WO2005095339A1 - Dicyanopyrrolidines inhibiteurs de la dipeptidyl peptidase iv - Google Patents

Dicyanopyrrolidines inhibiteurs de la dipeptidyl peptidase iv Download PDF

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Publication number
WO2005095339A1
WO2005095339A1 PCT/IB2005/000721 IB2005000721W WO2005095339A1 WO 2005095339 A1 WO2005095339 A1 WO 2005095339A1 IB 2005000721 W IB2005000721 W IB 2005000721W WO 2005095339 A1 WO2005095339 A1 WO 2005095339A1
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Prior art keywords
alkyl
phenyl
pyrrolidine
dicarbonitrile
acetyl
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PCT/IB2005/000721
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English (en)
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Lester Dennis Mcclure
Thanh Vu Olson
Stephen Wayne Wright
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Pfizer Products Inc.
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Publication of WO2005095339A1 publication Critical patent/WO2005095339A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to selective inhibitors of the enzyme dipeptidyl peptidase-IV (DPP-IV), pharmaceutical compositions thereof, and uses thereof for treating diseases associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X and/or insulin- resistance syndrome), hyperglycemia, Type 1 diabetes, obesity, and the like.
  • DPP-IV dipeptidyl peptidase-IV
  • pharmaceutical compositions thereof and uses thereof for treating diseases associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X and/or insulin- resistance syndrome), hyperglycemia, Type 1 diabetes, obesity, and the like.
  • DPP-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2-position.
  • the physiological roles of DPP-IV have not been fully elucidated, but it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation, among others.
  • DPP-IV has been implicated in the control of glucose homeostasis because its substrates include the incretin peptides glucagon-like peptide 1 (GLP-1 ) and gastric inhibitory polypeptide (GIP).
  • GLP-1 glucagon-like peptide 1
  • GIP gastric inhibitory polypeptide
  • GLP-1 has been shown to be an effective anti-diabetic therapy in Type 2 diabetic patients and to reduce the meal- related insulin requirement in Type 1 diabetic patients.
  • GLP-1 and/or GIP are believed to regulate satiety, lipidemia and osteogenesis.
  • Exogenous GLP-1 has been proposed as a treatment for patients suffering from acute coronary syndrome, angina, and ischemic heart disease.
  • Administration of DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, thereby increasing insulin secretion and improving glucose tolerance.
  • DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired.
  • treatment with DPP-IV inhibitors prevents degradation of Neuropeptide Y (NPY), a peptide associated with a variety of central nervous system disorders, and Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease.
  • NPY Neuropeptide Y
  • Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease, and inflammatory bowel disease.
  • the treatment of diabetes remains less than satisfactory.
  • the use of insulin necessary in Type 1 diabetic patients and about 10% of Type 2 diabetic patients in whom currently available oral hypoglycemic agents are ineffective, requires multiple daily doses, usually by self-injection. Determination of the appropriate dosage of insulin necessitates frequent estimations of the glucose concentration in urine or blood.
  • hypoglycemia causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma, or even death.
  • Treatment of Type 2 diabetes usually comprises a combination of diet, exercise, oral agents, and in more severe cases, insulin.
  • hypoglycemics can have side effects that limit their use.
  • Poorly controlled hyperglycemia is a direct cause of the multiplicity of complications (cataracts, neuropathy, nephropathy, retinopathy, cardiomyopathy) that characterize advanced Type 2 diabetes.
  • Type 2 diabetes is a comorbid disease that frequently confounds hyperlipidemia, atherosclerosis, and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases.
  • Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor for cardiovascular disease ("CVD") due to atherosclerosis.
  • CVD cardiovascular disease
  • Atherosclerosis is recognized to be a leading cause of death in the United States and Western Europe.
  • CVD is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors such as glucose intolerance, left ventricular hypertrophy and hypertension in this population.
  • Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
  • Hypertension is a condition that can occur in many patients in whom the underlying etiology is unknown. Such "essential" hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia and it is known that hypertension is positively associated with heart failure, renal failure, and stroke. Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension, together with insulin resistance and hyperlipidemia, comprise the constellation of symptoms characterizing metabolic syndrome, also known as insulin-resistance syndrome (IRS) and Syndrome X.
