WO2003095425A1 - Derives de cyanopyrrolidine - Google Patents

Derives de cyanopyrrolidine Download PDF

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Publication number
WO2003095425A1
WO2003095425A1 PCT/JP2003/005813 JP0305813W WO03095425A1 WO 2003095425 A1 WO2003095425 A1 WO 2003095425A1 JP 0305813 W JP0305813 W JP 0305813W WO 03095425 A1 WO03095425 A1 WO 03095425A1
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group
carbon atoms
substituted
atom
hydrogen atom
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PCT/JP2003/005813
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English (en)
Japanese (ja)
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Hiroshi Fukushima
Akira Hiratate
Masato Takahashi
Kazuya Kameo
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Taisho Pharmaceutical Co.,Ltd.
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Priority to AU2003235913A priority Critical patent/AU2003235913A1/en
Priority to JP2004508532A priority patent/JPWO2003095425A1/ja
Publication of WO2003095425A1 publication Critical patent/WO2003095425A1/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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

Definitions

  • the present invention relates to a novel Mi derivative (Background Art
  • DPP IV Dipidyl peptidase IV
  • DPP IV is a type of serine protease that hydrolyzes dipeptides from peptide chains having proline or alanine at the second position from the N-terminus.
  • DPP IV is widely distributed in tissues such as kidney and liver and plasma, and is involved in the metabolism of various bioactive peptides.
  • DPP IV is involved in the metabolism of glucagon-like peptide 11 (GLP-1).
  • DPPIV inactivates GLP-1 by hydrolyzing the dipeptide at the N-terminal His-Ala of GLP-1, and the inactivated form acts as an antagonist of the GLP-1 receptor. I have.
  • GLP-1 has physiological actions of promoting secretion of insulin from the kidney, prolonging the gastric emptying time, and suppressing feeding. Therefore, inhibition of DPPIV can enhance the action of GLP-1, enhance insulin action and improve glucose metabolism, and is expected to be useful for the treatment of type 2 diabetes.
  • DPP IV is involved in the metabolism of neuropeptide Y, a neuropeptide, activation of T cells, which are immunocompetent cells, adhesion of cancer cells to endothelium, and entry of HIV virus into lymphocytes.
  • T cells which are immunocompetent cells
  • adhesion of cancer cells to endothelium and entry of HIV virus into lymphocytes.
  • An object of the present invention is to provide a novel cyanopia lysine derivative exhibiting excellent DPPIV inhibitory activity in a living body and having physical properties required for a drug such as stability.
  • the present invention provides a compound of formula (1)
  • W is an acyl group derived from a natural amino acid
  • W 1 represents an alkanoyl group having 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group having 1 to 5 carbon atoms
  • W 2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • W 3 and W 4 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • X represents an oxygen atom or a sulfur atom
  • Y is the formula — CR 5 R 6 — [wherein R 5 and R 6 are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a zK acid group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group.
  • R 14 represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms.
  • the carbon number 1 which may be substituted with one or more groups selected from the group consisting of To 10 alkyl groups; or may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a propyloxyl group, an amino group, an aminocarbonyl group and a linear alkoxy group having 1 to 5 carbon atoms. It represents an alkenyl group having 2 to 10 carbon atoms.
  • R 7 , R 8 , R 9 and R 1 ° are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, C1-C5 hydroxyalkyl group, carboxyl group, mercapto group, C1-C5 alkylthio group , Guanidyl group, phenyl group which may be substituted, imidazolyl group, indolyl group
  • R 11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarpenyl group or a benzyloxycarponyl group
  • R 12 represents a hydrogen atom or — (CH 2 ) m -R 13 (where m represents an integer of 1 to 5, R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxy And a carboxyl group.
  • R 14 represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms
  • R 14 represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms
  • a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of an alkyl group and a linear alkoxy group having 1 to 5 carbon atoms
  • Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, and imidazolyl.
  • R 12 is a hydrogen atom or one (CH 2 ) -R 13 (formula In the formula, m represents an integer of 1 to 5, and R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group. .).
  • R 14 represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms. Represents an alkyl group of 1 to 10 or
  • Y and Z are joined together with an adjacent nitrogen atom to form a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and one OR 15 (wherein, R 15 is a group having 1 to 5 carbon atoms) And 5 represents a chain alkyl group, an aminocarbonylmethyl group or a benzyl group.5) which forms a cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: ]
  • the compound which is a cyanopyrrolidine derivative represented by these, or its pharmacologically acceptable salt is provided.
