WO2009113423A1 - 二環性ピロール化合物 - Google Patents
二環性ピロール化合物 Download PDFInfo
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- WO2009113423A1 WO2009113423A1 PCT/JP2009/053910 JP2009053910W WO2009113423A1 WO 2009113423 A1 WO2009113423 A1 WO 2009113423A1 JP 2009053910 W JP2009053910 W JP 2009053910W WO 2009113423 A1 WO2009113423 A1 WO 2009113423A1
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- -1 Bicyclic pyrrole compound Chemical class 0.000 title description 15
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- JAIOMMAAMDKJKB-PFEQFJNWSA-N 6-[(3R)-3-aminopiperidin-1-yl]-5-[(2-chloro-5-fluorophenyl)methyl]-1,3-dimethylpyrrolo[3,2-d]pyrimidine-2,4-dione hydrochloride Chemical compound Cl.C=1C(F)=CC=C(Cl)C=1CN1C=2C(=O)N(C)C(=O)N(C)C=2C=C1N1CCC[C@@H](N)C1 JAIOMMAAMDKJKB-PFEQFJNWSA-N 0.000 claims abstract description 4
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- 239000012312 sodium hydride Substances 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 239000004071 soot Substances 0.000 description 1
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- 229960002256 spironolactone Drugs 0.000 description 1
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- 238000013112 stability test Methods 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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- 229960000651 tasosartan Drugs 0.000 description 1
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- RFWCIZJOACFTKA-UHFFFAOYSA-N tert-butyl 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoate Chemical compound CSC(SC)=C(C#N)C(=O)OC(C)(C)C RFWCIZJOACFTKA-UHFFFAOYSA-N 0.000 description 1
- IVCPDTNLEQLFJF-CYBMUJFWSA-N tert-butyl 2-cyano-3-[(3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidin-1-yl]-3-methylsulfanylprop-2-enoate Chemical compound CC(C)(C)OC(=O)C(C#N)=C(SC)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1 IVCPDTNLEQLFJF-CYBMUJFWSA-N 0.000 description 1
- CMFJXFUZULSMQZ-LJQANCHMSA-N tert-butyl 5-[(2-chloro-5-fluorophenyl)methyl]-1,3-dimethyl-6-[(3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidin-1-yl]-2,4-dioxopyrrolo[3,2-d]pyrimidine-7-carboxylate Chemical compound C=1C(F)=CC=C(Cl)C=1CN1C=2C(=O)N(C)C(=O)N(C)C=2C(C(=O)OC(C)(C)C)=C1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1 CMFJXFUZULSMQZ-LJQANCHMSA-N 0.000 description 1
- IKLFTJQKKCELGD-LLVKDONJSA-N tert-butyl n-[(3r)-3-methylpiperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@]1(C)CCCNC1 IKLFTJQKKCELGD-LLVKDONJSA-N 0.000 description 1
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- 229960001288 triamterene Drugs 0.000 description 1
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- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- 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
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Definitions
- the present invention relates to 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d]
- the present invention relates to pyrimidine-2,4 (3H, 5H) -dione monohydrochloride hemihydrate (hereinafter sometimes abbreviated as compound A if necessary).
- the compound of the present invention is useful as a drug that can be put into practical use as a drug substance, and more specifically, is effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor.
- DPP-IV dipeptidyl peptidase-IV
- the present invention further relates to a therapeutic agent for diabetes containing the compound of the present invention as an active ingredient.
- Patent Document 1 discloses the compound of Example 6 represented by the formula (I) (hereinafter referred to as Compound B).
- Compound B has an excellent dipeptidyl peptidase-IV (DPP-IV) inhibitory action and can be expected to be useful as a therapeutic agent for diabetes.
- DPP-IV dipeptidyl peptidase-IV
- An object of the present invention is to provide a compound composed of a crystalline form that has a storage stability that can be put into practical use as a drug substance and is easy to handle.
- compound A which is a hemihydrate of compound B
- compound A can be obtained as a crystal exhibiting excellent stability.
- Compound A has been significantly improved in storage stability and ease of handling as compared with Compound B, and has been found to be extremely useful for practical use as a pharmaceutical.
- the present invention has been completed.
- the present invention [1] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine -2,4 (3H, 5H) -dione monohydrochloride hemihydrate, [2]
- the compound according to [1] which exhibits main peaks at diffraction angles (2 ⁇ ): 8.6 ⁇ 0.2 °, 14.9 ⁇ 0.2 ° and 15.4 ⁇ 0.2 ° in powder X-ray diffraction
- the compound according to [1] which exhibits
- the compound of the present invention has excellent storage stability and ease of handling, and is extremely useful for practical use as a medicine.
