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WO2009128360A1 - Agent thérapeutique pour le diabète - Google Patents

Agent thérapeutique pour le diabète Download PDF

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Publication number
WO2009128360A1
WO2009128360A1 PCT/JP2009/057089 JP2009057089W WO2009128360A1 WO 2009128360 A1 WO2009128360 A1 WO 2009128360A1 JP 2009057089 W JP2009057089 W JP 2009057089W WO 2009128360 A1 WO2009128360 A1 WO 2009128360A1
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WIPO (PCT)
Prior art keywords
agent
hypoglycemic
insulin
hypoglycemic agent
chloro
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PCT/JP2009/057089
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English (en)
Japanese (ja)
Inventor
道子 岸野
英仁 須軽
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大日本住友製薬株式会社
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Publication of WO2009128360A1 publication Critical patent/WO2009128360A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a hypoglycemic agent useful for the treatment of diabetes and the like by a combination of a pyrrolopyrimidinedione derivative having a dipeptidyl peptidase IV (DPP-IV) inhibitory action and a therapeutic agent for diabetes.
  • DPP-IV dipeptidyl peptidase IV
  • Diabetes is a group of metabolic diseases whose main feature is chronic hyperglycemia due to insufficient insulin action.
  • Insulin secretion from the pancreas is known as one of the mechanisms for lack of insulin action.
  • Incretin a type of gastrointestinal hormone that is secreted from the digestive tract when ingested, acts on the pancreas to promote insulin secretion and plays an important role in blood glucose control through various actions.
  • Glucagon like peptide-1 (hereinafter GLP-1) is known as a typical incretin, but GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (hereinafter DPP-IV) present in the body.
  • DPP-IV dipeptidyl peptidase IV
  • Converted to DPP-IV inhibitors are antidiabetic drugs with a new mechanism of action that regulate glycemic control by extending the in vivo half-life of incretins such as GLP-1 (Non-patent Document 1).
  • Drugs currently used for the treatment of diabetes include oral hypoglycemic drugs and insulin.
  • Oral hypoglycemic drugs are roughly classified into insulin secretory hypoglycemic drugs and non-insulin secretory hypoglycemic drugs.
  • insulin secretion-type hypoglycemic agents include SU agents that bind to sulfonylurea (SU) receptors of pancreatic ⁇ cells and exhibit an insulin secretion stimulating effect, fast-acting insulin secretion promoters, and the like.
  • SU sulfonylurea
  • non-insulin secretory hypoglycemic agent inhibits gluconeogenesis in the liver, suppresses sugar absorption from the gastrointestinal tract, and enhances insulin sensitivity in peripheral tissues
  • nuclear receptor transcription factor Peroxisome Examples include thiazolidine derivatives known as insulin resistance improving agents that have an activity of activating proliferator-activated receptor (PPAR) ⁇ , and ⁇ -glucosidase inhibitors that have a sugar absorption inhibitory effect.
  • PPAR proliferator-activated receptor
  • Non-Patent Document 2 So far, it has been known that DPP-IV inhibitors are used in combination with SU, such as glimepiride, etc., metformin, which is a biguanide, and pioglitazone, which is a thiazolidine derivative (Non-Patent Documents 3 and 4). However, it has not been reported that a combination of a pyrrolopyrimidinedione derivative having a DPP-IV inhibitory action and a therapeutic agent for diabetes is useful as a hypoglycemic agent. Patent Document 1 describes a pyrrolopyrimidinedione derivative having DPP-IV inhibitory activity. International Publication No.
  • An object of the present invention is to provide a hypoglycemic agent that is useful for the treatment of diabetes and the like and has no side effects.
  • the inventors found for the first time that the hypoglycemic effect was enhanced by combining a pyrrolopyrimidinedione derivative having a DPP-IV inhibitory action with pioglitazone or metformin as a therapeutic agent for diabetes, It has been found that it is extremely useful for practical use as a medicine, and the present invention has been completed.
