WO2009084497A1 - Dérivé de pipéridine substituée par un méthyle - Google Patents

Dérivé de pipéridine substituée par un méthyle Download PDF

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WO2009084497A1
WO2009084497A1 PCT/JP2008/073275 JP2008073275W WO2009084497A1 WO 2009084497 A1 WO2009084497 A1 WO 2009084497A1 JP 2008073275 W JP2008073275 W JP 2008073275W WO 2009084497 A1 WO2009084497 A1 WO 2009084497A1
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compound
acid
examples
tert
methyl
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PCT/JP2008/073275
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English (en)
Japanese (ja)
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Hiroyuki Nakahira
Yukihiro Nishio
Hidenori Kimura
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Dainippon Sumitomo Pharma Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 2-( ⁇ 6-[(3R) -3-amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra Hydro-5H-pyrrolo [3,2-d] pyrimidin-5-yl ⁇ methyl) -4-fluorobenzonitrile (hereinafter sometimes abbreviated as compound A if necessary) or a pharmaceutically acceptable salt thereof ( Hereinafter, the compound A or a pharmaceutically acceptable salt thereof may be abbreviated as the compound of the present invention as needed).
  • the compound of the present invention is useful as a medicine, and more specifically, is effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor.
  • the present invention further relates to a therapeutic agent for diabetes containing the compound of the present invention as an active ingredient.
  • Patent Documents 1 and 2 report that compounds having a pyrrolo [3,2-d] pyrimidine ring are effective as DPP-IV inhibitors. However, these documents do not specifically describe the compounds of the present invention.
  • International Publication No. 2006/068163 Pamphlet International Publication No. 2007/071738 Pamphlet
  • An object of the present invention is to provide a novel compound having excellent DPP-IV inhibitory activity.
  • the present inventors have found that the compound of the present invention has an excellent DPP-IV inhibitory action. Further, as will be apparent from the test examples described later, structurally similar compounds have time-dependent enhancement of metabolic reaction inhibition, that is, mechanism-based inhibition (MBI), whereas the compounds of the present invention can avoid MBI. The inventors have found that this is possible and have completed the present invention.
  • MBI mechanism-based inhibition
  • the present invention [1] 2-( ⁇ 6-[(3R) -3-Amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro -5H-pyrrolo [3,2-d] pyrimidin-5-yl ⁇ methyl) -4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof, [2] 2-( ⁇ 6-[(3R) -3-Amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro -5H-pyrrolo [3,2-d] pyrimidin-5-yl ⁇ methyl) -4-fluorobenzonitrile, [3] The compound according to [1] or a pharmaceutically acceptable salt thereof, or a dipeptidyl peptidase-IV inhibitor containing the compound according to [2] as an active ingredient, and [4] the compound according to [
  • the compound of the present invention has excellent DPP-IV inhibitory activity.
  • a compound having DPP-IV inhibitory activity acts on blood GLP-1 as described in, for example, WO 2006/068163 pamphlet, thereby promoting insulin secretion dependent on blood glucose level, pancreatic function It has effects such as improvement, improvement of postprandial hyperglycemia, improvement of glucose tolerance, and improvement of insulin resistance, and is useful as a treatment for type 2 diabetes (non-insulin dependent diabetes) (RAPederson et al., Diabetes Vol .47, p1253-1258, 1998).
  • MBI mechanism-based inhibition
  • A shows the results of measuring the metabolic activity of the substrate substance (midazolam) after preincubation of Compound A and human liver microsomes in the presence of NADPH, and examining the influence on the metabolic activity by preincubation.
  • B shows the results obtained in a similar test with Compound B.
  • C shows the result obtained in the same test with Compound C.
  • the vertical axis represents metabolic activity (%).
  • the horizontal axis indicates time (minutes).
  • ⁇ indicates 0 ⁇ M
  • ⁇ indicates 1 ⁇ M
  • ⁇ indicates 5 ⁇ M
  • ⁇ indicates 10 ⁇ M
  • ⁇ indicates 20 ⁇ M
  • ⁇ indicates 50 ⁇ M
  • ⁇ indicates 100 ⁇ M.
  • A shows the inactivation rate constant at each concentration of Compound A.
  • B shows the inactivation rate constant at each concentration of Compound B.
  • C represents an inactivation rate constant at each concentration of Compound C.
  • the vertical axis represents the inactivation rate constant (min ⁇ 1 ).
  • the horizontal axis indicates the concentration ( ⁇ M) of each compound.
  • Compound A is a compound represented by the following formula.
  • Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate, or acetate, propionate, oxalate, and succinate.
  • Organic salts such as lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonic acid, p-toluenesulfonate or ascorbate It is done.