- FIG. 1 shows the X-ray diffraction pattern of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- FIG. 2 shows the characteristic DSC curve of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- FIG. 3 shows a characteristic TGA curve of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- FIG. 4 shows the hygroscopicity of the compound of Example 1 (Compound A). ⁇ indicates the change in weight under moisture adsorption conditions. ⁇ indicates the change in weight under moisture desorption conditions.
- FIG. 5 shows the hygroscopicity of the compound (Compound B) of Example 6 of WO 2006/068163 pamphlet.
- ⁇ indicates the change in weight under moisture adsorption conditions.
- ⁇ indicates the change in weight under moisture desorption conditions.
- FIG. 6 shows a single crystal X-ray structural analysis of the compound of Example 1 (Compound A).
- Compound A is a compound represented by the following formula.
- 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 (1-3) can be produced by reacting compound (1-1) and 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 20 ° C to about 100 ° C.
- Step 2 Compound (1-5) is produced by reacting compound (1-3) with compound (1-4) 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 20 ° C. to about 100 ° C., but the reaction may be performed under reflux.
- Step 3 Compound (1-7) can be produced by reacting compound (1-5) with compound (1-6) 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 is usually selected from the range of about 10 ° C to about 80 ° C.
- Step 4 Compound (1-8) can be produced by reacting compound (1-7) 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.
- a mixed solvent of tert-butyl alcohol, acetonitrile, and heptane, or a mixed solvent of tert-butyl alcohol, acetonitrile, heptane, and toluene is preferable.
- the reaction temperature can usually be selected from the range of about 10 ° C to about 120 ° C.
- Step 5 Compound (1-9) is produced by reacting compound (1-8) 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 (1-10) is produced by reacting compound (1-9) 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 water, aprotic solvents (N, N-dimethylformamide, dimethylsulfoxide, etc.), and the reaction is usually carried out in a mixed solvent of water and N, N-dimethylformamide.
- the reaction temperature is usually selected from the range of about 20 ° C to about 100 ° C.
- Step 7 Compound (1-11) is produced by reacting compound (1-10) with methyl iodide in the presence of 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 50 ° C. It is also possible to react by adding methyl iodide to the reaction solution in Step 6.
- Step 8 Compound (1-12) is produced by reacting compound (1-11) with an inorganic acid in an inert solvent.
- inorganic acids include hydrochloric acid and sulfuric acid, and the use of sulfuric acid is preferred.
- the inert solvent include ether solvents (diethyl ether, 1,2-dimethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxane and the like), and mixed solvents thereof, and the use of tetrahydrofuran is preferable.
- the reaction temperature is usually selected from the range of about 30 ° C to about 120 ° C. After completion of the reaction, the organic solvent 1 and water are added to the reaction solution and separated.
- An inorganic base, water, and an organic solvent 2 are added to the aqueous layer to separate the liquid (operation 1).
- the organic solvent 2 is added again to the aqueous layer, followed by liquid separation (operation 2).
- the organic layer obtained in operation 1 and operation 2 is concentrated under reduced pressure.
- Alcohol is added to the resulting residue and heated in the range of about 50 ° C to about 100 ° C.
- Water is added dropwise, and after completion of the addition, the mixture is cooled to a range of about 10 ° C. to about 40 ° C. and stirred in a range of about ⁇ 5 ° C. to about 10 ° C.
- the resulting solid is obtained by filtration, washed with water, and dried under reduced pressure.
- Examples of the inorganic base include sodium hydroxide and potassium hydroxide.
- Examples of the organic solvent 1 include aromatic hydrocarbon solvents such as toluene, benzene, and xylene, and use of toluene is preferable.
- Examples of organic solvent 2 include ether solvents such as tetrahydrofuran or methyl tert-butyl ether, and tetrahydrofuran is preferably used.
- Examples of the alcohol include propanol, butanol, pentanol, hexanol, heptanol, octanol and the like, and use of isopropanol is preferable.