  • a compound according to the present invention wherein in formula (1), Y is —CH 2 —, and Z is selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms.
  • a cyanopyrrolidine derivative which is a branched or cyclic alkyl group having 4 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof, which may be substituted.
  • the present invention provides a compound of the formula (1) wherein Y is —CH 2 — and Z is a tert-butyl group, a (1-hydroxymethyl) cyclopentyl group or a (2-hydroxy_1
  • a cyanopyrrolidine derivative represented by the formula (1), wherein Y is -CR 5 R 6 — wherein R 5 is hydrogen and Z is a hydrogen atom. Or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of the formula (1), wherein Y is one CR 5 R 6 — (wherein R 5 is hydrogen and R 6 is a branched or branched C 3-6 carbon atom. A cyclic alkyl group), wherein Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of the formula (1) wherein Y is —CH [CH (CH 3 ) 2 ] —, CH (C (CH 3 ) 3 ] — or —CH [GH (CH 3 ) A compound which is CH 2 CH 3 ] — and is a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein Z is a hydrogen atom.
  • a medicament comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the aforementioned medicament for preventing or treating a disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV.
  • the medicament wherein the disease or condition that can be ameliorated by inhibiting the dipeptidyl peptidase IV is diabetes.
  • the medicament wherein the disease or condition ameliorated by inhibiting the dipeptidyl peptidase IV is an immune disease.
  • chain means a linear or branched chain.
  • Asyl groups derived from natural amino acids include, for example, alanine, arginine, asparagine, aspartic acid, cystine, glutamine, glutamic acid, glycine (i.e., aminoacetyl group), histidine, isoleucine, leucine, lysine, methionine, fenylalanine, Examples include acyl groups derived from proline, serine, threonine, tyrosine, valine and the like.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the alkoxy group having 1 to 5 carbon atoms means a linear, branched or cyclic alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, Butoxy, isobutoxy, tert-butoxy, cyclopropylmethoxy, pentyloxy, isopentyloxy and the like.
  • the alkanoyl group having 1 to 5 carbon atoms means a linear or branched alkanoyl group, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group. And so on.
  • the arylcarbonyl group which may be substituted means a substituted or unsubstituted arylcarbonyl group, for example, a benzyl group, an 11-naphthoyl group, a 2-naphthoyl group and the like.
  • an o-toluyl group can be mentioned.
  • the alkyl group having 1 to 5 carbon atoms means a linear, branched or cyclic alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group.
  • the alkyl group having 1 to 10 carbon atoms which may be substituted means a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, for example, a methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, noel, decyl, carbon number 3-10 cycloalkyl groups (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclobutylmethyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.), cycloalkenyl group having 4-8 carbon atoms (For example, cyclobutenyl group, cyclopentenyl group,
  • the substituted phenyl group of the phenyl group which may be substituted is, for example, substituted with one or more groups selected from the group consisting of a hydroxyl group and a linear or branched alkoxy group having 1 to 5 carbon atoms. Phenyl groups (eg, 4-hydroxyphenyl group, 3,4-dimethoxyphenyl group, etc.).
  • the substituted pyridyl group of a pyridyl group which may be substituted is, for example, selected from the group consisting of a cyano group, a nitro group, a halogen atom, and an aminocaprol group.
  • Pyridyl groups substituted with one or more of the following groups for example, 5-cyanopyridine-12-yl group, 5-ditropyridine-12-yl group, 5-cyclopentylpyridine-2-yl group, Minocarbonylpyridine-2-yl group).
  • Hydroxyalkyl groups having 1 to 5 carbon atoms include hydroxymethyl group, 1-hydroxyl group, 2-hydroxyethyl group, 1-hydroxypropyl group and 2-hydrido Roxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxy-1-methylethyl, 4-hydroxybutyl, 5-hydroxypentyl and the like.
  • alkylthio group having 1 to 5 carbon atoms examples include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group, and a pentylthio group.
  • the optionally substituted alkenyl group having 2 to 10 carbon atoms means a substituted or unsubstituted linear, branched or cyclic alkenyl group having 2 to 10 carbon atoms, for example, a vinyl group or an aryl group.
  • Alkenyl groups such as a benzyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a cyclopentenyl group, and a cyclohexenyl group.
  • Alkenyl groups can be mentioned.