  • IRS insulin-resistance syndrome
  • 01 -3670 occurs when a person meets three or more of the following criteria: 1 ) abdominal obesity (waist circumference >102 cm in men and >88 cm in women); 2) hypertriglyceridemia ( ⁇ 150 mg/dl); 3) low HDL cholesterol ( ⁇ 40mg/dl in men and ⁇ 50 mg/dl in women); 4) high blood pressure (>130/85 mmHg); (5) high fasting glucose (>110 mg/dl).
  • Obesity is a well-known and common risk factor for the development of atherosclerosis, hypertension, and diabetes. The incidence of obesity and its related sequelae is increasing worldwide. Currently, few pharmacological agents are available that reduce adiposity effectively and acceptably.
  • Osteoporosis is a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality.
  • Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease. Acute coronary syndrome denotes patients who have or are at high risk of developing an acute myocardial infarction (Ml).
  • the invention provides compounds of formula (I),
  • phenyl(C 0 -C 8 )alkyl is: (a) phenyl(C 0 -C 8 )alkyl; (b) phenoxy(C C 8 )alkyl; or (c) heterocyclyl(C 0 -C 8 )alkyl, wherein said phenyl, said phenoxy, or said heterocyclyl, in the definitions of phenyl(Co-C 8 )alkyl, phenoxy(C C 8 )alkyl, and heterocyclyl(C 0 -C 8 )alkyl respectively, is optionally substituted independently with one to three (CrC 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C ⁇ -C 8 )alkoxy, cyano, halogen, (C C 8 )alkylsulfonyl, (C C 8 )alkylthio, -CO 2 (C C 8 )alkyl, -CO 2 H
  • heterocyclyl(C 0 -C 8 )alkyl optionally substituted independently with one to three hydroxy, cyano, (C C 3 )hydroxyalkyl, or R X-; or
  • R 4 is: (f) (C r C 8 )alkyl, (g) (C 3 -C 8 )cycloalkyl, (h) heterocyclyl, or (i) phenyl(C 0 -C 8 )alkyl, wherein said (d-C 8 )alkyl and (C 3 -C 8 )cycloalkyl are optionally substituted independently with one to three (C ⁇ -C 8 )alkoxy, (C C 8 )(cycloalkyl)oxy, cyano, halogen, (CrC 4 )alkylsulfonyl, (CrC )alkylthio, (C 3 -C 8 )(cycloalkyl)thio, hydroxy, trifluoromethyl, amino, or nitro; and wherein said heterocyclyl and said phenyl are optionally substituted independently with one to three (C C 8 )alkyl, (g) (C 3 -C 8 )cycloalkyl
  • Generally preferred compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs comprise those compounds wherein both nitrile substituents on the pyrrolidine ring are s-oriented with respect thereto as depicted in the formula below. 2005/095339
  • a generally preferred subgroup of the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, comprises those compounds wherein R is:
  • (d) (d-C 12 )alkyl optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C C 3 )hydroxyalkyl, (C C 8 )alkoxy, (d- C 8 )alkylsulfonyl, (C C 8 )alkylthio, phenyl, or phenyl-SO 2 -, wherein said phenyl is optionally substituted independently with one to three (d-C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (CrCs)alkoxy, cyano, halogen, (CrC 8 )alkylsulfonyl, (C C 8 )alkylthio, -CO 2 (C ⁇ -C 8 )alkyl, -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, hydroxy, trifluoromethyl, amino, or nitro; or (e) (C 3
  • 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, Columbus, OH) 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 prefix (C a -C b )alkyl indicates an alkyl moiety of the integer "a" to "b” carbon atoms, inclusive.
  • (d-C 6 )alkyl refers to an alkyl group of one to six carbon atoms inclusive.
  • alkoxy refers to straight or branched, monovalent, saturated aliphatic chains of carbon atoms bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups include methoxy, ethoxy, propoxy, butoxy, /so-butoxy, terf-butoxy, and the like. 2005/095339 10
  • alkyl means straight, or branched, monovalent chains of carbon atoms, wherein the alkyl group optionally incorporates one or more double or triple bonds, or a combination of double and triple bonds.
  • alkyl groups include, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, allyl, 2-methylpropenyl, 2- butenyl, 1 ,3-butadienyl, ethynyl, propargyl, and the like.