- Step 9 Compound A is produced by adding hydrochloric acid to an aqueous solution of compound (1-12). After completion of the reaction, toluene is added to the reaction solution and concentrated under reduced pressure. The operation of concentration under reduced pressure may be performed a plurality of times. Hydrous alcohol is added to the resulting residue and heated in the range of about 50 ° C to about 120 ° C. Ethyl acetate is added dropwise, and after completion of the addition, the mixture is cooled to a range of about 10 ° C. to about 40 ° C. and stirred in a range of about 0 ° C. to about 20 ° C. The resulting solid is obtained by filtration, washed with ethyl acetate, and dried under reduced pressure.
- hydrous alcohol examples include propanol, butanol, pentanol, hexanol, heptanol, octanol and the like, and use of isopropanol is preferable.
- the ratio of water in the hydrous alcohol is in the range of about 5% to about 30%, preferably in the range of about 10% to about 20%, by volume ratio with respect to the alcohol.
- 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 of the patent document (Japanese Patent Laid-Open No. 2007-262040).
- 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 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 is administered to an adult (weight 50 kg).
- / Day preferably 1 to 300 mg / day is administered once a day or divided into 2 to 3 times a day. 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 drugs are preferably GLP-1, GLP-1 analogs, ⁇ -glucosidase inhibitors, biguanides, insulin secretion promoters, insulin resistance improvers 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.
- the X-ray powder diffraction pattern of the monohydrochloride hemihydrate (Compound A) crystal of Example 1 was obtained by using Philips Analytical's X 'pert Pro or equivalent instrument. Cu K ⁇ 1 was used as the X-ray source.
- FIG. 1 shows the X-ray diffraction pattern of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- the diffraction peak value at the diffraction angle 2 ⁇ (°) described below may cause some measurement error depending on the measurement equipment or measurement conditions. Specifically, the measurement error may be within a range of ⁇ 0.2, preferably ⁇ 0.1.
- This hemihydrate (compound A) has a diffraction angle of 4.3 °, 8.6 °, 12.9 °, 14.9 °, 15.4 °, 17.2 °, 18.7 °, 23.0 °, 25.2 °, 26.4 °, 30.3 ° and 34.7 ° [ 2 ⁇ (°)] had a characteristic peak. Among these, more characteristic peaks are 8.6 °, 14.9 ° and 15.4 °.
- FIG. 2 shows a characteristic DSC curve of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- a DSC Q1000 from Tea Instruments or an equivalent device was used.
- Aluminum hermetic was used as a pan, and measurement was performed in a temperature range of 10 ° C to 250 ° C through a nitrogen flow of 50.0 mL / min.
- This hemihydrate (compound A) showed characteristic endothermic peaks at around 150 ° C and 200 ° C.
- FIG. 3 shows a characteristic TGA curve of the crystal of monohydrochloride hemihydrate of Example 1 (Compound A).
- a TGA Q500 or similar equipment from Tea Instruments was used. Platinum was used as a pan, and measurement was performed in a temperature range of 10 ° C. to 250 ° C. using a nitrogen flow of 40.0 ⁇ mL / min as a balance gas and a nitrogen flow of 60.0 ⁇ mL / min as a sample gas.
- This hemihydrate (compound A) showed a weight loss of about 2.0% at around 100 ° C.
- Test example 1 Amorphous system of the crystalline monohydrochloride hemihydrate of Example 1 (compound A) produced by the method of the present invention and the compound of Example 6 (compound B) of WO 2006/068163 produced by the prior art Each powder was measured for hygroscopicity at room temperature. The results are shown in FIG. 4 and FIG.
- Test example 2 Crystal of monohydrochloride hemihydrate of Example 1 (Compound A) prepared by the method of the present invention and amorphous of Compound (Compound B) of Example 6 of International Publication No. 2006/068163 pamphlet prepared by conventional techniques About each type
- the residual rate (%) of the compound was determined from the percent remaining value of the compound measured using high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- the compound of Example 6 (Compound B) in International Publication No. 2006/068163 had low stability and a decrease in content in both the 1000 Lux and 4000 Lux light sources.
- the compound of Example 1 of the present invention (Compound A) has high stability, and extremely high stability was confirmed under both conditions of 1000 Lux and 4000 Lux.
- the compound of Example 1 (Compound A) is a pale yellow compound, but in any of 1000Lux and 4000Lux light sources, there was no change in appearance and no color change was observed after this stability test. I could't.
- the compound of Example 6 (Compound B) in WO 2006/068163 clearly turned yellow.