  • the optionally substituted cycloalkyl group having 3 to 8 carbon atoms means a substituted or unsubstituted cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group.
  • cycloalkyl groups such as butyl group and cyclooctyl group
  • hydrogen atoms of these cycloalkyl groups can be replaced with halogen atoms, hydroxyl groups, hydroxyl groups, amino groups, aminocarbonyl groups, linear or branched carbon atoms. Examples thereof include a cycloalkyl group substituted with one or more groups selected from the group consisting of an alkyl group having 1 to 5 prime numbers and a linear or branched alkoxy group having 1 to 5 carbon atoms.
  • a cycloalkenyl group having up to 8 means a substituted or unsubstituted cycloalkenyl group, for example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group, etc.
  • cycloalkenyl groups are replaced by halogen atoms, hydroxyl groups, propyloxyl groups, amino groups, aminocarbonyl groups, linear or branched alkyl groups having 1 to 5 carbon atoms and Linear or branched C1-C5 alkoxy group
  • the optionally substituted bicycloalkyl group having 5 to 10 carbon atoms means a substituted or unsubstituted bicycloalkyl group, for example, a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group,
  • bicycloalkyl groups such as a bicyclononyl group and a bicyclodecyl group
  • hydrogen atoms of these bicycloalkyl groups are replaced with halogen atoms, hydroxyl groups, carbonyl groups, amino groups, aminoamino groups, linear or branched carbon atoms of 1 to 1.
  • Examples thereof include a bicycloalkyl group substituted with one or more groups selected from the group consisting of an alkyl group of 5 and a linear or branched alkoxy group having 1 to 5 carbon atoms.
  • the optionally substituted bicycloalkenyl group having 5 to 10 carbon atoms means a substituted or unsubstituted bicycloalkenyl group, for example, a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclo
  • bicycloalkenyl groups such as octenyl group, bicyclononel group and bicyclodecel group
  • hydrogen atoms of these bicycloalkenyl groups are replaced with halogen atoms, hydroxyl groups, carbonyl groups, amino groups, aminoamino groups, linear or branched chains.
  • the optionally substituted cyclic amino group having 2 to 10 carbon atoms refers to a substituted or unsubstituted amino group having one or more nitrogen atoms in the ring and optionally having one or more oxygen atoms and sulfur atoms.
  • a hydrogen atom of a cyclic amino group in which a benzene ring or a pyridine ring is condensed to these cyclic amino groups or a hydrogen atom of a cyclic amino group (including a benzene ring or a pyridine ring condensed with a cyclic amino group) is a halogen atom, a hydroxyl group, an amino group, or the like.
  • salts include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, and trifluoroacetic acid. And salts with organic acids such as methanesulfonic acid. The preferred embodiment of the compound of the present invention is shown.
  • Z represents a hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, a phenyl group which may be substituted and NH R 1 1 may be substituted with (wherein R 1 1 is a pyridyl group which may be substituted) of the group consisting of one or more, preferably an alkyl group having a carbon number of 1 to 1 0.
  • Z is preferably substituted with one or more of a group consisting of a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms and an alkoxyl group having 1 to 5 carbon atoms.
  • a branched or cyclic alkyl group more preferably a substituted or unsubstituted alkyl group having 4 to 10 carbon atoms, which may be substituted with at least one of a group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms.
  • Y is a group represented by the formula —CR 5 R 6 — (wherein R 5 is hydrogen and R 6 may be substituted with an alkyl group having 1 to 10 carbon atoms or a group represented by the formula CR 7 R s _ CR 9 R 1 ° — (where R 8 and R 1 Q are hydrogen, and R 7 and R 9 are taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms)
  • Z is preferably H or CH 3 .
  • Y is a group represented by the formula _CR 5 R 6 — ⁇ wherein R 5 is hydrogen, R 6 is a hydroxyl group and one OR 14 (where R "is a linear group having 1 to 5 carbon atoms) Or a branched or branched alkyl group or a benzyl group), which is a branched or cyclic alkyl group having 3 to 6 carbon atoms which may be substituted with one or more selected from the group consisting of Z is a hydrogen atom, more preferably Y is CR 5 R 6 — wherein R 5 is hydrogen , R 6 is a branched or cyclic alkyl group having 3 to 6 carbon atoms), Z is a hydrogen atom, and still more preferably, Y is one CH [CH (CH 3 ) 2 ] _, When it is one CH [C (CH 3 ) 3] — or one CH [CH (CH 3 ) CH 2 CH 3 ] —, Z is a hydrogen atom
  • Y and Z together with an adjacent nitrogen atom form a cyclic amino group having 2 to 10 carbon atoms which may be substituted include a pyrrolidyl group and a piperidyl group A group or a cyclic amino group in which a benzene ring is condensed to these groups, and preferred substituents include a hydroxyl group and one OR 15 (wherein R 15 is as defined above).