  • cycloalkyl denotes a monocyclic or polycylic cycloalkyl group, optionally fused to an aromatic hydrocarbon group, wherein the cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double and triple bonds.
  • cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, decahydronaphthalinyl, indanyl, noradamantyl (hexahydro-2,5-methano-pentalen- 3a-yl), tetrahydronaphthyl, and the like.
  • halogen represents chloro, bromo, fluoro, or iodo.
  • heterocyclyl denotes a saturated, unsaturated, or partially saturated, 5- or 6-membered, or 9- or 10-membered, monocyclic or polycyclic cycloalkyl group, in which from one to five carbon atoms have replaced with nitrogen, oxygen, or sulfur heteroatoms. If the heterocyclyl group contains more than one heteroatom, the heteroatoms may be the same or different.
  • heterocyclyl groups include pyridyl, piperazinyl, pyranyl, pyrrolyl, imidazolyl, indolyl, furanyl, piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, quinuclidinyl, and the like.
  • mamal means animals including, for example, dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans.
  • oxo denotes a carbonyl substituent formed between a carbon atom and an oxygen atom.
  • perfluoroalkyl as used herein, means a saturated monovalent straight or branched aliphatic hydrocarbon radical, in which the valences normally occupied by hydrogen have been entirely replaced by fluorine and wherein the number of carbon atoms may be defined in a parenthetical where the term is used.
  • perfluoroalkyl groups include trifluoromethyl, pentafluoroethylethyl, heptafluoropropyl, nonafluorobutyl, and the like.
  • phrases "pharmaceutically acceptable” indicates that the designated carrier, vehicle, diluent, or excipient(s) is generally chemically and/or physically compatible with the other ingredients comprising the formulation, and physiologically compatible with the patient being treated therewith.
  • pharmaceutically acceptable salt as used herein in relation to compounds of formula (I) preferably includes pharmaceutically acceptable anionic salts.
  • pharmaceutically acceptable anion refers to a negative ion that is compatible chemically and/or toxicologically with the other ingredients of a pharmaceutical composition and the patient being treated therewith.
  • Suitable anions include, but are not limited to chloride, iodide, bromide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, (d-C 12 )alkylsulfonates (e.g., mesylate, ethylsulfonate, etc.), arylsulfonates (e.g., phenylsulfonate, tosylate, etc.), (d-
  • the salts maybe prepared in situ during the isolation or purification step(s), or by separately reacting the compound, prodrug, or stereoisomer with a suitable organic or inorganic counterion and isolating the salt so formed.
  • prodrug means a compound that is transformed in vivo to yield a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • Such compounds include, but are not limited to, N-acyl and N-carboalkoxy derivatives as well as imine derivatives. The transformation may occur via various mechanisms, including hydrolysis in blood. See, for example, T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S.
  • reaction-inert solvent refers to a solvent, or mixture of solvents, that does not adversely interact with starting materials, reagents, intermediates, or products.
  • substituted means that a designated atom or functional group on a molecule has been replaced with a different atom or functional group. The atom or functional group replacing the designated atom is denoted a "substituent.”
  • the terms “treating”, “treated”, or “treatment” as employed herein includes preventative (e.g., prophylactic), palliative, or curative use or result.
  • a cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended.
  • the term "pyridyl” includes 2-, 3-, or 4-pyridyl.
  • Some of the compounds of formula (I) contain at least one stereogenic center; consequently, those skilled in the art will appreciate that all stereoisomers (e.g., enantiomers and diasteroisomers, and racemic mixtures thereof) of the compounds of formula (I) are within the scope of the present invention.
  • the pyrrolidine moiety of the compounds of formula (I) may also contain stereogenic centers, such as, for example, where the configuration between the nitrile groups on the pyrollidine ring in formula (I) is trans. All stereoisomers (e.g., enantiomers and diasteroisomers, and racemic mixtures thereof) of the compounds of formula (I) are within the scope of the present invention.
  • the compounds of formula (I) can exist in crystalline form as hydrates wherein molecules of water are incorporated within the crystal structure thereof and as solvates wherein molecules of a solvent are incorporated therein. All such hydrate and solvate forms are embraced within the scope of the invention.
