 g, 2.19 mmol, 0.03 eq) were dissolved in DMSO (550 ml). The reaction mixture was bubbled through with N 2 -gas for 15 min and then heated to 50° C. and stirred for 2.5 h.
  • reaction was concentrated to recover 0.26 g of methyl (trans-4- ⁇ 4-[(7S)-4-amino-7-methyl-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl]phenyl cyclohexyl)acetate.
  • Lithium hydroxide (11.3 mg, 0.472 mmol) was added to a solution of methyl (trans-4- ⁇ 4-[(7S)-4-amino-7-methyl-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl]phenyl cyclohexyl)acetate (50 mg, 0.12 mmol), from Example 4, in 2.76 ml of THF/methanol/water (3:2:1) and the resulting solution was stirred at room temperature. After completion, reaction was acidified with 1N NaOH until acidic pH, and concentrated reaction mixture. EtOAc and water were added, and repulped product for two hours.
  • the title compound was prepared as follows. A mixture of methyl 2-(4-(4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-3-fluorophenyl)cyclohexyl)acetate (20 mg, 0.045 mmol), from Preparation 4, in 0.5M ammonia in dioxane was stirred at 50° C., in a tightly capped flask, for 3 hours. The reaction mixture was concentrated to give a white solid, which was carried on to the next step without further purification.
  • the compounds of the following Examples 28-46 were prepared utilizing the method of Examples 26-27 wherein an amide is formed by reacting a carboxylic acid with an amine.
  • the compounds of Examples 33-44 were separated using reverse phase column chromatography utilizing YMC ODS-AQ (2.0 ⁇ 50 mm 5 ⁇ m), which is a reversed-phase packing material with both a hydrophobic high carbon loading and a relatively hydrophilic surface (YMC Co., Ltd., Tokyo, Japan) and 0.05% TFA in water as an eluent.
  • Step 4 A solution of 4-chloro-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (279 mg, 0.70 mmol) in 0.5 N ammonia in p-dioxane was stirred in a sealed tube for 18 hours. Concentration of the reaction mixture, followed by chromatography (10 g silica gel, 0-5% methanol:chloroform) afforded the title compound of Preparation 5 as a white solid, 122 mg.
  • Example 52 To form the named compound, shown above, the compound of Example 52 was hydrolyzed utilizing the conditions described in Example 2 to afford the title compound as light brown solid, 11 mg.
  • Step 3 The title compound was prepared as follows. A solution of ( ⁇ )- ⁇ (1R,3aS,4R,6aS)-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]octahydropentalen-1-yl ⁇ malonic acid (87 mg, 0.19 mmol) in xylenes (3 mL) and dimethylsulfoxide (0.5 mL) was stirred at 150° C. for 2 hours. After cooling the reaction mixture was diluted in EtOAc, washed with water and a precipitate formed in the organic layer.
  • the utility of the compounds of formula (1), the pharmaceutically acceptable salts of the compounds, (such as are described herein) in animals, particularly mammals (e.g., humans) may be demonstrated by the activity thereof in conventional assays known to one of ordinary skill in the relevant art, including the in vitro and in vivo assays discussed below. Such assays also provide a means whereby the activities of the compounds of formula (1) can be compared with the activities of other known compounds.
  • DGAT-1 Human full-length diacylglycerol:acylCoA acyltransferase 1 (DGAT-1) was expressed in Sf9 insect cells which are then lysed and a crude membrane fraction (105,000 ⁇ g pellet) was prepared.
  • the DGAT-1 gene is a human DGAT-1 gene described in J. Biol. Chem. 273:26765, 1998 and U.S. Pat. No. 6,100,077.
  • the cells were cultured as follows. Sf9 cells (20 L) were infected with 4 mL of DGAT1 Baculovirus Infected Insect Cells (BIIC) for 72 hours in a Wave Bioreactor System 20/50P (Wave Biotec/GE Healthcare).
  • BIIC Baculovirus Infected Insect Cells
  • Crude DGAT-1 microsomes were prepared as follows. Cell pellets were washed once with ice-cold Dulbecco's phosphate-buffered saline. Cells were collected in tabletop centrifuge (Beckman GS-6KR), 15 minutes, 2000 ⁇ g, 4° C. Twenty (20) mL of ice-cold Microsome Buffer (MB) was added per 5 g of cell pellet. The suspension was passed through a microfluidizer 3 times (18K psi). The lysate was transferred to centrifuge tubes and centrifuged for 20 minutes at 5000 ⁇ g (Beckman-Coulter, Inc.
  • the Microsome Buffer used for microsome preparation, was prepared by conventional means and contained 125 mM sucrose, 3 mM imidazole, 0.2 ⁇ g/mL aprotinin, 0.2 ⁇ g/mL leupeptin and 5 mM dithiothreitol (Cleland's reagent), DGAT-1 activity was measured in 384-well format in a total assay volume of 25 ⁇ l that contained, Hepes buffer (50 mM, pH 7.5), MgCl 2 (10 mM), bovine serum albumin (0.6 mg/ml), [ 14 C]decanoylCoA (20 ⁇ M, 58 Ci/mol) and membranes (25 ⁇ g/ml) into which 1,2 dioleoyl-sn-glycerol (75 ⁇ M) in acetone has already been incorporated.
  • Inhibitors in DMSO were pre-incubated with membranes before initiating the DGAT-1 reaction by the addition of decanoylCoA.