  • the present invention [1] Antidiabetic drug and 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2 -d] a hypoglycemic agent in combination with pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof; [2] The hypoglycemic agent according to [1], wherein the antidiabetic agent is a non-insulin secretory hypoglycemic agent; [3] The hypoglycemic agent according to [1], wherein the antidiabetic agent is an insulin secretory hypoglycemic agent; [4] The hypoglycemic agent according to [1], wherein the antidiabetic agent is an insulin preparation; [5] The hypoglycemic agent according to [2], wherein the non-insulin secretory hypoglycemic agent is an insulin sensitizer
  • the hypoglycemic agent of the present invention has an excellent postprandial hyperglycemic correcting effect and is useful for the treatment of diabetes and the like.
  • the hypoglycemic agent of the present invention has an excellent hypoglycemic effect and blood insulin elevating effect on diabetic patients, and further diabetic to diabetic complications (eg, diabetic neuropathy, diabetic nephropathy, diabetic retina). Development to arteriosclerosis).
  • the hypoglycemic agent of the present invention can reduce the dose of the antidiabetic agent while having a certain hypoglycemic effect, the side effects of the antidiabetic agent can be reduced.
  • hypoglycemic agent of the present invention can be safely administered over a long period to patients suffering from diabetes.
  • FIG. 1 shows the blood glucose level transition of the oral glucose tolerance test carried out 30 minutes after administration on the 15th day (mean ⁇ SD).
  • ⁇ indicates solvent
  • ⁇ indicates compound A (10 mg / kg)
  • ⁇ indicates pioglitazone (PIO) (10 mg / kg)
  • ⁇ indicates compound A (10 mg / kg) + PIO (10 mg / kg) .
  • the figure on the right shows the area under the blood glucose level curve of the oral glucose tolerance test (mean ⁇ SD). ** P ⁇ 0.01 (comparison with solvent group), ## P ⁇ 0.01 (comparison with compound A group), $$ P ⁇ 0.01 (comparison with PIO group), (Student's t-test).
  • FIG. 2 shows HbA1c before and after the administration of Compound A (10 mg / kg), pioglitazone (PIO) (10 mg / kg), or both of these drugs daily for 21 days to db / db mice (mean ⁇ SD). ** P ⁇ 0.01 (comparison with solvent group), ## P ⁇ 0.01 (comparison with compound A group), $ P ⁇ 0.05 (comparison with PIO group), (Student's t test).
  • FIG. 3 shows the area under the blood glucose level curve during the oral glucose tolerance test performed 30 minutes after administration (mean ⁇ SD). ** P ⁇ 0.01 (Comparison with the solvent group), ## P ⁇ 0.01 (Comparison with the compound A group), $ P ⁇ 0.05 (Comparison with the Met group), (Student's t test).
  • the therapeutic agent for diabetes of the present invention means a compound that lowers blood glucose.
  • the compound may be peptidic or non-peptidic.
  • the form of the antidiabetic agent may be different before and after administration to the living body. That is, the therapeutic agent for diabetes may be an “active metabolite” having anti-diabetic activity after it has undergone in vivo metabolism to become a structural change body.
  • the therapeutic agent for diabetes may be a “prodrug” that is converted into an active form by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
  • Specific examples of antidiabetic agents include oral hypoglycemic agents and insulin preparations.
  • insulin secretion-type hypoglycemic agent as an oral hypoglycemic agent
  • examples of the insulin secretion-type hypoglycemic agent as an oral hypoglycemic agent include SU agents and fast-acting insulin secretion promoters.
  • examples of the SU agent include glibenclamide, gliclazide, glipizide, glimepiride and the like
  • examples of the fast-acting insulin secretagogue include repaglinide, nateglinide, mitiglinide and the like.