  • the basicity of the nitrogen atom is attenuated by the presence of W, and the instability of the compound derived from the basicity of the nitrogen atom is improved.
  • W greatly reduces the dipeptidyl peptidase IV inhibitory activity of the compound of the present invention
  • the W portion is eliminated by an enzyme or the like in vivo, and the dipeptidyl peptidase IV activity is reduced. Strongly inhibits. That is, using a general expression, the compound of the present invention belongs to the category of a prodrug.
  • the introduction of W has effects such as improvement of oral absorbability and continuation of drug activity, and enables reduction of the dose and the number of times of administration.
  • the compound of the present invention can suppress dipeptidyl peptidase IV in a living body, thereby enhancing insulin action and improving glucose metabolism. It can contribute to suppressing cell activation, suppressing adhesion of cancer cells to endothelium, and preventing HIV virus from entering lymphocytes.
  • the present invention relates to a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV, for example, diabetes (particularly type 2), immune disease, arthritis, obesity, osteoporosis, glucose tolerance damage.
  • diabetes particularly type 2
  • immune disease arthritis
  • obesity obesity
  • osteoporosis glucose tolerance damage.
  • the present invention provides the above-mentioned medicament for preventing or treating conditions, benign prostatic hypertrophy, skin diseases and the like.
  • Immunosuppressive agents in tissue transplantation; for example, cytokine inhibitory inhibitors in various autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis (RA); Drugs useful in the prevention and treatment of AIDS by preventing HIV from entering cells, preventing metastasis, especially preventing breast and prostate tumors from metastasizing to the lungs Drugs and the like.
  • the medicament of the present invention can be administered systemically or locally orally or rectally, subcutaneously, intramuscularly, intravenously, transdermally, or the like.
  • the compound of the present invention in any form of a solid composition, a liquid composition, and other compositions, and an optimum one is selected as necessary.
  • the medicament of the present invention can be produced by compounding a pharmaceutically acceptable carrier with the compound of the present invention. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, or aqueous or non-aqueous solvents, etc. are added, and by conventional formulation techniques, They can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like.
  • Excipients and bulking agents include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa batata, ethylene glycol, and others. You can give something.
  • the compound of the present invention can be formulated by forming an inclusion compound with j3, arcyclodextrin, methylated cyclodextrin and the like.
  • the dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, administration route and the like, but is preferably about 1 to about 100 mg / person / day for oral administration to an adult. More preferably, the dose is about 10 to about 200 mg / day, which can be administered once or several times a day.
  • the compound of the formula (1) can be produced by the following general production method.
  • A represents a leaving group such as a halogen atom.
  • This method is a method of introducing an oxypropyl group into an amino group, and further converting A, which is a leaving group, to W 1 .
  • an oxycarbonyl group can be introduced using 1-chloroalkyl formate in the presence of a suitable base.
  • a suitable base include amines such as triethylamine and disopropylethylamine, and inorganic bases such as carbonated lime.
  • the reaction solvent include dichloromethane, chloroform, 1,2-dichloromethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like. The reaction can be performed at -50 to 50 ° C.
  • An example of converting A, which is a leaving group, to W 1 is a method of introducing an acyloxy group using a carboxylic acid sodium salt when A is a chlorine atom.
  • sodium iodide, potassium iodide, or the like that promotes the reaction can be used.
  • the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be performed at -50 to 50 ° C. Anti
  • This method is to introduce an oxypropyl group into an amino group.
  • a 1-acyloxyalkoxycarbonyl group can be introduced.
  • an appropriate base can be used.
  • the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
  • the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, dioxane, ruene, and ethyl acetate. The reaction can be carried out at a temperature of 50-50 ° C. Reaction formula 3
  • W 5 represents an acyl group derived from a natural amino acid and having an amino group protected, and W 5 represents an acyl group derived from a natural amino acid. Represents a group.
  • an acyl group derived from a natural amino acid and having an amino group protected is introduced and further deprotected.
  • the amidation reaction can be carried out using an acyl halide such as acyl chloride or bromide in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be performed using a base.
  • Examples of the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and lithium 2-ethylhexanoate.
  • Inorganic bases such as organic acid salts and potassium carbonate; These reactions can be performed at 150-100 ° C.
  • the reaction can be carried out using an active ester such as 1-benzotriazolyl ester / succinimidyl ester.
  • active ester such as 1-benzotriazolyl ester / succinimidyl ester.
  • the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be performed at -50 to 50 ° C.
  • amidation can be performed using a carboxylic acid and a dehydrating condensing agent.
  • the dehydration condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, and phenyldiimidazole.
  • Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used accordingly.
  • reaction solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be carried out using a base.
  • the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
  • the reaction can be carried out at a temperature of 150 to 50 ° C. Further, for example, amidation can be carried out using a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate.
  • the solvent for these reactions is examples of solvents that do not participate in the reaction include furan, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate.
  • the reaction can be carried out using a base.
  • the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as carbon dioxide lime.
  • the organic solvent examples include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloromethane, and the like.
  • the protecting group is benzyloxy
  • a hydrogenolysis reaction such as a carbonyl group
  • a metal catalyst such as palladium.
  • a solvent that does not participate in the reaction such as ethanol, methanol, tetrahydrofuran, and ethyl acetate can be used.
  • the reaction can be performed at O-100 ° C.
  • hydrogen gas can be used for this reaction, or the reaction can be performed using a combination of reagents such as ammonium formate and formate.
  • a base such as getylamine, piperidine, ammonia, sodium hydroxide, potassium carbonate or the like is used. Can be deprotected. These bases can be used alone or diluted, dissolved or suspended in a solvent. At this time, water, ethanol, methanol, tetrahydrofuran, N, N —Dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like can be used. The reaction can be performed at O-100 ° C.
  • a compound in which the protecting group is a group that can be deprotected by a metal catalyst such as an aryloxy group
  • a metal catalyst such as an aryloxy group
  • tetrakis (triphenylphosphine) palladium as a catalyst or a reagent.
  • the reaction can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, tetrahydrofuran, and the like.
  • the reaction can be performed at 0-1 oo ° c.
  • W 3 —C ⁇ —CH2C (W 4 ) — (where W 3 and W 4 are each a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) is introduced into an amino group.
  • it can be synthesized by a dehydration-condensation reaction of a / 3-diketone such as acetylacetone with an amine compound.
  • the reaction can be performed using a base or an acid.
  • the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
  • Examples of the acid include hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
  • Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at 0 to 50 ° C. Reaction formula 5
  • Ra represents a cyano group, an aminocarboyl group or an alkoxyl group
  • Rb represents a protecting group for an amino group
  • R 1 represents a fluorine atom or a hydroxyl group.
  • Rc represents a leaving group such as a halogen atom or a sulfonyloxy group, or a group that can be converted to a leaving group.
  • Rc is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, are ethylamine, isopropylamine, tert-butylamine, benzylamine, substituted benzylamine,
  • the substitution reaction can be performed using primary amines (Z-NH 2 ) such as phenethylamine, substituted phenethylamine, and 2- (substituted pyridylamino) ethylamine.
  • these amines may be used in excess or a base may be separately added.
  • the base to be added include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. Also, in some cases, Sodium iodide or the like can be added to proceed.
  • the reaction solvent such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
  • Sodium iodide or the like can be added to proceed.
  • reaction can be performed at 0-100 ° C.
  • Examples of a group that can convert R c to a leaving group include a hydroxyl group.
  • a group that can convert R c to a leaving group include a hydroxyl group.
  • the chlorination reaction include a method using carbon tetrachloride and triphenylphosphine, a method using phosphorous chloride, or a method using tosyl chloride or the like as a leaving group, followed by replacement with lithium salt or the like. can give.
  • a solvent that does not participate in the reaction such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or the like can be used.
  • These reactions can be performed at —50-100 ° C.
  • An example of the bromination reaction is a method using carbon tetrabromide and triphenylphosphine. This reaction can be carried out at 150 to 50 ° C. using a solvent which does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide and the like.
  • Examples of iodination reactions include methods using iodine, triphenylphosphine and imidazole. This reaction can use a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, and the like. These reactions can be performed at —50 to 100 ° C. Methanesulfonylation and p-toluenesulfonylation can be carried out using methanesulfonyl chloride, p-toluenesulfonyl chloride and the like, respectively. At this time, a suitable base may be added.