  • This invention also includes isotopically-labeled compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein 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 0, 17 O, 35 S, 36 CI, 125 I, 129 l, and 18 F respectively.
  • 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. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • the isotopically labeled compounds of formula (I), and the prodrugs and stereoisomers thereof can generally be prepared according to the procedures disclosed in the instant Schemes and/or Examples by substituting isotopically labeled reagents for non-isotopically labeled reagents.
  • the invention is directed to pharmaceutical compositions comprising an amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer, and a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the invention is directed to pharmaceutical compositions comprising amounts of: a) a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug, or stereoisomer; ⁇ b) an antidiabetic agent, a prodrug or pharmaceutically acceptable salt thereof, insulin or an analog thereof, insulinotropin, a biguanide, an ⁇ 2 -antagonist, an imidazoline, a glitazone, an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a fatty acid oxidation inhibitor, an ⁇ -glucosidase inhibitor, a ⁇ -agonist, a phosphodiesterase inhibitor, a lipid-lowering agent, an antiobesity agent, a vanadate, a vanadium complex, a peroxovanadium complex, an amylin antagonist, a glucagon antagonist, a
  • the invention is directed to methods of inhibiting DPP-IV which methods comprise administering to a mammal in need of such inhibition a DPP-IV inhibiting amount of a compound of formula (I), a prodrug or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, prodrug or stereoisomer, either alone or in combination with an antidiabetic agent described above.
  • the invention is directed to methods of treating conditions mediated by DPP-IV inhibition which methods comprise administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), a prodrug or.
  • Conditions treatable according to the instant methods are Type 2 diabetes, progression of disease in Type 2 diabetes, metabolic syndrome (Syndrome X and/or IRS), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, arthritis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, short stature due to bone growth deficiency, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, or
  • the condition is Type 2 diabetes.
  • the compounds of formula (I), the prodrugs and stereoisomers thereof, and the . pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers may be administered to mammals at dosage levels in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 1 mg/kg/day, in single or divided doses. Some variations 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. Preferably, a single dose is administered orally.
  • the compounds of formula (I) 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.
  • 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 (I), or the prodrug or stereoisomer being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated, and/or the severity of the conditions being treated.
  • Administration may be in single (e.g., once daily) or multiple doses or via constant infusion.
  • the compounds may also be administered alone or, preferably, 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.
  • the pharmaceutical 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.
  • compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as sodium citrate, calcium carbonate and/or calcium phosphate
  • disintegrants such as starch, alginic acid and/or certain complex silicates
  • 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.
  • Suitable materials for oral 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 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 of formula (I) 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.
  • a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
  • the compounds of formula (I), the prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers may be prepared according to the exemplary routes disclosed in the Schemes and Examples below, as well as by other conventional preparative procedures known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • the methods disclosed in the instant Schemes and Examples are intended for purposes of exemplifying the instant invention, and are not to be construed in any manner as limitations thereon.
  • BOC tert- butoxycarbonyl
  • Cbz benzyloxycarbonyl
  • THF tetrahydrofuran
  • DMF N,N- dimethylformamide
  • NMP N-methyl-2-pyrrolidinone
  • DMAC N,N- dimethylacetamide
  • DME dimethylacetamide
  • DMSO dimethylsulfoxide
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • DIPEA diisopropylethylamine
  • EDC (1 - (3-dimethylaminopropyl)-3-carbodiimide)
  • DCC dicyclohexylcarbodiimide
  • CDI (1 ,1 '-carbonyldiimidazole
  • HOBT N-hydroxybenzotriazole
  • EEDQ 2-ethoxy- 1 -ethoxycarbonyl-1 ,2-dihydroquinoline
  • an appropriately-substituted amine RNH 2 is coupled with a compound of formula II, wherein Lv is a suitable leaving group, for example, halo, alkylsulfonyloxy, perfluoroalkylsulfonoxy, or phenylsulfonyloxy (wherein phenyl, phenoxy, and heterocyclyl are optionally substituted independently with from one to three (d-C 8 )alkyl).
  • the reaction is effected in a reaction-inert solvent, preferably an aprotic solvent, optionally in the presence of a base.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, DMF, THF, 1 ,4-dioxane, or chloroform.