  • examples of the non-insulin secretion-type hypoglycemic agent as an oral hypoglycemic agent include insulin resistance improving agents, biguanide drugs, ⁇ -glucosidase inhibitors and the like.
  • insulin sensitizers include pioglitazone or a salt thereof, or rosiglitazone or a salt thereof, Aleglitazar (R1439), TAK-379, Reglixane (JTT-501), Netoglitazone (Netoglitazone) (MCC-555), Riboglitazone (CS-011), Tesaglitazar (AZ-242), Ragaglitazar (NN-622), Muraglitazar (BNS-298585), Edaglitazone ( Edaglitazone) (BM-13-1258), Naveglitazar (LY-818), Metaglidasen (MBX-102), Balaglitazone (NN-2344), and the like.
  • a thiazolidinedione compound Preferably a thiazolidinedione compound, more preferably pioglitazone or a salt thereof.
  • biguanides include metformin or a salt thereof, buformin or a salt thereof, or phenformin or a salt thereof.
  • metformin hydrochloride is used.
  • the ⁇ -glucosidase inhibitor include voglibose, acarbose, miglitol, emiglitate and the like.
  • Other specific examples of compounds that lower blood glucose include GLP-1 preparations, sodium-dependent glucose transporter (SGLT) inhibitors, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors, glucokinase activators, and the like.
  • GLP-1 preparations include liraglutide, exenatide, Inslinotropin (GLP-1), Albiglutide (GSK-716155), CJC-1131 (DAC; GLP-1), AVE-0010 (ZP-10 , ZP-10A), BIM-51077 (ITM-077, R-1583), GLP1-INT (TT-233 / GLP1), PC-DAC: Exendin-4 (CJC-1134-PC), etc.
  • SGLT inhibitors As, for example, Dapagliflozin, Sergliflozin, Remogliflozin, AVE-2268, GSK-189075, ASP-1941, YM-543, KGT1075, TA7284, CDG-452 (R-7201), SAR-7226, KGA-2727, etc. Can be mentioned.
  • the 11 ⁇ -hydroxysteroid dehydrogenase inhibitor include PF-915275 and INCB123739
  • examples of the glucokinase activator include R1551, AZD6370, LY2599506, TTP355, and the like.
  • salts include salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate or nitrate, or acetate, oxalate, citrate, malate, tartaric acid, for example.
  • Salts with organic acids such as salts, fumarate, maleate, methanesulfonate or benzenesulfonate;
  • a salt with an organic base such as diethanolamine salt, ethylenediamine salt or N-methylglucamine salt, a salt with alkaline earth metal such as calcium salt or magnesium salt, or an alkali such as lithium salt, potassium salt or sodium salt
  • examples include salts with metals.
  • the antidiabetic agent or the like may be an anhydride or a solvate such as a hydrate.
  • preferable examples of the pharmaceutically acceptable salt include hydrochloride. More preferred 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 or a pharmaceutically acceptable salt thereof includes 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:
  • the hypoglycemic agent of the present invention is a combination of (A) a therapeutic agent for diabetes, etc., and a compound A, etc., and (A) a therapeutic agent for diabetes, etc., and (B) a compound A, etc. can be combined at the time of administration. Anything is possible. Therefore, the pharmaceutical composition of the present invention can be used in combination with (A) a therapeutic agent for diabetes, and (B) a compound A or the like at the time of administration. Even if it is a single preparation obtained by simultaneously compounding compound A etc., at least two kinds of preparations obtained by separately formulating (A) a therapeutic agent for diabetes, etc. and (B) compound A etc. It may be a combination.
  • the dosage form is not particularly limited.
  • compositions containing (A) a therapeutic agent for diabetes and the like and (B) compound A or the like, that is, administration as a single preparation (b) ( (B) Simultaneous administration of two preparations obtained by separately formulating a therapeutic agent for diabetes, etc., and (B) Compound A, etc.