  • the present invention also includes hydrates of the compounds of the present invention or solvates such as ethanol solvates. Furthermore, the present invention also includes all tautomeric forms of the compounds of the present invention, all stereoisomers present, and crystal forms of all embodiments.
  • the compound of the present invention can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized according to the method described in International Publication No. 2006/068163 pamphlet. An example is shown below.
  • Step 1 Compound (1-5) can be produced by reacting compound (1-1) with compound (1-2) in an inert solvent.
  • the inert solvent include aromatic hydrocarbon solvents such as toluene, benzene, and xylene.
  • the reaction temperature can usually be selected from the range of about 30 ° C. to about 100 ° C.
  • Step 2 Compound (1-7) is produced by reacting compound (1-5) with compound (1-6) in the presence of an organic base in an inert solvent.
  • the inert solvent include nitrile solvents such as acetonitrile or propionitrile.
  • the organic base include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene, or 1,4-diazabicyclo. [5.4.0] undec-7-ene and the like.
  • the reaction temperature is usually selected from the range of about 30 ° C. to about 80 ° C., but the reaction may be performed under reflux.
  • Step 3 Compound (1-9) can be produced by reacting compound (1-7) with compound (1-8) in the presence of a base in an inert solvent.
  • the base include alkali carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate, and preferably potassium carbonate.
  • an aprotic solvent N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • an ether solvent diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.
  • a ketone acetone, etc.
  • the reaction temperature can usually be selected from the range of about 10 ° C to about 60 ° C.
  • Step 4 Compound (1-10) can be produced by reacting compound (1-9) with a base in an inert solvent.
  • the base include alkali amides such as lithium amide or sodium amide, or alkali hydrides such as sodium hydride or potassium hydride.
  • the inert solvent include aromatic hydrocarbon solvents such as toluene, benzene, and xylene, hydrocarbon solvents such as hexane and heptane, tert-butyl alcohol, acetonitrile, N, N-dimethylformamide, ether solvents (diethyl). Ether, tetrahydrofuran or 1,4-dioxane), or a mixed solvent thereof.
  • lithium amide is preferred as the base.
  • a mixed solvent of ter-butyl alcohol and acetonitrile, or a mixed solvent of ter-butyl alcohol, acetonitrile, heptane, and toluene is preferable.
  • the reaction temperature can usually be selected from the range of about 10 ° C to about 100 ° C.
  • Step 5 Compound (1-11) is produced by reacting compound (1-10) with potassium cyanate in an inert solvent.
  • the inert solvent include water, an organic acid such as acetic acid or propionic acid, or an aromatic hydrocarbon solvent such as toluene, benzene, or xylene.
  • the reaction is performed in a mixed solvent of water, acetic acid, and toluene. Is done.
  • the reaction temperature is usually selected from the range of about 20 ° C to about 80 ° C.
  • Step 6 Compound (1-12) is produced by reacting compound (1-11) with an inorganic base in an inert solvent.
  • the inorganic base include potassium carbonate, cesium carbonate, sodium carbonate, and the like.
  • the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethylsulfoxide and the like), and the use of N, N-dimethylformamide is preferred.
  • the reaction temperature is usually selected from the range of about 20 ° C to about 80 ° C.
  • Step 7 Compound (1-14) is produced by reacting compound (1-12) with methyl iodide in an inert solvent.
  • the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethylsulfoxide and the like), and the use of N, N-dimethylformamide is preferred.
  • the reaction temperature is usually selected from the range of about 20 ° C to about 50 ° C. It is also possible to react by adding methyl iodide to the reaction solution in Step 6.
  • Step 8 Compound (1-15) is produced by cyanating compound (1-14) in an inert solvent in the presence of zinc cyanide and a Pd catalyst, in the presence or absence of phosphine.
  • the inert solvent include N-methyl-2-pyrrolidone or N, N-dimethylformamide.
  • Pd catalysts include tris (dibenzylideneacetone) dipalladium complex Pd 2 (dba) 3 .CHCl 3 , bis [tri (tert-butyl) phosphine] palladium complex Pd [(tert-Bu) 3 P] 2 , tetrakis ( Triphenylphosphine) palladium complex Pd (PPh 3 ) 4 , bis (trifluoroacetoxy) palladium complex Pd (OCOCF 3 ) 2 can be mentioned, and phosphine includes triphenylphosphine [Ph 3 P], tri (tert-butyl) Examples include phosphine [(tert-Bu) 3 P], tri-o-toluylphosphine [(o-Tol) 3 P], diphenylphosphinoferrocene [DPPf], diphenylphosphinobutane [DPPb], and the like.