  • Two control DGAT-1 reactions were also incubated in parallel: 1) DMSO without inhibitor to measure zero percent effect of inhibition and 2) and a maximally inhibited DGAT-1 reaction (“blank”) incubated with 1 ⁇ M ⁇ trans-4-[4-(4-amino-2,7,7-trimethyl-7 H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl ⁇ acetic acid (WO2004/047755).
  • the DMSO concentration was 2.5%.
  • the inhibitors were present at a range of eight concentrations to generate an apparent IC 50 for each compound.
  • the eight inhibitor concentration employed ranged from 10 ⁇ M to 3 nM (from high to low concentration). Specifically, the eight concentrations used were 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 300 nM, 100 nM, 30 nM, 10 nM and 3 nM.
  • the compounds of the present invention described in Examples 1-3 and 5-57, were tested for in vitro DGAT-1 inhibition, and were found to generally exhibit DGAT-1 inhibition with IC 50 values of 1000 nM or less. Where this DGAT-1 inhibition assay was performed on a compound more than once, an inhibition range is also provided for that compound. Preferably, the compounds of the present invention exhibit DGAT-1 inhibition with IC 50 values of 100 nM or less.
  • Oral glucose tolerance tests (“OGTT”) have been in use in humans since, at least, the 1930s, Pincus et al., Am. J. Med. Sci, 188: 782 (1934), and are routinely used in the diagnosis of human diabetes, though not to evaluate the efficacy of therapeutic agents in patients.
  • KK mice have been used to evaluate glitazones (Fujita et al. Diabetes 32:804-810 (1983); Fujiwara et al., Diabetes 37: 1549-48 (1988); Izumi et al. Biopharm Durg. Dispos. 18:247-257 (1997)), metformin (Reddi et al. Diabet. Metabl. 19:44-51 (1993)), glucosidase inhibitors (Hamada et al. Jap. Pharmacol. Ther. 17:17-28 (1988); Matsuo et al. Am. J. Clin. Nutr.
  • KK mice are derived from an inbred line first established by Kondo et al. (Kondo et al. Bull. Exp. Anim. 6:107-112 (1957)). The mice spontaneously develop a hereditary form of polygenic diabetes that progresses to cause renal, retinal and neurological complications analogous to those seen in human diabetic subjects, but they do not require insulin or other medication for survival. Another aspect of the invention is directed to the use of KK mice to evaluate the effects of insulin secretagogue agents in the context of an oral glucose tolerance test.
  • the following screen may be used to evaluate the efficacy of test compounds for inhibiting food intake in Sprague-Dawley rats after an overnight fast.
  • Male Sprague-Dawley rats are individually housed and fed powdered chow. They are maintained on a 12 hour light/dark cycle and received food and water ad libitum. The animals are acclimated to the vivarium for a period of one week before testing is conducted. Testing is completed during the light portion of the cycle.
  • rats are transferred to individual test cages without food the afternoon prior to testing, and the rats are fasted overnight. After the overnight fast, rats are dosed the following morning with vehicle or test compounds.
  • a known antagonist is dosed (3 mg/kg) as a positive control, and a control group receives vehicle alone (no compound).
  • the test compounds are dosed at ranges between 0.1 and 100 mg/kg depending upon the compound.
  • the standard vehicle is 0.5% (w/v) methylcellulose in water and the standard route of administration is oral. However, different vehicles and routes of administration may be used to accommodate various compounds when required.
  • Food is provided to the rats 30 minutes after dosing and an Oxymax automated food intake system (Columbus Instruments, Columbus, Ohio) is started.
  • rat food intake is recorded continuously at 10-minute intervals for a period of two hours. When required, food intake is recorded manually using an electronic scale; food is weighed every 30 minutes after food is provided up to four hours after food is provided. Compound efficacy is determined by comparing the food intake pattern of compound-treated rats to vehicle and the standard positive control.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US12/174,820 2007-08-02 2008-07-17 Substituted bicyclolactam compounds Abandoned US20090036425A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/174,820 US20090036425A1 (en) 2007-08-02 2008-07-17 Substituted bicyclolactam compounds
US12/357,544 US7718645B2 (en) 2007-08-02 2009-01-22 Substituted bicyclolactam compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95350707P 2007-08-02 2007-08-02
US12/174,820 US20090036425A1 (en) 2007-08-02 2008-07-17 Substituted bicyclolactam compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US95350707P Continuation 2007-08-02 2007-08-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/357,544 Continuation US7718645B2 (en) 2007-08-02 2009-01-22 Substituted bicyclolactam compounds