  • (A) a therapeutic agent for diabetes and the like, and (B) a concomitant drug in combination with compound A and the like, and the concomitant drug can be used for the purpose of enhancing blood glucose lowering action and blood insulin raising action.
  • the hypoglycemic agent 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, transplanted organ fragment It is useful for the suppression of rejection, treatment of obesity, treatment of eating disorders, treatment of HIV infection, suppression of cancer metastasis, treatment of benign prostatic hyperplasia, treatment of periodontitis, and treatment of osteoporosis.
  • the hypoglycemic agent of the present invention is used as a pharmaceutical composition as an oral or parenteral (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, Or nasally).
  • oral or parenteral eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, Or nasally.
  • 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 of the hypoglycemic agent of the present invention varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but is usually non-insulin for adults (weight 50 kg).
  • Each of the secretory hypoglycemic agent and Compound A is administered in an amount of 0.01 to 3000 mg / day, preferably 0.1 to 2550 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.
  • Example 1 C57BL / KsJ-db / db mice (hereinafter referred to as db / db mice) (12-week-old, male, CLEA Japan), which is a type 2 diabetes model, combined with an insulin resistance improving drug and a DPP-IV inhibitor The obtained antidiabetic action was examined.
  • db / db mice were divided into 4 groups (12 each), 1 group with solvent, 2 group with 10 mg / kg Compound A, 3 group with 10 mg / kg pioglitazone (trade name: Actos: Takeda Yakuhin Kogyo Co., Ltd.) was orally administered by gavage once every day so that Compound A and pioglitazone were 10 mg / kg each.
  • HbA1c glycated hemoglobin
  • Table 1 shows the blood glucose level at any time 1 hour after administration on the seventh day from the start of administration.
  • Tables 2, 3 and 1 show the blood glucose transition and the area under the blood glucose curve in the oral glucose tolerance test on the 15th day from the start of administration.
  • Table 4 and FIG. 2 show HbA1c before the start of administration and on the 21st day of administration.
  • Example 2 Using Zucker fatty rats (13 weeks old, male, Japanese Charles River), a type 2 diabetes model, the hypoglycemic effect obtained by the combination of metformin, a biguanide, and a DPP-IV inhibitor was examined.
  • Zucker fatty rats were divided into 4 groups (6-7 each), fasted for 24 hours, 1 group with solvent, 2 group with 0.03 mg / kg Compound A, 3 group with 300 mg / kg Metformin (Sigma) was administered by single oral gavage so that Compound A and metformin were 0.03 mg / kg and 300 mg / kg, respectively, in Group 4. After 30 minutes, a glucose tolerance test (2 g / kg glucose) was performed. As shown in Table 5, Table 6, and FIG. 3, a synergistic blood glucose lowering effect was recognized by using Compound A and metformin together.
  • Example 3 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, Isopropanol (4.49 kg) containing 15% water was added to 4 (3H, 5H) -dione hydrochloride (see WO 2006/068163) and heated to 80 ° C. After becoming a homogeneous solution, ethyl acetate (16.64 kg) was added dropwise. After slowly returning to room temperature, the mixture was stirred in an ice bath for 1 hour.
  • Example 4 The following component 1-5 is mixed, wet granulated using an aqueous solution of component 6, and mixed with component 7. The resulting mixture is tableted to obtain 620 mg tablets. 1. Compound A 10 mg / tablet 2. 2. Metformin per 500 mg / tablet Lactose 72.5mg / tablet 4. Corn starch 30 mg / tablet 5. Carboxymethylcellulose calcium 5mg / tablet 6. Hydroxypropylcellulose (HPC-L) 2 mg / tablet 7. Magnesium stearate 0.5mg / tablet
  • Example 5 The following component 1-5 is mixed, wet granulated using an aqueous solution of component 6, and mixed with component 7. The resulting mixture is tableted to obtain 135 mg tablets. 1. Compound A 10 mg / tablet 2. 2. pioglitazone 15mg / tablet Lactose 72.5mg / tablet 4. Corn starch 30 mg / tablet 5. Carboxymethylcellulose calcium 5mg / tablet 6. Hydroxypropylcellulose (HPC-L) 2 mg / tablet 7. Magnesium stearate 0.5mg / tablet
  • Example 6 (1) The following components 1-4 are mixed, wet granulated using the aqueous solution of component 5, and mixed with component 6. The resulting mixture is tableted to obtain 120 mg tablets. 1. Compound A 10 mg / tablet 2. Lactose 72.5 mg / tablet 3 Corn starch 30 mg / tablet 4 Carboxymethylcellulose calcium 5 mg / tablet 5. Hydroxypropylcellulose (HPC-L) 2 mg / tablet 6. Magnesium stearate 0.5 mg / tablet (2) The above tablet (1) and metformin 500 mg, or the above tablet (1) and pioglitazone 15 mg are simultaneously administered to diabetic patients.
  • HPC-L Hydroxypropylcellulose
  • the hypoglycemic agent of the present invention has an excellent postprandial hyperglycemic correcting effect and is useful for the treatment of diabetes and the like.
  • the hypoglycemic agent of the present invention has an excellent hypoglycemic effect and blood insulin elevating effect on diabetic patients, and further diabetic to diabetic complications (eg, diabetic neuropathy, diabetic nephropathy, diabetic retina). Development to arteriosclerosis).
  • the hypoglycemic agent of the present invention can reduce the dose of the antidiabetic agent while having a certain hypoglycemic effect, the side effects of the antidiabetic agent can be reduced.
  • hypoglycemic agent of the present invention can be safely administered over a long period to patients suffering from diabetes.

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Abstract

L'invention porte sur un agent hypoglycémique utile pour le traitement du diabète ou similaire. L'agent hypoglycémique comprend une combinaison de 6-[(3R)-3-aminopipéridin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-diméthyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione qui est un dérivé de la pyrrolopyrimidinedione ayant une activité inhibitrice sur la dipeptidyl peptidase IV (DPP-IV) ou d'un sel pharmaceutiquement acceptable de celle-ci, et d'un agent thérapeutique pour le diabète.
PCT/JP2009/057089 2008-04-18 2009-04-07 Agent thérapeutique pour le diabète WO2009128360A1 (fr)

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JP2008-108499 2008-04-18

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
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
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

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WO2006022428A1 (fr) * 2004-08-26 2006-03-02 Takeda Pharmaceutical Company Limited Remède contre le diabète
WO2006068163A1 (fr) * 2004-12-24 2006-06-29 Dainippon Sumitomo Pharma Co., Ltd. Dérivés bicycliques de pyrrole
WO2006129785A1 (fr) * 2005-06-03 2006-12-07 Mitsubishi Tanabe Pharma Corporation Agents pharmaceutiques concomitants et leur utilisation
WO2007033350A1 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
WO2007033266A2 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003535898A (ja) * 2000-06-19 2003-12-02 スミスクライン ビーチャム パブリック リミテッド カンパニー 真性糖尿病の治療用のジペプチジルペプチダーゼｉｖ阻害剤および他の抗糖尿病剤の組み合わせ
WO2006022428A1 (fr) * 2004-08-26 2006-03-02 Takeda Pharmaceutical Company Limited Remède contre le diabète
WO2006068163A1 (fr) * 2004-12-24 2006-06-29 Dainippon Sumitomo Pharma Co., Ltd. Dérivés bicycliques de pyrrole
WO2006129785A1 (fr) * 2005-06-03 2006-12-07 Mitsubishi Tanabe Pharma Corporation Agents pharmaceutiques concomitants et leur utilisation
WO2007033350A1 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
WO2007033266A2 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP3646859A1 (fr) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Traitement de patients diabétiques génotypés avec des inhibiteurs de dpp-iv tels que la linagliptine
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
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
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

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