  • reaction temperature is usually selected from the range of about 80 ° C to about 130 ° C.
  • literature for example, Synth. Commun. 24, 887 (1994), Organic Letters 9, 1711 (2007), Tetrahedron Lett. 40, 8193 (1999), Tetrahedron Lett. 45, 1441 (2004), etc. ) Can be referred to.
  • Step 9 As step 9, the following production method (A) and production method (B) can be used.
  • the inorganic base include sodium hydroxide and potassium hydroxide, which are usually used as an aqueous solution.
  • the inert solvent include alcohol solvents (ethanol, methanol, 2-propanol, etc.), and nitrile solvents (acetonitrile, propionitrile, etc.). Usually, a mixed solvent of an alcohol solvent and a nitrile solvent is used. It is done.
  • the reaction temperature can usually be selected from the range of about 50 ° C. to about 100 ° C.
  • the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform.
  • the inorganic acid include hydrochloric acid and the like.
  • the reaction temperature can usually be selected from the range of about ⁇ 10 ° C. to about 30 ° C.
  • the raw materials and reagents used above are commercially available compounds, or can be produced from known compounds using known methods.
  • the compound (1-2) can be synthesized according to the method described in the literature (Organic® Letters® 7, 55-58® (2005)).
  • the compound of the present invention can be synthesized as a racemate and fractionated by column chromatography using a filler bound with an optically active ligand.
  • the compound of the present invention can be converted into a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like.
  • pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, or acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid,
  • the organic acid include maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and ascorbic acid.
  • the compound of the present invention can be applied to the treatment of various diseases because of its inhibitory action on DPP-IV.
  • the compounds described herein inhibit postprandial hyperglycemia in pre-diabetic conditions, treat non-insulin dependent diabetes, treat autoimmune diseases such as arthritis and rheumatoid arthritis, treat intestinal mucosal diseases, promote growth, transplant organs It is useful for inhibiting rejection of fragments, treating obesity, treating eating disorders, treating HIV infection, inhibiting cancer metastasis, treating benign prostatic hyperplasia, treating periodontitis, and treating osteoporosis.
  • compositions for oral or parenteral eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc.
  • compositions for parenteral administration include, for example, injections.
  • Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned.
  • These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.
  • the dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually 0.1 to 1000 mg of the compound of the present invention for adults (weight 50 kg) / Day, preferably 1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.
  • the compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug).
  • a concomitant drug a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug).
  • a concomitant drug can be used in combination.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), ⁇ -glucosidase inhibitor ( Examples, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride Sulfonylurea drugs; repaglinide, sena
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-112, etc.), neurotrophic factors (eg, NGF) , NT-3, BDNF, etc.), PKC inhibitors (eg, LY-333531), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), active oxygen elimination Examples thereof include drugs (eg, thioctic acid) and cerebral vasodilators (eg, thioprid, mexiletine, etc.).
  • aldose reductase inhibitors eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-11
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Can be mentioned.
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts
  • squalene synthase inhibitors eg., squalene synthase inhibitors, ACAT inhibitors, etc.
  • an angiotensin converting enzyme inhibitor eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.
  • angiotensin II antagonist eg, olmesartan, medoxomil, candesalmil, candesalmil
  • Cilexetil losartan
  • calcium antagonists eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.
  • renin inhibitors aliskiren, etc.
  • anti-obesity agents examples include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like.
  • central anti-obesity agents eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.
  • pancreatic lipase inhibitors eg, orlistat, etc.
  • peptide anorectic agents Eg, leptin, CNTF (ciliary neurotrophic factor), etc.
  • diuretics examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • the concomitant drug is preferably GLP-1, GLP-1 analog, ⁇ -glucosidase inhibitor, biguanide, insulin secretagogue, insulin resistance improver and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of these drugs used can be reduced within a safe range considering the side effects of the drug.
  • biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented.
  • the dosage of diabetic complications, antihyperlipidemic agents, antihypertensives, etc. can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.
  • Heptane (146 ml) was added to lithium amide (9.6 g), and a mixed solution of tert-butyl alcohol (268 g) and heptane (30 ml) was added dropwise at 80 ° C. After 1 hour, the mixture was cooled to 30 ° C., and acetonitrile (340 ml) was added. A toluene (350 ml) solution of the compound of Reference Example 3 (124.10 g) was added to the mixture and stirred. Two hours later, the solvent was distilled off under reduced pressure, and toluene (700 ml) and water (370 ml) were added.
  • the compound of Reference Example 13 (5.45 g) was dissolved in toluene (30 ml), and triethylamine (2.09 g) was added.