Publications (1)

Publication Number Publication Date
US20090036425A1 true US20090036425A1 (en) 2009-02-05

Family

ID=39926534

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/174,820 Abandoned US20090036425A1 (en) 2007-08-02 2008-07-17 Substituted bicyclolactam compounds
US12/357,544 Expired - Fee Related US7718645B2 (en) 2007-08-02 2009-01-22 Substituted bicyclolactam compounds

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/357,544 Expired - Fee Related US7718645B2 (en) 2007-08-02 2009-01-22 Substituted bicyclolactam compounds

Country Status (34)

Country Link
US (2) US20090036425A1 (fr)
EP (1) EP2185567B1 (fr)
JP (1) JP4629808B2 (fr)
KR (1) KR20100032443A (fr)
CN (1) CN101772504A (fr)
AP (1) AP2010005163A0 (fr)
AR (1) AR067780A1 (fr)
AT (1) ATE502948T1 (fr)
AU (1) AU2008281545B2 (fr)
BR (1) BRPI0815067A2 (fr)
CA (1) CA2695291C (fr)
CL (1) CL2008002227A1 (fr)
CO (1) CO6251365A2 (fr)
CR (1) CR11223A (fr)
CY (1) CY1111628T1 (fr)
DE (1) DE602008005757D1 (fr)
DK (1) DK2185567T3 (fr)
DO (1) DOP2010000046A (fr)
EA (1) EA201000050A1 (fr)
EC (1) ECSP109932A (fr)
ES (1) ES2361716T3 (fr)
HN (1) HN2008001191A (fr)
HR (1) HRP20110335T1 (fr)
MA (1) MA31580B1 (fr)
PA (1) PA8791601A1 (fr)
PE (1) PE20090897A1 (fr)
PL (1) PL2185567T3 (fr)
PT (1) PT2185567E (fr)
SI (1) SI2185567T1 (fr)
TN (1) TN2010000053A1 (fr)
TW (1) TWI356059B (fr)
UA (1) UA94833C2 (fr)
WO (1) WO2009016462A2 (fr)
ZA (1) ZA201000255B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242653A1 (en) * 2006-06-23 2008-10-02 Huaqing Liu Cyclopropyl amine derivatives
WO2012112364A1 (fr) * 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1
WO2012162129A1 (fr) * 2011-05-20 2012-11-29 Glaxosmithkline Llc Nouveaux composés en tant qu'inhibiteurs de diacylglycérol acyltransférase
WO2014081994A1 (fr) 2012-11-23 2014-05-30 Glaxosmithkline Llc Nouveaux composés utilisés comme inhibiteurs de diacylglycérol acyltransférase
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US9738658B2 (en) 2012-11-23 2017-08-22 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
US9809604B2 (en) 2013-08-23 2017-11-07 Qingdao Huanghai Pharmaceutical Co., Ltd. DGAT1 inhibitor and preparation method and use thereof