- Test Example 3 Pharmacological test In Vitro DPP-IV Inhibitory Effect Measurement Test Solutions containing test compounds at various concentrations were prepared and added to microassay plates. Furthermore, human recombinant DPP IV (R & D system) was added and preincubated at room temperature for 100 to 110 minutes, and then the substrate (Glycyl-L-proline 4-methylcoumaryl-7-amide, Peptide Laboratory; final concentration 40 ⁇ mol / L) was added to start the enzyme reaction. Using a fluorescence plate reader, the fluorescence change was measured over time for 10 minutes after 10 minutes from the start of substrate addition (excitation wavelength: 380 nm / measurement wavelength: 460 nm), and the enzyme reaction rate was determined. From the obtained results, the compound concentration showing 50% inhibition was calculated as the IC 50 value.
- 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
Description
〔1〕6-[(3R)-3-アミノピペリジン-1-イル]-5-(2-クロロ-5-フルオロベンジル)-1,3-ジメチル-1H-ピロロ[3,2-d]ピリミジン-2,4(3H,5H)-ジオン モノハイドロクロライド ヘミハイドレート、
〔2〕粉末X線回折において回折角(2θ): 8.6±0.2°, 14.9±0.2°および15.4±0.2° に主ピークを示す、〔1〕記載の化合物、
〔3〕粉末X線回折において回折角(2θ): 4.3±0.2°, 8.6±0.2°, 12.9±0.2°, 14.9±0.2°, 15.4±0.2°, 17.1±0.2°, 18.7±0.2°, 23.0±0.2°, 25.2±0.2°,26.4±0.2°,30.3±0.2°および34.7±0.2° に主ピークを示す、〔1〕記載の化合物、
〔4〕〔1〕~〔3〕のいずれかに記載の化合物を有効成分として含有する医薬、
〔5〕〔1〕~〔3]のいずれかに記載の化合物を有効成分として含有するジペプチジルペプチダーゼ-IV阻害剤、
〔6〕〔1〕~〔3〕のいずれかに記載の化合物を有効成分として含有する糖尿病治療剤、および
〔7〕治療を必要とする患者に、〔1〕~〔3〕のいずれかに記載の化合物の有効量を投与することからなる、糖尿病の治療方法に関する。
化合物(1-3)は、化合物(1-1)と化合物(1-2)を、不活性溶媒中で反応させることにより製造することができる。不活性溶媒としては、例えば、トルエン、ベンゼン、もしくはキシレンなどの芳香族炭化水素系溶媒等が挙げられる。反応温度としては、通常、約20℃~約100℃の範囲から選択することができる。
化合物(1-5)は、化合物(1-3)と化合物(1-4)を、有機塩基存在下、不活性溶媒中、反応させることにより製造される。不活性溶媒としては、アセトニトリルもしくはプロピオニトリル等のニトリル系溶媒等が挙げられる。有機塩基としては、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、1,5-ジアザビシクロ[4.3.0]ノナ-5-エン、もしくは1,4-ジアザビシクロ[5.4.0]ウンデカ-7-エン等が挙げられる。反応温度としては、通常、約20℃~約100℃の範囲から選択されるが、還流下に反応を行ってもよい。
化合物(1-7)は、不活性溶媒中、塩基の存在下、化合物(1-5)と化合物(1-6)を反応させることにより製造することができる。塩基としては、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウムまたは炭酸水素ナトリウム等の炭酸アルカリ等が挙げられ、好適には、炭酸カリウム等が挙げられる。不活性溶媒としては、非プロトン性溶媒(N,N-ジメチルホルムアミドまたはジメチルスルホキシド等)、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、ケトン(アセトン等)、またはこれらの混合溶媒等が挙げられ、好適には、N,N-ジメチルホルムアミド等が挙げられる。反応温度としては、通常、約10℃~約80℃の範囲から選択される。
化合物(1-8)は、不活性溶媒中、化合物(1-7)と塩基を反応させることにより製造することができる。塩基としては、リチウムアミドもしくはナトリウムアミド等のアルカリアミド、または水素化ナトリウムまたは水素化カリウム等の水素化アルカリ等が挙げられる。不活性溶媒としては、トルエン、ベンゼン、もしくはキシレン等の芳香族炭化水素系溶媒、ヘキサンもしくはヘプタン等の炭化水素系溶媒、tert-ブチルアルコール、アセトニトリル、N,N-ジメチルホルムアミド、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、またはこれらの混合溶媒等が挙げられる。塩基としては、リチウムアミドが好ましい。溶媒としてはtert-ブチルアルコール、アセトニトリル、およびヘプタンの混合溶媒、またはtert-ブチルアルコール、アセトニトリル、ヘプタン、およびトルエンの混合溶媒が好ましい。反応温度としては、通常、約10℃~約120℃の範囲から選択することができる。