  • Test example Test Example 1 In vitro DPP-IV Inhibitory Action Measurement Test Test substance solutions having various concentrations were prepared so that the final concentration of human plasma containing DPP IV enzyme was 10%, and added to a microassay plate. Furthermore, a substrate (Glycyl-L-Proline 4-Methylcoumaryl-7-Amide, Peptide Institute) was added to a final concentration of 50 ⁇ M, and fluorescence intensity (excitation wavelength: 380 nm, measurement wavelength) using a fluorescence plate reader at room temperature. 460 nm) was continuously measured to determine enzyme activity. The test substance concentration (IC 50 value) that inhibits the enzyme activity by 50% was calculated.
  • Test Example 2 Mechanism-based inhibition (MBI) evaluation test for CYP3A4
  • concentrations of test compounds are added to human liver microsomes and preincubated for 15 minutes at 37 ° C. in the presence or absence of NADPH. Thereafter, the reaction solution was diluted 20 times with a mixed solution of midazolam and NADPH, which are CYP3A4 substrates, and further reacted at 37 ° C. for 5 minutes. The reaction was stopped by adding 3 times the amount of methanol, and CYP3A4 activity was evaluated by measuring the amount of metabolites (1-Hydroxy midazolam) produced using LC / MS / MS.
  • the activity during preincubation in the absence of NADPH was used as a control, and the value obtained by dividing the decrease in activity during preincubation in the presence of NADPH by the time (15 minutes) was defined as the inactivation rate constant (kobs).
  • the maximum inactivation rate constant (kinact) and the apparent dissociation constant (K'app) were calculated by regression analysis using a nonlinear least square method, and the MBI intensity was determined by the value of kinact / K'app. The obtained results are shown in FIGS.
  • Compound B, Compound A, and Compound C differ from each other only in that the substituent on 3-aminopiperidine is a hydrogen atom, a methyl group, or an ethyl group.
  • the DPP-IV inhibitory activity IC 50 (nM) is higher in the compound B (0.34 nM) having a hydrogen atom and the compound A (1.6 nM) having a methyl group, and the compound C having an ethyl group as compared with these. Is very low in activity (26 nM).
  • the present invention can provide a compound having DPP-IV inhibitory activity and improved in safety, toxicity and the like.
  • the compound of the present invention suppresses postprandial hyperglycemia in a prediabetic state, treatment of non-insulin-dependent diabetes, treatment of autoimmune diseases such as arthritis and rheumatoid arthritis, treatment of intestinal mucosal disease, growth promotion, rejection of transplanted organ fragments It is useful for suppression, obesity treatment, eating disorder treatment, HIV infection treatment, cancer metastasis inhibition, prostate hypertrophy treatment, periodontitis treatment, and osteoporosis treatment.

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Abstract

La présente invention concerne un 2-({6-[(3R)-3-amino-3-méthylpipéridin-1-yl]-1,3-diméthyl-2,4-dioxo-1,2,3,4-tétrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}méthyl)-4-fluorobenzonitrile présentant une activité inhibitrice du DPP-IV élevée, une innocuité et une toxicité améliorées, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2008/073275 2007-12-28 2008-12-22 Dérivé de pipéridine substituée par un méthyle WO2009084497A1 (fr)

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WO2010086411A1 (fr) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Traitement du diabète chez des patients pédiatriques
WO2010092163A2 (fr) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Médicaments antidiabétiques
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
WO2011064352A1 (fr) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Traitement de patients diabétiques génotypés par des inhibiteurs de dpp-iv tels que la linagliptine
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
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WO2011138421A1 (fr) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combinaison thérapeutique
WO2011161161A1 (fr) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Thérapie du diabète
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
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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
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WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
EP3626238A1 (fr) 2008-08-15 2020-03-25 Boehringer Ingelheim International GmbH Inhibiteurs de dpp-4 destinés à l'utilisation dans la cicatrisation des lésions des diabétiques
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EP2990037A1 (fr) 2008-08-06 2016-03-02 Boehringer Ingelheim International GmbH Traitement du diabète chez les patients non appropriés pour la thérapie au metformine
EP3626238A1 (fr) 2008-08-15 2020-03-25 Boehringer Ingelheim International GmbH Inhibiteurs de dpp-4 destinés à l'utilisation dans la cicatrisation des lésions des diabétiques
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WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
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
WO2012145603A1 (fr) 2011-04-22 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
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2013174767A1 (fr) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
JP2020511453A (ja) * 2017-03-13 2020-04-16 リヒター ゲデオン エヌワイアールティー． ラセミ３−アルキルピペリジン−カルボン酸エチルエステルの光学異性体の分離方法

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