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2588162A1 (fr) 2004-12-14 2006-06-22 Astrazeneca Ab Derives d'oxadiazole en tant qu'inhibiteurs de dgat
EP1966221A1 (fr) 2005-12-22 2008-09-10 AstraZeneca AB Pyrimido-[4,5-]-oxazines pour utilisation en tant qu'inhibiteurs de dgat
DK2402317T3 (da) 2006-03-31 2013-10-07 Novartis Ag DGAT-inhibitor
MX2008015228A (es) 2006-05-30 2008-12-12 Astrazeneca Ab Acido 5-fenilamino-1,3,4-oxadiazol-2-ilcarbonilamino-4-fenoxi-cicl ohexanocarboxilico sustituido como inhibidor de diacilglicerol aciltransferasa de acetil coenzima a.
AR066169A1 (es) 2007-09-28 2009-07-29 Novartis Ag Derivados de benzo-imidazoles, utiles para trastornos asociados con la actividad de dgat
WO2010086820A1 (fr) * 2009-02-02 2010-08-05 Pfizer Inc. Dérivés de 4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazépin-6(5h)-yl)phényle
TW201040174A (en) * 2009-02-03 2010-11-16 Pfizer 4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one derivatives
JP2012516885A (ja) * 2009-02-04 2012-07-26 ファイザー・インク ４−アミノ−７，８−ジヒドロピリド［４，３−ｄ］ピリミジン−５（６Ｈ）−オン誘導体
DK3366686T3 (da) 2009-03-20 2020-11-23 Metabasis Therapeutics Inc Inhibitorer af diacylglycerol-o-acyltransferase 1 (dgat-1) og anvendelser deraf
PT2547679E (pt) 2010-03-19 2016-01-27 Pfizer Derivados de 2,3-di-hidro-1h-indeno-1-il-2,7-diazaspiro[3.6]nonano e sua utilização como antagonistas ou agonistas inversos do receptor de grelina
WO2011121350A1 (fr) 2010-04-01 2011-10-06 Astrazeneca Ab Inhibiteurs de dgat1 à base de 4-amino-7,8-dihydropyrimido[5,4,f][1,4]oxazépin-5(6h)-one
KR20150006899A (ko) 2010-10-29 2015-01-19 화이자 인코포레이티드 N1/N2-락탐 아세틸-CoA 카복실라아제 억제제
WO2012122075A1 (fr) * 2011-03-08 2012-09-13 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1
ME02312B (me) 2011-04-22 2016-06-20 Pfizer DERIVATI PIRAZOLOSPIROKETONA, NAMIJENJENI UPOTREBI KAO INHIBITORI ACETIL-CoA-KARBOKSILAZE
BR112013028886A2 (pt) 2011-05-10 2016-08-09 Gilead Sciences Inc compostos heterocíclicos fundidos como moduladores dde canal de sódio
NO3175985T3 (fr) 2011-07-01 2018-04-28
UY34171A (es) 2011-07-01 2013-01-31 Gilead Sciences Inc Compuestos heterocíclicos fusionados como moduladores del canal iónico
WO2013011402A1 (fr) 2011-07-15 2013-01-24 Pfizer Inc. Modulateurs de gpr 119
EP2734503B1 (fr) 2011-07-22 2015-09-16 Pfizer Inc. Modulateurs des récepteurs de quinolinylglucagon
ES2605565T3 (es) 2011-08-31 2017-03-15 Pfizer Inc Compuestos de hexahidropirano [3,4-D][1,3]tiazin-2-amina
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2013068439A1 (fr) * 2011-11-09 2013-05-16 Intervet International B.V. Composés 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazépine comme inhibiteurs de dgat1
EP2776405A1 (fr) 2011-11-11 2014-09-17 Pfizer Inc 2-thiopyrimidinones
WO2013119040A1 (fr) 2012-02-07 2013-08-15 Kainos Medicine, Inc. Composés comme inhibiteurs de l'enzyme diacylglycérol o-acyltransférase de type 1