化合物(1-9)は、不活性溶媒中、化合物(1-8)とシアン酸カリウムを反応させることにより製造される。不活性溶媒としては、水、酢酸もしくはプロピオン酸等の有機酸、またはトルエン、ベンゼン、もしくはキシレンなどの芳香族炭化水素系溶媒等が挙げられ、通常は水、酢酸およびトルエンの混合溶媒中で実施される。反応温度としては、通常、約20℃~約80℃の範囲から選択される。
化合物(1-10)は、不活性溶媒中、化合物(1-9)と無機塩基を反応させることにより製造される。無機塩基としては、炭酸カリウム、炭酸セシウム、もしくは炭酸ナトリウム等が挙げられる。不活性溶媒としては、水、非プロトン性溶媒(N,N-ジメチルホルムアミドまたはジメチルスルホキシド等)等が挙げられ、通常は水およびN,N-ジメチルホルムアミドの混合溶媒中で実施される。反応温度としては、通常、約20℃~約100℃の範囲から選択される。
化合物(1-11)は、不活性溶媒中、無機塩基存在下、化合物(1-10)とヨウ化メチルを反応させることにより製造される。無機塩基としては、炭酸カリウム、炭酸セシウム、もしくは炭酸ナトリウム等が挙げられる。不活性溶媒としては、非プロトン性溶媒(N,N-ジメチルホルムアミドまたはジメチルスルホキシド等)等が挙げられ、N,N-ジメチルホルムアミドの使用が好ましい。反応温度としては、通常、約20℃~約50℃の範囲から選択される。また、工程6における反応溶液にヨウ化メチルを加えて反応させることも可能である。
化合物(1-12)は、不活性溶媒中、化合物(1-11)と無機酸を反応させることにより製造される。無機酸としては、塩酸または硫酸等が挙げられ、硫酸の使用が好ましい。不活性溶媒としては、エーテル系溶媒(ジエチルエーテル、1,2-ジメトキシエタン、ジグリム、テトラヒドロフランまたは1,4-ジオキサン等)、またはこれらの混合溶媒等が挙げられ、テトラヒドロフランの使用が好ましい。反応温度としては、通常、約30℃~約120℃の範囲から選択される。反応終了後、有機溶媒1および水を反応溶液に加え分液する。水層に無機塩基、水、および有機溶媒2を加え分液する(操作1)。水層に有機溶媒2を再び加え分液する(操作2)。操作1および操作2で得られた有機層を減圧濃縮する。得られた残渣にアルコールを加え、約50℃~約100℃の範囲で加熱する。水を滴下し、滴下終了後、約10℃~約40℃の範囲まで冷却し、約-5℃~約10℃の範囲で攪拌する。生じた固体をろ過により取得し、水で洗浄後、減圧下乾燥する。無機塩基としては、水酸化ナトリウムまたは水酸化カリウム等が挙げられる。有機溶媒1としては、トルエン、ベンゼン、またはキシレン等の芳香族炭化水素系溶媒等が挙げられ、トルエンの使用が好ましい。有機溶媒2としては、テトラヒドロフランまたはメチルtert-ブチルエーテル等のエーテル系溶媒等が挙げられ、テトラヒドロフランの使用が好ましい。アルコールとしては、プロパノール、ブタノール、ペンタノール、ヘキサノール、ヘプタノール、またはオクタノール等が挙げられ、イソプロパノールの使用が好ましい。
化合物Aは、化合物(1-12)の水溶液に塩酸を加えることにより製造される。反応終了後、トルエンを反応溶液に加え、減圧濃縮する。減圧濃縮の操作は、複数回実施してもよい。得られた残渣に対し、含水アルコールを加え、約50℃~約120℃の範囲で加熱する。酢酸エチルを滴下し、滴下終了後、約10℃~約40℃の範囲まで冷却し、約0℃~約20℃の範囲で攪拌する。生じた固体をろ過により取得し、酢酸エチルにて洗浄後、減圧乾燥する。含水アルコールのアルコールとしては、プロパノール、ブタノール、ペンタノール、ヘキサノール、ヘプタノール、またはオクタノール等が挙げられ、イソプロパノールの使用が好ましい。含水アルコールにおける水の割合は、アルコールに対する容積比において、約5%~約30%の範囲であり、約10%~約20%の範囲が好ましい。
以下に本発明を、参考例、実施例および試験例により、さらに具体的に説明するが、本発明はもとよりこれに限定されるものではない。尚、以下の参考例および実施例において示された化合物名は、必ずしもIUPAC命名法に従うものではない。なお、記載の簡略化のために略号を使用することもあるが、これらの略号は前記記載と同義である。
tert-ブチル 3-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-2-シアノ-3-(メチルチオ)アクリレート
tert-ブチル 3-[(2-クロロ-5-フルオロベンジル)アミノ]-3-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-2-シアノアクリレート
tert-ブチル 3-[(2-クロロ-5-フルオロベンジル)(2-エトキシ-2-オキソエチル)アミノ]-3-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-2-シアノアクリレート
4-tert-ブチル 2-エチル 3-アミノ-1-(2-クロロ-5-フルオロベンジル)-5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-1H-ピロール-2,4-ジカルボキシレート
4-tert-ブチル 2-エチル 3-[(アミノカルボニル)アミノ]-1-(2-クロロ-5-フルオロベンジル)-5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-1H-ピロール-2,4-ジカルボキシレート
tert-ブチル 5-(2-クロロ-5-フルオロベンジル)-6-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]-ピペリジン-1-イル}-1,3-ジメチル-2,4-ジオキソ-2,3,4,5-テトラハイドロ-1H-ピロロ[3,2-d]ピリミジン-7-カルボキシレート
6-[(3R)-3-アミノピペリジン-1-イル]-5-(2-クロロ-5-フルオロベンジル)-1,3-ジメチル-1H-ピロロ[3,2-d]ピリミジン-2,4(3H,5H)-ジオン
6-[(3R)-3-アミノピペリジン-1-イル]-5-(2-クロロ-5-フルオロベンジル)-1,3-ジメチル-1H-ピロロ[3,2-d]ピリミジン-2,4(3H,5H)-ジオン ハイドロクロライド ヘミハイドレート