  • Suitable bases include, for example, DIPEA, TEA, 2,6-lutidine, sodium carbonate, or potassium carbonate.
  • the coupling is generally conducted at ambient pressure and temperature.
  • the amine starting material may be prepared by known procedures, by techniques that are analogous to the synthesis of known compounds, or by the procedures described in the examples hereinbelow.
  • the compounds of formula II may be prepared by known methods or according to the methods described in Schemes II, III, and IV hereinbelow.
  • the compounds of formula II, wherein Lv is bromo are prepared by treating dinitrile III, prepared as disclosed in Scheme V below, with a reactive bromoacetyl compound, for example bromoacetyl bromide or bromoacetyl chloride, in a reaction-inert solvent.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, or chloroform, preferably acetonitrile.
  • the reaction is generally conducted at ambient pressure and temperature.
  • the compounds of Formula II wherein Lv is halo, alkylsulfonyloxy, perfluoroalkylsulfonoxy, or phenylsulfonyloxy (wherein phenyl, phenoxy, and heterocyclyl are optionally substituted independently with from one to three (C ⁇ -C 8 )alkyl), may be prepared by first coupling diamide IV with an acid of the formula LvCH 2 CO 2 H, or an acid chloride of the formula LvCH 2 COCI, to afford V. Compound V is then treated with a dehydrating agent to furnish II.
  • Step 1 diamide IV, prepared as disclosed in Scheme VI below, and a carboxylic acid of the formula LvCH 2 CO 2 H are coupled in a reaction- inert solvent, at ambient temperature, in the presence of a coupling agent and an optional adjuvant.
  • Coupling agents include EDC, DCC, EEDQ, GDI, or diethylphosphorylcyanide.
  • Optional adjuvants include HOBT or N- hydroxysuccinimide.
  • EDC or DCC is the coupling agent and HOBT is the adjuvant.
  • Suitable solvents include, for example, DMF, DMAC, NMP, or water, preferably water admixed with DMF.
  • diamide IV and an acid chloride LvCH 2 COCI may be reacted in a reaction-inert solvent in the presence of an organic base, such as 2,6-lutidine, 2,4,6-collidine, N-methylimidazole, N-methylmorpholine, TEA, or DIPEA.
  • organic base such as 2,6-lutidine, 2,4,6-collidine, N-methylimidazole, N-methylmorpholine, TEA, or DIPEA.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, pyridine, and chloroform.
  • pyridine is employed as both the solvent and base.
  • the starting materials LvCH 2 CO 2 H and LvCH COCI may be prepared by known methods or obtained commercially. Methods of coupling carboxylic acids are well-known in the art. See, for example, Houben-Weyl, Vol XV, Part II, E.
  • Step 2 compound V is reacted with a dehydrating agent in a reaction-inert solvent, optionally in the presence of a base, to afford II.
  • dehydrating agents useful in Step 2 include TFAA, phosphorus oxychloride, p-toluenesulfonyl chloride, cyanuric chloride, DCC, or ethylene chlorophosphite.
  • Bases include pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, N-methylimidazole, N- methylmorpholine, TEA, or DIPEA.
  • TFAA or phosphorus oxychloride is used as the dehydrating agent and pyridine or imidazole is the base.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, chloroform, THF, or pyridine.
  • pyridine admixed with dichloromethane is used as the solvent.
  • Step 2 is generally conducted at a temperature of between about -20 °C and about 25 °C.
  • dinitrile II may be prepared as disclosed in Scheme IV below by reacting protected dinitrile VI with a reactive chloroacetyl, bromoacetyl, or iodoacetyl compound.
  • the reaction is effected by reacting dinitrile VI, prepared as disclosed in Scheme VII below, wherein Lv is chloro, bromo, or iodo, and Prot is a suitable nitrogen-protecting group, and a reactive chloroacetyl, bromoacetyl, or iodoacetyl compound, preferably chloroacetyl chloride or bromoacetyl bromide, in a reaction- inert solvent.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, and chloroform, preferably acetonitrile.
  • Suitable nitrogen-protecting groups may include for example, but are not limited to, Boc and Cbz.
  • the reaction is generally conducted at ambient temperature. Dinitrile III, useful in preparing intermediates of formula II in Scheme II hereinabove, may be prepared as disclosed in Scheme V.