KR20140137404A (ko) 2012-04-06 2014-12-02 화이자 인코포레이티드 디아실글리세롤 아실트랜스퍼라제 2 억제제
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9321728B2 (en) 2012-04-25 2016-04-26 Korea Research Institute Of Chemical Technology Beta-alanine derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical composition comprising same as active ingredient
ES2585262T3 (es) 2012-05-04 2016-10-04 Pfizer Inc Compuestos heterocíclicos de hexahidropiran[3,4-d][1,3]tiazin-2-amina sustituidos como inhibidores de PPA, BACE1 y BACE2
EA201492283A1 (ru) 2012-06-20 2015-04-30 Ф. Хоффманн-Ля Рош Аг Замещенные соединения пиразола в качестве антагонистов рецепторов лизофосфатидной кислоты (lpar)
EP2897964A1 (fr) 2012-09-20 2015-07-29 Pfizer Inc. Composés de hexahydropyrano [3,4-d][1,3]thiazin-2-amine substitués par alkyle
WO2014054053A1 (fr) 2012-10-03 2014-04-10 Advinus Therapeutics Limited Composés spirocycliques et leurs compositions et applications médicinales
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
CA2893256A1 (fr) 2012-12-11 2014-06-19 Pfizer Inc. Composes d'hexahydropyrano [3,4-d][1,3]thiazin-2-amine en tant qu'inhibiteurs de bace1
WO2014097038A1 (fr) 2012-12-19 2014-06-26 Pfizer Inc. Composés hexahydropyrano[3,4-d][1,3]thiazin-2-amine substitués carbocycliques et hétérocycliques
WO2014125394A1 (fr) 2013-02-13 2014-08-21 Pfizer Inc. Composés hexahydropyrano [3,4-d][1,3] thiazin-2-amine substitués par un hétéroaryle
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2014140241A1 (fr) * 2013-03-15 2014-09-18 Intervet International B.V. Dérivés de pyridine en tant qu'inhibiteurs de dgat-1
CA2926568C (fr) 2013-10-09 2017-09-05 Pfizer Inc. Antagonistes de recepteur ep3 de prostaglandine
DK3119757T3 (en) 2014-03-17 2018-06-18 Pfizer DIACYLGYLERIC-ACYL TRANSFERASE-2 INHIBITORS TO USE IN THE TREATMENT OF METABOLIC AND RELATED DISEASES
CU24406B1 (es) 2014-04-04 2019-05-03 Pfizer 1-{[(2s,3s,4s)-3-etil-4-fluoro-5-oxopirrolidin-2-il]metoxi}-7 -metoxiisoquinolin-6-carboxamida
AP2016009493A0 (en) 2014-04-10 2016-10-31 Pfizer 2-AMINO-6-METHYL-4,4a,5,6-TETRAHYDROPYRANO[3,4-d][1,3]THIAZIN-8a(8H)-YL-1,3-THIAZOL-4-YL AMIDES
WO2016092413A1 (fr) 2014-12-10 2016-06-16 Pfizer Inc. Composés indoliques et indazoliques qui activent l'ampk
JP2017538769A (ja) 2014-12-22 2017-12-28 ファイザー・インク プロスタグランジンｅｐ３受容体の拮抗薬
WO2016178113A1 (fr) 2015-05-05 2016-11-10 Pfizer Inc. 2-thiopyrimidinones
WO2016193844A1 (fr) 2015-05-29 2016-12-08 Pfizer Inc. Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs de l'enzyme vanine-1
KR102426986B1 (ko) 2015-06-17 2022-07-28 화이자 인코포레이티드 삼환형 화합물 및 포스포다이에스터라제 억제제로서 이의 용도
WO2016203335A1 (fr) 2015-06-18 2016-12-22 Pfizer Inc. Nouvelles pyrido [2,3-b] pyrazinones utilisées en tant qu'inhibiteurs de bromodomaines de la famille bet
AU2016305590A1 (en) 2015-08-13 2018-02-15 Pfizer Inc. Bicyclic-fused heteroaryl or aryl compounds