1H NMR (400 MHz, DMSO) δ 8.12 (brs, 3H), 7.53-7.56 (m, 1H), 7.13-7.18 (m, 1H), 6.10-6.15 (m, 2H), 5.39-5.50 (m, 2H), 3.39 (s, 3H), 3.22-3.27 (m, 2H), 3.13 (s, 3H), 2.82-2.88 (m, 2H), 2.66-2.71 (m, 1H), 1.83-1.92 (m, 1H), 1.71-1.78 (m, 1H),1.40-1.52 (m, 2H).
MS (ESI+) 420(M++1, 100%).
mp 205~208 ℃
元素分析値
実測値 C, 51.49; H, 5.39; N, 14.93; Cl, 15.19; F, 3.92
理論値 (C20H25Cl2FN5O2.5)
C, 51.62; H, 5.41; N, 15.05; Cl, 15.24; F, 4.08
本発明の方法で製造した実施例1の結晶一塩酸塩0.5水和物(化合物A)および従来技術により製造した国際公開第2006/068163号パンフレット実施例6の化合物(化合物B)の無晶系粉末について、室温でのそれぞれの吸湿性を測定した。その結果を図4および図5に示す。
本発明の方法で製造した実施例1の一塩酸塩0.5水和物(化合物A)の結晶および従来技術により製造した国際公開第2006/068163号パンフレット実施例6の化合物(化合物B)の無晶系粉末について、それぞれについて1000Luxおよび4000Luxの光源下で2週間保存後の残存率を測定した。その結果を表1に示す。
移動相(A/B):10 mMりん酸ナトリウム緩衝液(pH= 6.9)/CH3CN
移動相(Bの割合):30%(0 min)→90%(45 min)
カラム温度:40℃
流速:1 mL/min
UV波長:254 nm
In vitro DPP-IV 阻害作用測定試験
種々の濃度で被験化合物を含む溶液を調製し、マイクロアッセイプレートに添加した。更にヒト組換えDPP IV(R&D system)を添加し、室温にて100から110分間プレインキュベートした後、基質(Glycyl-L-proline 4-methylcoumaryl-7-amide、ペプチド研究所;最終濃度40 μmol/L)を添加して酵素反応を開始した。蛍光プレートリーダーを用いて、基質の添加開始10分後から10分間、蛍光変化を経時的に測定し(励起波長380 nm/測定波長 460 nm)、酵素反応速度を求めた。得られた結果より、50%の阻害を示す化合物濃度をIC50値として算出した。
本発明化合物は、前糖尿病状態における食後高血糖の抑制、非インスリン依存性糖尿病の治療、関節炎や関節リウマチなど自己免疫性疾患の治療、腸管粘膜疾患の治療、成長促進、移植臓器片の拒絶反応抑制、肥満治療、摂食障害の治療、HIV感染の治療、癌転移の抑制、前立腺肥大症の治療、歯根膜炎の治療、および骨粗鬆症の治療に有用である。
Claims (7)
- 6-[(3R)-3-アミノピペリジン-1-イル]-5-(2-クロロ-5-フルオロベンジル)-1,3-ジメチル-1H-ピロロ[3,2-d]ピリミジン-2,4(3H,5H)-ジオン モノハイドロクロライド ヘミハイドレート。
- 粉末X線回折において回折角(2θ): 8.6±0.2°, 14.9±0.2°および15.4±0.2° に主ピークを示す、請求項1記載の化合物。
- 粉末X線回折において回折角(2θ): 4.3±0.2°, 8.6±0.2°, 12.9±0.2°, 14.9±0.2°, 15.4±0.2°, 17.1±0.2°, 18.7±0.2°, 23.0±0.2°, 25.2±0.2°,26.4±0.2°,30.3±0.2°および34.7±0.2° に主ピークを示す、請求項1記載の化合物。
- 請求項1~3のいずれか一項に記載の化合物を有効成分として含有する医薬。
- 請求項1~3のいずれか一項に記載の化合物を有効成分として含有するジペプチジルペプチダーゼ-IV阻害剤。
- 請求項1~3のいずれか一項に記載の化合物を有効成分として含有する糖尿病治療剤。
- 治療を必要とする患者に、請求項1~3のいずれか一項に記載の化合物の有効量を投与することからなる、糖尿病の治療方法。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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US12/921,529 US20110009433A1 (en) | 2008-03-10 | 2009-03-03 | Bicyclic pyrrole compound |
CA2718252A CA2718252A1 (en) | 2008-03-10 | 2009-03-03 | Bicyclic pyrrole compound |
MX2010009873A MX2010009873A (es) | 2008-03-10 | 2009-03-03 | Compuesto de pirrol biciclico. |
AU2009222696A AU2009222696A1 (en) | 2008-03-10 | 2009-03-03 | Bicyclic pyrrole compound |
BRPI0908168A BRPI0908168A2 (pt) | 2008-03-10 | 2009-03-03 | composto, medicamento, inibidor de dipeptidil peptidase-iv, agente terapêutico para diabetes, e, método de tratamento de diabetes |
EP09721067A EP2264034A1 (en) | 2008-03-10 | 2009-03-03 | Bicyclic pyrrole compound |
CN2009801085112A CN101970442A (zh) | 2008-03-10 | 2009-03-03 | 二环吡咯化合物 |
JP2010502774A JPWO2009113423A1 (ja) | 2008-03-10 | 2009-03-03 | 二環性ピロール化合物 |