  • Examples of the base to be added include amines such as triethylamine and diisopropylethylamine and inorganic bases such as carbonated lime.
  • Examples of the reaction solvent include solvents that do not participate in the reaction, such as N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, and the like. Can be done in C. Reaction formula 7
  • R c is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group
  • R c is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group
  • p The compound which is a leaving group such as —toluenesulfonyloxy group is subjected to a substitution reaction using a compound represented by Z—NH—R b (wherein Z and R b are the same as described above).
  • Z—NH—R b wherein Z and R b are the same as described above.
  • sodium hydride, potassium tert-butoxide, n-butyllithium, lithium diisopro R pyramide and the like can be used as the base.
  • N N-dimethylformamide, tetrahydrofuran, dioxane and the like can be used.
  • the reaction can be performed at -50
  • Examples of a group that can convert R c to a leaving group include a hydroxyl group.
  • Rd represents a leaving group such as a halogen atom or a sulfonyloxy group.
  • the target product can be obtained by allowing Z—Rd to act on the amino group of the raw material.
  • R d is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or the like
  • the reaction can be carried out with an amino form as a raw material in the presence of a suitable base.
  • the base to be added include: Examples thereof include amines such as triethylamine and disopropylethylamine, and inorganic bases such as lithium carbonate.
  • the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like. The reaction can be performed at O to 100 ° C.
  • the reaction can be carried out under conditions using a primary amino group as a raw material and an appropriate reduction method.
  • the reduction method used include a reducing agent such as sodium borohydride and sodium cyanoborohydride, and hydrogenation using palladium.
  • a solvent to be used a solvent that does not participate in the reaction, such as ethanol, methanol, tetrahydrofuran, dioxane, and water can be used.
  • the reaction can be carried out at a temperature between 20 and 100 ° C.
  • It can be produced by converting an aminocarbonyl group into a cyano group by a general dehydration reaction.
  • An example of this is a method using trifluoroacetic anhydride.
  • the solvent to be used include solvents that do not participate in the reaction such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, and N, N-dimethylformamide.
  • a base such as triethylamine, diisopropylethylamine, sodium hydrogencarbonate or potassium carbonate can be added.
  • the reaction can be performed at -50 to 50 ° C.
  • Another example is a method using phosphorus oxychloride.
  • dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, pyridine and the like can be used alone or as a mixture of two or more kinds as solvents.
  • imidazole and the like may be added. This reaction can be carried out at a temperature of 50-50 ° C.
  • the fluorination method include a method using methylaminosulfur trifluoride / dimethylsulfur trifluoride or the like.
  • the reaction is started at a temperature of from 78 ° C to room temperature using a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, and toluene. Achieved by continuous reaction.
  • fluorination is a method of converting a hydroxyl group into a leaving group and then converting it into a fluoro group. Conversion to a leaving group can be carried out in the same manner as described in Scheme 6.
  • a method of converting to a fluoro group after converting to a leaving group a method of reacting tetrabutylammonium fluoride, cesium fluoride or the like can be mentioned. These reactions can be carried out using a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, and water.
  • Reaction formula 1 2 Reaction formula 1 2
  • an amide or Amides or olebamates can be produced.
  • the amidation reaction uses acyl octyl chloride, such as acyl chloride,
  • the reaction can be performed in a solvent that does not participate in the reaction, such as chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be performed using a base.
  • the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and 2-ethylhexanoic acid rim.
  • Inorganic bases such as organic acid salts and carbonated lime are mentioned. These reactions can be performed at —50-100 ° C.
  • the reaction can be carried out using an active ester such as 1-benzotriazolyl ester or succinimidyl ester.
  • active ester such as 1-benzotriazolyl ester or succinimidyl ester.
  • the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be performed at -50 to 50 ° C.
  • amidation can be performed using a carboxylic acid and a dehydrating condensing agent.
  • the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, and lipoeldiimidazole.
  • Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used accordingly.
  • reaction solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate.
  • the reaction can be carried out using a base.
  • the base include amines such as triethylamine and diisopropylethylamine, sodium salts such as sodium 2-ethylhexanoate, and organic acid salts such as sodium 2-hexylhexanoate, And inorganic bases such as potassium carbonate.
  • the reaction can be carried out at a temperature of 50 to 50 ° C.
  • amidation can be performed using a mixed acid anhydride obtained from a carboxylic acid and chlorocarbonate.
  • Solvents for these reactions include tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylform. Solvents that do not participate in the reaction, such as muamide, toluene, and ethyl acetate.
  • the reaction can be carried out using a base.
  • the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and 2-ethylhexanoic acid rim.
  • Inorganic bases such as organic acid salts and carbonated lime are mentioned. These reactions can be carried out at a temperature of 50 to 50 ° C.
  • the protection of the amino group can be carried out using di-tert-butyldicarboxylate, benzyloxycarboechloride, fluorenylmethoxycarbonyl chloride or the like in the presence of a suitable base.
  • the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as carbonated lime.
  • Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, ethyl acetate, and water. These reactions can be carried out at a temperature of from 50 to 50 ° C. ⁇ , Equation 1 3
  • R Re is the same as described above.
  • R f represents a hydrogen atom or a lower alkyl group, a benzyl group, an aryl group, or the like.
  • a compound in which COOR f is a carbonyl group or a salt thereof is used as a raw material, synthesis can be performed using ammonia under general amidation conditions.
  • amidation there is a method in which a carboxyl group or a salt thereof is converted to an acid chloride using thionyl chloride, phosphorus oxychloride, oxalyl chloride or the like, and then condensed with ammonia.
  • Solvents for these reactions include Solvents that do not participate in the reaction include butane, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at -50 to 50 ° C.
  • Another example is amidation using a dehydrating condensing agent and ammonia.
  • a reaction using a condensing agent such as 11-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, carboxydiimidazole, etc.
  • Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be added.
  • Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, ethyl acetate, and acetonitrile. . These reactions can be carried out at a temperature of 50 to 50 ° C.
  • amidation can be carried out using ammonia and a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate.
  • Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at —50-50 ° C.
  • the conversion of a compound in which COOR ⁇ is an ester to an aminocarbonyl group can be carried out by directly reacting with ammonia, or can be once converted to a carboxylic acid or a salt thereof and then converted to an aminocarbonyl group by the above method. it can.
  • a method for converting an ester to a carboxylic acid or a salt thereof the method described in PROTECTIVE GROUPS IN ORGAN IC SYNTHESIS, THEODORA W. GREENE and PETER GM WU TS can be used.
  • the reaction of direct conversion with ammonia uses ammonia gas or ammonia water in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or toluene, or without solvent.
  • a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or toluene, or without solvent.
  • O can be performed in a temperature range of 100 ° C. In some cases, it can be carried out in a sealed system to prevent the volatilization of ammonia.
  • Rb which is a protecting group for an amino group
  • Rb can be deprotected by, for example, the method described in Reaction Scheme 3.
  • the resulting amine can be removed as a base or as a salt of a suitable acid.
  • suitable acids include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid and the like.
  • (2S, 4S) -1-1 (tert-butylamino) acetyl-2-cyano-14-fluoropyrrolidine (0.26g) ).
  • This part (0.25 g) was added to an ice-cooled getyl ether solution of 4 M hydrochloric acid (ethyl acetate solution, 0.3 mL), and the mixture was stirred at room temperature for 1 hour. The insolubles were collected by filtration to give the title compound (0.28 g) as a colorless powder.
  • Dipeptidyl peptidase IV (DPP IV) activity inhibition experiments were performed according to the method described in Diabetes, 47, 764-769, 1998.
  • Plasma containing dipeptidyl peptidase IV was prepared by collecting blood from healthy volunteers and centrifuging. The enzymatic reaction was carried out using a 96-well flat bottom plate in a buffer consisting of 25 mM HEPES, 14 OmM NaC 1% BSA, pH 7.8.
  • the reaction was stopped by adding 50 1 of 25% acetic acid aqueous solution.
  • the amount of the released 7-amino-4-methylcoumarin was measured at 460 nm when excited at 390 nm using a fluorescence plate reader (1420 ARVOTM Multi-absorber; Wa11ac).
  • the fluorescence intensity when the reaction time was set to 0 minutes after the addition of the solvent was defined as a blank value, and the value obtained by subtracting the blank value from each measured value was defined as the specific fluorescence intensity. From the obtained specific fluorescence intensity, the inhibition rate (%) of dipeptidyl peptidase IV activity was determined by the following equation.
  • the test compound was prepared by preparing a dimethylsulfoxide solution having a 1000-fold higher concentration, and diluting it with the above buffer. From the inhibition rate at each concentration, the concentration of the compound showing 50% inhibition ( IC5Q value) was calculated. As a result, the compound of Reference Example 1 exhibited an excellent DPPIV inhibitory activity with an IC 50 of 0.6 nM.
  • OGTT in Zucker fatty rats was carried out with reference to the method described in Diabetologia, 42, 1324-1331, 1999.
  • 10-week-old male Zucker fatty rats (Nippon Charus Riva) were used after a 16-hour fast. Water was taken freely until immediately before use, and thereafter water was cut off until the end of the test. Blood was collected via heparin-treated blood collection tube (Drummond Scientific) before the start of the test; blood was collected from the fundus vein. The test compound was orally administered as a solution.
  • Sugar was dissolved in water for injection in the Japanese Pharmacopoeia and administered orally as a sugar at a dose of 1 g / kg body weight or 2 gZkg body weight 15 or 30 minutes after administration of the test compound and water for injection.
  • Blood was collected from the fundus vein at 15, 30 and 60 minutes after glucose administration.
  • the blood sample was immediately mixed with heparin (manufactured by Shimizu Pharmaceutical), centrifuged at 3000 rpm for 15 minutes at 4 ° C, and the plasma was collected and immediately frozen.
  • the blood glucose level (mg / dl) of the frozen sample was measured with a glucose CII test II (manufactured by Wako Pure Chemical Industries, Ltd.) and the area under the curve (min * mgZd 1) was calculated. (However, the blood glucose level of the sample obtained by blood collection before the test was started was used as the 0-minute blood glucose level.)
  • the compounds of the examples suppressed an increase in blood glucose level.
  • DPPIV dipeptidyl peptidase IV

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Abstract

L'invention concerne des dérivés de cyanopyrrolidine représentés par la formule générale (1) ou des sels acceptables d'un point de vue pharmaceutique de ceux-ci, formule dans laquelle W est un groupe acyle dérivé d'un acide aminé naturel, un groupe représenté par la formule générale (2) (dans laquelle W1 est alcanoyle C1-5, arylcarbonyle éventuellement substitué, ou alkyle C1-5; et W2 est hydrogène ou alkyle C1-5), ou un groupe représenté par la formule générale (3) (dans laquelle W3 et W4 sont chacun hydrogène ou alkyle C1-5); X est de l'oxygène ou du soufre; Y est -CR5R6- (R5 et R6 étant chacun indépendamment hydrogène, halogéno, ou un autre élément semblable) ou -CR7R8-CR9R10- (R7, R8, R9, et R10 étant chacun indépendamment hydrogène, halogéno, ou un autre élément semblable); et Z est hydrogène ou alkyle C1-10 éventuellement substitué, ou Y et Z et l'atome d'azote adjacent à ceux-ci peuvent former un groupe amino cyclique éventuellement substitué comprenant de 2 à 10 atomes de carbone.
PCT/JP2003/005813 2002-05-09 2003-05-09 Derives de cyanopyrrolidine WO2003095425A1 (fr)

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Cited By (20)

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WO2004101514A1 (fr) * 2003-05-15 2004-11-25 Taisho Pharmaceutical Co., Ltd. Derive du type cyanofluoropyrrolidine
WO2007102286A1 (fr) 2006-03-08 2007-09-13 Kyorin Pharmaceutical Co., Ltd. Procede de production d'un derive aminoacetylpyrrolidinecarbonitrile et intermediaire utilise pour sa production
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
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy

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WO2002038541A1 (fr) * 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
WO2003002553A2 (fr) * 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003002531A2 (fr) * 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase

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WO2002038541A1 (fr) * 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
WO2003002553A2 (fr) * 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004101514A1 (fr) * 2003-05-15 2004-11-25 Taisho Pharmaceutical Co., Ltd. Derive du type cyanofluoropyrrolidine
US8053465B2 (en) 2004-02-05 2011-11-08 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
US7465732B2 (en) 2004-05-12 2008-12-16 Pfizer Inc (2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
JP5101489B2 (ja) * 2006-03-08 2012-12-19 杏林製薬株式会社 アミノアセチルピロリジンカルボニトリル誘導体の製造方法およびその製造中間体
WO2007102286A1 (fr) 2006-03-08 2007-09-13 Kyorin Pharmaceutical Co., Ltd. Procede de production d'un derive aminoacetylpyrrolidinecarbonitrile et intermediaire utilise pour sa production
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
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
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
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US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy

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