CA2996389C (fr) 2015-08-27 2020-04-07 Pfizer Inc. Composes heteroaryle ou aryle bicycliques fusionnes en tant que modulateurs d'irak 4
WO2017037567A1 (fr) 2015-09-03 2017-03-09 Pfizer Inc. Régulateurs de la frataxine
JP2018531924A (ja) 2015-09-24 2018-11-01 ファイザー・インク テトラヒドロピラノ［３，４−ｄ］［１，３］オキサジン誘導体、およびｂａｃｅ阻害剤としてのその使用
EP3353183A1 (fr) 2015-09-24 2018-08-01 Pfizer Inc N-[2-(2-amino-6,6-disubstitués-4,4a,5,6-tétrahydropyrano[3,4-d][1,3]thiazin-8a(8h)-yl)-1,3-thiazol-4-yl]amides
JP2018534251A (ja) 2015-09-24 2018-11-22 ファイザー・インク Ｂａｃｅ阻害剤として有用なｎ−［２−（３−アミノ−２，５−ジメチル−１，１−ジオキシド−５，６−ジヒドロ−２ｈ−１，２，４−チアジアジン−５−イル）−１，３−チアゾール−４−イル］アミド
SG11201804363UA (en) 2015-12-29 2018-07-30 Pfizer Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors
KR20190026902A (ko) 2016-07-14 2019-03-13 화이자 인코포레이티드 바닌-1 효소의 억제제로서의 신규 피리미딘 카르복스아미드
AR109179A1 (es) 2016-08-19 2018-11-07 Pfizer Inhibidores de diacilglicerol aciltransferasa 2
CN108164548B (zh) * 2016-12-07 2020-09-08 四川大学 嘧啶并吗啉衍生物及其制备方法和用途
WO2019133445A1 (fr) 2017-12-28 2019-07-04 Inception Ibd, Inc. Aminothiazoles utilisés en tant qu'inhibiteurs de vanin-1
CR20210110A (es) 2018-08-31 2021-05-13 Pfizer Combinaciones para tratamiento de ehna/ehgna y enfermedades relacionadas
WO2020102575A1 (fr) 2018-11-16 2020-05-22 Inception Ibd, Inc. Aminothiazoles hétérocycliques et leurs utilisations
CA3140972C (fr) 2019-05-20 2024-06-18 Pfizer Inc. Combinaisons comprenant du benzodioxol en tant qu'agonistes de glp-1r destinees a etre utilisees dans le traitement de la nash/nafld et de maladies associees
TW202115086A (zh) 2019-06-28 2021-04-16 美商輝瑞大藥廠 Bckdk抑制劑
JP7498199B2 (ja) 2019-06-28 2024-06-11 ファイザー・インク 種々の疾患を処置するために有用なｂｃｋｄｋ阻害剤としての５－（チオフェン－２－イル）－１ｈ－テトラゾール誘導体
TWI771766B (zh) 2019-10-04 2022-07-21 美商輝瑞股份有限公司 二醯基甘油醯基轉移酶２ 抑制劑
JP2022058085A (ja) 2020-02-24 2022-04-11 ファイザー・インク ジアシルグリセロールアシルトランスフェラーゼ２阻害剤とアセチル－ＣｏＡカルボキシラーゼ阻害剤との組合せ
WO2023026180A1 (fr) 2021-08-26 2023-03-02 Pfizer Inc. Forme amorphe de (s)-2-(5-((3-éthoxypyridin-2-yl)oxy)pyridin-3-yl)-n-(tétrahydrofuran-3-yl)pyrimidine-5-carboxamide
IL312296A (en) 2021-12-01 2024-06-01 Pfizer 3-PHENYL-1-BENZOTHIOPEN-2-CARBOXYLIC ACID DERIVATIVES AS INHIBITORS OF BRANCHED ALPHA KETO ACID DEHYDROGENSIS KINASE FOR THE TREATMENT OF DIABETES, KIDNEY DISEASES, NASH AND HEART
WO2023198140A1 (fr) 2022-04-14 2023-10-19 Gasherbrum Bio, Inc. Agonistes hétérocycliques de glp-1
WO2024075051A1 (fr) 2022-10-07 2024-04-11 Pfizer Inc. Inhibiteurs et/ou agents de dégradation de hsd17b13
WO2024118524A1 (fr) 2022-11-28 2024-06-06 Cerevel Therapeutics, Llc Composés d'azaindole et leur utilisation en tant qu'inhibiteurs de phosphodiestérase
WO2024125602A1 (fr) 2022-12-15 2024-06-20 Gasherbrum Bio, Inc. Sels et formes solides d'un composé ayant une activité agoniste de glp-1
WO2024127297A1 (fr) 2022-12-16 2024-06-20 Pfizer Inc. Inhibiteurs et/ou agents de dégradation contenant du 3-fluoro-4-hydroxybenzmide et leurs utilisations