  • dinitrile III is prepared by reacting aminodiphenylmethane with a mixture of potassium cyanide and 2,5-dimethoxytetrahydrofuran in an aqueous solution of citric acid in a manner analogous to that described by Mclntosh, J. Org. Chem., 1988, 447 or Takahishi, et. al., Heterocycles, 1986, 2905. The reaction is generally conducted at ambient temperature. Diamide IV of Scheme III may be prepared as disclosed hereinbelow in Scheme VI.
  • Step 1 is typically effected in a reaction-inert solvent, for example, benzene, toluene, or xylene at ambient temperature. Toluene is generally preferred.
  • the catalytic hydrogenolysis of Step 2 is typically conducted in a reaction- inert solvent, for example, methanol, ethanol, and water, preferably methanol, in the presence of 10% palladium on carbon (Pd/C) or palladium hydroxide.
  • a reaction- inert solvent for example, methanol, ethanol, and water, preferably methanol
  • the mixture is hydrogenated at a suitable hydrogen pressure, such as between about 30 psi and about 60 psi, preferably about 45 psi, for a period of time sufficient to bring the reaction to completion, usually overnight.
  • a suitable hydrogen pressure such as between about 30 psi and about 60 psi, preferably about 45 psi, for a period of time sufficient to bring the reaction to completion, usually overnight.
  • Deprotected diester VIII is then treated with excess ammonia in Step 3 in a reaction-inert solvent.
  • Suitable solvents include, for example, methanol, ethanol, or water, preferably methanol.
  • the mixture is generally kept at ambient temperature and at between ambient pressure and about 30 psi.
  • Protected dinitrile VI of Scheme IV may be prepared as disclosed hereinbelow in Scheme VII.
  • Step 1 is generally conducted at ambient temperature.
  • Step 2 is effected by treating protected diamide IX with a dehydrating agent, and an optional base, in a reaction-inert solvent to provide protected dinitrile VI.
  • Typical dehydrating agents include TFAA, phosphorus oxychloride, p- toluenesulfonyl chloride, cyanuric chloride, DCC, or ethylene chlorophosphite.
  • Optional bases include pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, N- methylimidazole, N-methylmorpholine, TEA, or DIPEA.
  • TFAA or phosphorus oxychloride is used as the dehydrating agent and pyridine or imidazole is used as the optional base.
  • Suitable solvents include, for example, acetonitrile, dichloromethane, chloroform, THF, or pyridine, preferably pyridine admixed with dichloromethane. Step 2 is generally conducted at a temperature of between about -20 °C and about 25 °C.
  • BIOLOGICAL PROTOCOLS The utility of the compounds of formula I, the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, in the treatment or prevention of the conditions enumerated hereinabove in mammals may be demonstrated in conventional assays known to one of ordinary skill in the relevant art, including the in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula (I) can be compared with the activities of other known compounds.
  • DPP-IV inhibition may be demonstrated in vitro by the following assay, which is adapted from methods of Scharpe, et al., A. Clin. Chem., 1988, 2299 and Lodja, Z Czechoslovak Medicine, 1988, 181 .
  • 150 ⁇ L of an enzyme-substrate solution is pipetted into microtiter wells of a polystyrene 96-well plate, and maintained at 4°C.
  • the enzyme-substrate solution comprises 50 ⁇ M Gly-Pro-4-methoxy- ⁇ - naphthylamide hydrochloride in 50mM Tris assay buffer pH 7.3 containing 0.1 M sodium chloride, 0.1 % (v/v) Triton and 50 ⁇ U/mL DPP-IV (MP Biomedicals, Livermore, CA; DPP-IV 5 mU/mL stock). 5 ⁇ L per well of compounds of Formula I are added, bringing the final compound of Formula I concentrations to 3 ⁇ M - 10 nM per well. Controls. Enzyme is omitted from four (4) wells, as a reagent blank.
  • the reaction is quenched by adding 10 ⁇ L of Fast Blue B solution (0.5 mg/mL Fast Blue B in a buffer comprising 0.1 M sodium acetate pH 4.2 and 10% (v/v) Triton X-100 to each well, followed by shaking for approximately 5 minutes at room temperature.
  • the plates may be analyzed on a Spectramax spectrophotometer (Molecular Devices; Sunnyvale, CA), or equivalent equipment, (absorption maximum at 525 nm).
  • IC 50 data for compounds may be obtained by measuring the activity of DPP-IV over a range of compound concentrations from 10nM to 3 ⁇ M.
  • KK/H1J mice Jackson Labs; Bar Harbor, ME
  • Oral glucose tolerance tests OGTT
  • KK mice have been used to evaluate (i) glitazones (Fujita et al.
  • KK mice are derived from an inbred line first established and described by
  • 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, however, they do not require insulin or other medication for survival.
  • mice (10 per group) are then orally dosed with a solution of a compound of formula I in 0.5% methylcellulose (0.2 mL/mouse).
  • Two controls groups receive only 0.5% methylcellulose.
  • the mice are bled, as described above, and then dosed with 1 mg/kg glucose in distilled water (0.2 mlJmouse).
  • the first control group is dosed with glucose.
  • the second control group is dosed with water.
  • mice 45 minutes, the mice are again bled, as described above.
  • the blood samples are centrifuged, the plasma collected and analyzed for glucose content on a Roche- Hitachi 912 glucose analyzer (Roche Diagnostics Corp.; Indianpolis, IN).
  • the data may be expressed as percent (%) inhibition of glucose excursion relative to the two control groups (i.e., the glucose level in the animals receiving glucose but no test compound representing 0% inhibition and the glucose concentration in the animals receiving only water representing 100% inhibition).
  • GENERAL EXPERIMENTAL PROCEDURES Melting points were determined on a capillary melting point apparatus by Thomas Scientific (Swedesboro, NJ), and are uncorrected. Flash chromatography was performed according to the method described by Still et al., J. Org. Chem., 1978, 2923. Hydrogenations were performed in a Parr (Parr Instrument Co.; Moline, IL) 3911 shaker type hydrogenation apparatus (hereafter referred to as a Parr hydrogenator) at the pressures indicated. Proton NMR chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on a Varian Unity 400 MHz spectrometer (Varian Inc.; Palo Alto, CA).
  • H e.g., 1 H, 2 H
  • M molar mg(s) - milligram(s) min(s) - minute(s) mL - milliliter(s) mmol - milimole(s) mp - melting point
  • MS mass spectrum
  • NMR nuclear magnetic resonance pH - negative logarithm of hydronium ion concentration psi - pounds per square inch q - quartet peak s - singlet peak t - triplet peak
  • Step 2 A solution of 164 g (480 mmol) of the product of Step 1 in 250 mL of dichloromethane was stirred vigorously with 250 mL of 5 M ammonium hydroxide for 15 mins at 20 °C. The dichloromethane solution was separated, washed with brine, dried over sodium sulfate, and concentrated to give a colorless oil. The oil was dissolved in 500 mL of methanol, 4.8 g of 10% Pd/C was added, and the mixture was shaken under 50 psi of hydrogen at 20 °C for about 18 hrs.
  • Step 2 A solution of 6.70 g (26 mmol) of the product of Step 1 was dissolved in 65 mL of pyridine. The solution was diluted with 260 mL of dichloromethane and imidazole (7.08 g, 104 mmol) was added. The solution was cooled to 0 °C and 19 mL (208 mmol) of phosphorus oxychloride was added dropwise.
  • Preparation 6 1 -Bromoacetyl-pyrrolidine-2,5-fra ⁇ s-dicarbonitrile
  • Preparation 7 1 -Chloroacetyl-pyrrolidine-2,5-cis-dicarbonitrile
  • a solution of 0.66 g (3 mmol) of the title compound of Preparation 3 was dissolved in 12 mL of acetonitrile.
  • To this solution was added 0.34 g (3 mmol) of chloroacetyl chloride with stirring at 20 °C.
  • the mixture was stirred at 20 °C for about 3 hrs, after which the solvent was removed by evaporation.
  • the residue was dissolved in dichloromethane and the dichloromethane was washed with sodium bicarbonate solution and dried over anhydrous sodium sulfate.
  • Preparation 8 1 -Methyl-cyclopentylamine hydrochloride A solution of 2.00 g (20 mmol) of 1 -methylcyclopentanol in 25 mL of benzene was treated with 3.18 mL (24 mmol) of azidotrimethylsilane and 3.04 mL (24 mmol) of boron trifluoride etherate as described by Zwierzak, et al., Tetrahedron Letters, 1987, 6513. After about 24 hrs, the solution was poured into 50 mL of 1 M sodium bicarbonate solution and stirred for 30 minutes, adding solid sodium bicarbonate as needed to maintain pH > 7. The benzene layer was separated and dried over anhydrous calcium chloride.
  • Step 2 A suspension of 1.40 g (3.8 mmol) of the product of Step 1 in 30 mL of dichloromethane was treated with 15 mL of TFA with cooling in ice. After 15 mins, the reaction mixture was concentrated to dryness. The residue was treated with 40 mL of dichloromethane and 8 mL of 2 M sodium hydroxide solution. The mixture was stirred for 5 minutes and separated. The dichloromethane was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford
  • Example 8 1 -[(1 -hydroxymethyl- cyclopentylamino)-acetyl]-pyrrolidine-2,5-c/s-dicarbonitrile, was prepared from 20 g (173 mol) of 1 -hydroxymethyl-cyclohexylamine (Aldrich Chemical Co.; Milwaukee, Wl) and 14 g (57 mmol) of 1 -bromoacetyl-pyrrolidine-2,5-cis-dicarbonitrile to afford 11.4 g of a white solid.

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Abstract

L'invention concerne des composés représentés par la formule (I), les promédicaments et les stéréoisomères de ceux-ci, et les sels acceptables d'un point de vue pharmaceutique des composés, des promédicaments, et des stéréoisomères, R étant tel que défini dans la description. L'invention concerne également des compositions pharmaceutiques, des combinaisons et des utilisations desdits composés dans le traitement des complications diabétiques, y compris la neuropathie diabétique, la néphropathie diabétique, la microangiopathie diabétique, et autres.
PCT/IB2005/000721 2004-03-31 2005-03-18 Dicyanopyrrolidines inhibiteurs de la dipeptidyl peptidase iv WO2005095339A1 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
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WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
JP2009532454A (ja) * 2006-04-03 2009-09-10 マトリックス ラボラトリーズ リミテッド 新規ジペプチジルペプチダーゼｉｖ阻害因子およびその調製方法、ならび該阻害因子を含む医薬組成物
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2010079413A2 (fr) 2009-01-09 2010-07-15 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
WO2010115836A1 (fr) 2009-04-08 2010-10-14 Boehringer Ingelheim International Gmbh Pipéridines substituées comme antagonistes de ccr3
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
CN104262226A (zh) * 2011-04-19 2015-01-07 中国科学院化学研究所 手性伪核苷类化合物及其制备方法与应用
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2018162722A1 (fr) * 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Inhibiteurs de dpp-4 à utiliser dans le traitement de fractures osseuses
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
JP2009532454A (ja) * 2006-04-03 2009-09-10 マトリックス ラボラトリーズ リミテッド 新規ジペプチジルペプチダーゼｉｖ阻害因子およびその調製方法、ならび該阻害因子を含む医薬組成物
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2010079413A2 (fr) 2009-01-09 2010-07-15 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
WO2010079413A3 (fr) * 2009-01-09 2010-12-02 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
US8466145B2 (en) 2009-01-09 2013-06-18 Orchid Chemicals & Pharmaceuticals Limited Dipeptidyl peptidase IV inhibitors
AU2010204144B2 (en) * 2009-01-09 2012-02-16 Orchid Research Laboratories Ltd. Dipeptidyl peptidase IV inhibitors
WO2010115836A1 (fr) 2009-04-08 2010-10-14 Boehringer Ingelheim International Gmbh Pipéridines substituées comme antagonistes de ccr3
US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
CN104262226A (zh) * 2011-04-19 2015-01-07 中国科学院化学研究所 手性伪核苷类化合物及其制备方法与应用
CN104262226B (zh) * 2011-04-19 2016-08-17 中国科学院化学研究所 手性伪核苷类化合物及其制备方法与应用
WO2018162722A1 (fr) * 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Inhibiteurs de dpp-4 à utiliser dans le traitement de fractures osseuses
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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