IL208060A IL208060A0 (en) | 2008-03-10 | 2010-09-07 | Bicyclic pyrrole compound |
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JP2008059471 | 2008-03-10 | ||
JP2008-059471 | 2008-03-10 |
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PCT/JP2009/053910 WO2009113423A1 (ja) | 2008-03-10 | 2009-03-03 | 二環性ピロール化合物 |
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US (1) | US20110009433A1 (ja) |
EP (1) | EP2264034A1 (ja) |
JP (1) | JPWO2009113423A1 (ja) |
KR (1) | KR20100137452A (ja) |
CN (1) | CN101970442A (ja) |
AU (1) | AU2009222696A1 (ja) |
BR (1) | BRPI0908168A2 (ja) |
CA (1) | CA2718252A1 (ja) |
IL (1) | IL208060A0 (ja) |
MX (1) | MX2010009873A (ja) |
RU (1) | RU2010141562A (ja) |
WO (1) | WO2009113423A1 (ja) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2011161030A1 (de) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclisch substituierte methoxyphenylderivate mit oxogruppe, verfahren zu ihrer herstellung und ihre verwendung als gpr40 rezeptor modulatoren |
WO2012004269A1 (de) | 2010-07-05 | 2012-01-12 | Sanofi | ( 2 -aryloxy -acetylamino) - phenyl - propionsäurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012004270A1 (de) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclisch substituierte 1,3-propandioxidderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012010413A1 (de) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylen-substituierte hydroxy-phenyl-hexinsäuren, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2014064215A1 (en) | 2012-10-24 | 2014-05-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL |
WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003004496A1 (en) * | 2001-07-03 | 2003-01-16 | Novo Nordisk A/S | Dpp-iv-inhibiting purine derivatives for the treatment of diabetes |
WO2003024965A2 (en) * | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
JP2003300977A (ja) * | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | キサンチン誘導体 |
WO2003104229A1 (ja) * | 2002-06-06 | 2003-12-18 | エーザイ株式会社 | 新規縮合イミダゾール誘導体 |
WO2006068163A1 (ja) | 2004-12-24 | 2006-06-29 | Dainippon Sumitomo Pharma Co., Ltd. | 二環性ピロール誘導体 |
WO2007071738A1 (en) * | 2005-12-23 | 2007-06-28 | Novartis Ag | Condensed heterocyclic compounds useful as dpp-iv inhibitors |
JP2007262040A (ja) | 2006-03-30 | 2007-10-11 | Dainippon Sumitomo Pharma Co Ltd | 3−置換アミノ環状アミン誘導体の製造方法 |
-
2009
- 2009-03-03 AU AU2009222696A patent/AU2009222696A1/en not_active Abandoned
- 2009-03-03 CN CN2009801085112A patent/CN101970442A/zh active Pending
- 2009-03-03 RU RU2010141562/04A patent/RU2010141562A/ru unknown
- 2009-03-03 US US12/921,529 patent/US20110009433A1/en not_active Abandoned
- 2009-03-03 KR KR1020107020156A patent/KR20100137452A/ko not_active Application Discontinuation
- 2009-03-03 CA CA2718252A patent/CA2718252A1/en not_active Abandoned
- 2009-03-03 EP EP09721067A patent/EP2264034A1/en not_active Withdrawn
- 2009-03-03 BR BRPI0908168A patent/BRPI0908168A2/pt not_active Application Discontinuation
- 2009-03-03 WO PCT/JP2009/053910 patent/WO2009113423A1/ja active Application Filing
- 2009-03-03 JP JP2010502774A patent/JPWO2009113423A1/ja active Pending
- 2009-03-03 MX MX2010009873A patent/MX2010009873A/es not_active Application Discontinuation
-
2010
- 2010-09-07 IL IL208060A patent/IL208060A0/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003004496A1 (en) * | 2001-07-03 | 2003-01-16 | Novo Nordisk A/S | Dpp-iv-inhibiting purine derivatives for the treatment of diabetes |
WO2003024965A2 (en) * | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
JP2003300977A (ja) * | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | キサンチン誘導体 |
WO2003104229A1 (ja) * | 2002-06-06 | 2003-12-18 | エーザイ株式会社 | 新規縮合イミダゾール誘導体 |
WO2006068163A1 (ja) | 2004-12-24 | 2006-06-29 | Dainippon Sumitomo Pharma Co., Ltd. | 二環性ピロール誘導体 |
WO2007071738A1 (en) * | 2005-12-23 | 2007-06-28 | Novartis Ag | Condensed heterocyclic compounds useful as dpp-iv inhibitors |
JP2007262040A (ja) | 2006-03-30 | 2007-10-11 | Dainippon Sumitomo Pharma Co Ltd | 3−置換アミノ環状アミン誘導体の製造方法 |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2011161030A1 (de) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclisch substituierte methoxyphenylderivate mit oxogruppe, verfahren zu ihrer herstellung und ihre verwendung als gpr40 rezeptor modulatoren |
WO2012004269A1 (de) | 2010-07-05 | 2012-01-12 | Sanofi | ( 2 -aryloxy -acetylamino) - phenyl - propionsäurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012004270A1 (de) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclisch substituierte 1,3-propandioxidderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012010413A1 (de) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylen-substituierte hydroxy-phenyl-hexinsäuren, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2014064215A1 (en) | 2012-10-24 | 2014-05-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL |
WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
Also Published As
Publication number | Publication date |
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IL208060A0 (en) | 2010-12-30 |
KR20100137452A (ko) | 2010-12-30 |
MX2010009873A (es) | 2010-09-30 |
CA2718252A1 (en) | 2009-09-17 |
BRPI0908168A2 (pt) | 2015-12-15 |
US20110009433A1 (en) | 2011-01-13 |
CN101970442A (zh) | 2011-02-09 |
RU2010141562A (ru) | 2012-04-20 |
AU2009222696A1 (en) | 2009-09-17 |
EP2264034A1 (en) | 2010-12-22 |
JPWO2009113423A1 (ja) | 2011-07-21 |
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