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2472835A1 (fr) * 2002-01-18 2003-07-31 Kyorin Pharmaceutical Co., Ltd. Derives de pyrimidine fusionnes bicycliques
MXPA05005425A (es) * 2002-11-22 2005-11-23 Japan Tobacco Inc Heterociclos que contienen nitrogeno, biciclicos, fusionados.
EP1718309A2 (fr) 2004-01-30 2006-11-08 Japan Tobacco, Inc. Composes anorexigene
JP2006056881A (ja) * 2004-07-21 2006-03-02 Takeda Chem Ind Ltd 縮合環化合物
EP1966221A1 (fr) * 2005-12-22 2008-09-10 AstraZeneca AB Pyrimido-[4,5-]-oxazines pour utilisation en tant qu'inhibiteurs de dgat

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US20080242653A1 (en) * 2006-06-23 2008-10-02 Huaqing Liu Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
WO2012112364A1 (fr) * 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Dérivés de lactame en tant qu'inhibiteurs de dgat-1
EA023030B1 (ru) * 2011-05-20 2016-04-29 Глэксосмитклайн Интеллекчуал Проперти (No.2) Лимитед Новые соединения в качестве ингибиторов диацилглицеролацилтрансферазы
CN103703009B (zh) * 2011-05-20 2016-08-17 葛兰素史密斯克莱知识产权（第2号）有限公司 作为二酰基甘油酰基转移酶抑制剂的新化合物
US8859536B2 (en) 2011-05-20 2014-10-14 Glaxosmithkline Intellectual Property (No.2) Limited Compounds as diacylglycerol acyltransferase inhibitors
US9040517B2 (en) 2011-05-20 2015-05-26 Glaxosmithkline Intellectual Property (No. 2) Limited Compounds as diacylglycerol acyltransferase inhibitors
KR101919080B1 (ko) 2011-05-20 2018-11-16 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 디아실글리세롤 아실트랜스퍼라제 억제제로서의 신규 화합물
WO2012162129A1 (fr) * 2011-05-20 2012-11-29 Glaxosmithkline Llc Nouveaux composés en tant qu'inhibiteurs de diacylglycérol acyltransférase
JP2014517839A (ja) * 2011-05-20 2014-07-24 グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー２、リミテッド ジアシルグリセロールアシルトランスフェラーゼ阻害剤としての新規化合物
US9273069B2 (en) 2011-05-20 2016-03-01 Glaxosmithkline Intellectual Property (No.2) Limited Compounds as diacylglycerol acyltransferase inhibitors
CN103703009A (zh) * 2011-05-20 2014-04-02 葛兰素史密斯克莱知识产权（第2号）有限公司 作为二酰基甘油酰基转移酶抑制剂的新化合物
WO2014081994A1 (fr) 2012-11-23 2014-05-30 Glaxosmithkline Llc Nouveaux composés utilisés comme inhibiteurs de diacylglycérol acyltransférase
US9738658B2 (en) 2012-11-23 2017-08-22 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
US9796729B2 (en) 2012-11-23 2017-10-24 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
US9879031B2 (en) 2012-11-23 2018-01-30 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
KR20150087852A (ko) * 2012-11-23 2015-07-30 글락소스미스클라인 엘엘씨 디아실글리세롤 아실트랜스퍼라제 억제제로서의 신규 화합물
EA031114B1 (ru) * 2012-11-23 2018-11-30 ГЛЭКСОСМИТКЛАЙН ЭлЭлСи ПРОИЗВОДНЫЕ ДИГИДРОПИРИМИДО[5,4-f]ОКСАЗЕПИНА В КАЧЕСТВЕ ИНГИБИТОРОВ ДИАЦИЛГЛИЦЕРИН АЦИЛТРАНСФЕРАЗЫ
US10174049B2 (en) 2012-11-23 2019-01-08 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
EP3492474A1 (fr) * 2012-11-23 2019-06-05 GlaxoSmithKline LLC Intermediares pour la procuction d'inhibiteurs de diacylglycérol acyltransférase
US10385066B2 (en) 2012-11-23 2019-08-20 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
KR102176463B1 (ko) 2012-11-23 2020-11-09 글락소스미스클라인 엘엘씨 디아실글리세롤 아실트랜스퍼라제 억제제로서의 신규 화합물
US9809604B2 (en) 2013-08-23 2017-11-07 Qingdao Huanghai Pharmaceutical Co., Ltd. DGAT1 inhibitor and preparation method and use thereof

Also Published As

Publication number Publication date
ZA201000255B (en) 2011-03-30
HN2008001191A (es) 2012-01-17
CN101772504A (zh) 2010-07-07
EP2185567B1 (fr) 2011-03-23
BRPI0815067A2 (pt) 2015-02-10
CR11223A (es) 2010-02-04
ATE502948T1 (de) 2011-04-15
DE602008005757D1 (de) 2011-05-05
CO6251365A2 (es) 2011-02-21
MA31580B1 (fr) 2010-08-02
WO2009016462A3 (fr) 2009-03-26
ECSP109932A (es) 2010-03-31
US20090137551A1 (en) 2009-05-28
DOP2010000046A (es) 2010-03-31
CY1111628T1 (el) 2015-10-07
CA2695291A1 (fr) 2009-02-05
AP2010005163A0 (en) 2010-02-28
TN2010000053A1 (fr) 2011-09-26
TWI356059B (en) 2012-01-11
CA2695291C (fr) 2012-04-17
AU2008281545A1 (en) 2009-02-05
US7718645B2 (en) 2010-05-18
KR20100032443A (ko) 2010-03-25
AR067780A1 (es) 2009-10-21
UA94833C2 (en) 2011-06-10
JP2010535190A (ja) 2010-11-18
JP4629808B2 (ja) 2011-02-09
EP2185567A2 (fr) 2010-05-19
ES2361716T3 (es) 2011-06-21
TW200916471A (en) 2009-04-16
PA8791601A1 (es) 2009-12-16
PT2185567E (pt) 2011-05-27
DK2185567T3 (da) 2011-05-16
HRP20110335T1 (hr) 2011-06-30
PL2185567T3 (pl) 2011-07-29
AU2008281545B2 (en) 2011-12-08
EA201000050A1 (ru) 2010-08-30
PE20090897A1 (es) 2009-08-06
CL2008002227A1 (es) 2009-04-17
SI2185567T1 (sl) 2011-06-30
WO2009016462A2 (fr) 2009-02-05

Similar Documents

Publication Publication Date Title
US7718645B2 (en) Substituted bicyclolactam compounds
US20240059710A1 (en) KRAS G12D Inhibitors
US7511037B2 (en) N-[[4-fluoro-2-(5-methy-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4-,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide as an HIV integrase inhibitor
UA128498C2 (uk) Агоніст рецептора glp-1 і його застосування
CN110267962B (zh) Magl抑制剂
KR20180083427A (ko) 케토헥소키나제 억제제로서의 치환된 3-아자비시클로[3.1.0]헥산
AU2018298733B2 (en) Fused-ring derivative having MGAT2 inhibitory activity
US7678783B2 (en) Macrocyclic tertiary amine beta-secretase inhibitors for the treatment of alzheimer's disease
US20210292340A1 (en) Cell necrosis inhibitor, preparation method therefor and use thereof
AU2001253538B2 (en) Inhibitors of alpha l beta 2 mediated cell adhesion
US20220185816A1 (en) Jak kinase inhibitor, preparation method for same, and applications thereof in field of medicine
US20210261569A1 (en) Fused heterocyclic derivatives having selective bace1 inhibitory activity
JP2021512049A (ja) カルボン酸基を含む窒素含有ベンゾ複素環化合物、その調製方法及び使用
AU2003210862B2 (en) Inhibitors of alpha L beta 2 integrin mediated cell adhesion
US11964942B2 (en) SSAO inhibitors and use thereof
US8729095B2 (en) 3-(biaryloxy)propionic acid derivatives for prevention and/or treatment of thromboembolic diseases
JP2020158390A (ja) Ｍｇａｔ２阻害活性を有する非芳香族複素環誘導体およびそれらを含有する医薬組成物
US20220340580A1 (en) Imidazo[4,5-d]pyridazinonyl derivatives as trpa1 inhibitors
US20220340590A1 (en) 3h,4h-thieno[2,3-d]pyrimidin-4-one derivatives as trpa1 inhibitors
CN114616229A (zh) 三环化合物及其药物用途
US20240124427A1 (en) Hydroxyheterocycloalkane-carbamoyl derivatives
IL301706A (en) Tetrazole history as TRPA1 inhibitors
TW202043213A (zh) Pcsk9抑制劑及其使用方法
TW202014191A (zh) 具有選擇性ｂａｃｅ１抑制活性的四氫哌喃并衍生物

Legal Events

Date Code Title Description
AS Assignment

Owner name: PFIZER INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DOW, ROBERT L.;MUNCHHOF, MICHAEL J.;REEL/FRAME:021256/0219;SIGNING DATES FROM 20080711 TO 20080715

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE