WO2011002011A1

WO2011002011A1 - Combined medicine of sglt1 inhibitor and dpp-iv inhibitor

Info

Publication number: WO2011002011A1
Application number: PCT/JP2010/061126
Authority: WO
Inventors: 芳和藤森; 俊浩井上; 浩加藤; 俊哉中村
Original assignee: キッセイ薬品工業株式会社; 大日本住友製薬株式会社
Priority date: 2009-07-01
Filing date: 2010-06-30
Publication date: 2011-01-06
Also published as: TW201105338A; JPWO2011002011A1

Abstract

A medicinal agent useful for the treatment of hyperglycemia-related diseases, which comprises a combination of 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H- pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2- dimethylpropionamide, which has an inhibitory activity on SGLT1 (sodium-dependent glucose cotransporter 1), or a pharmacologically acceptable salt thereof and a DPP-IV inhibitor.

Description

Medicament combining SGLT1 inhibitor and DPP-IV inhibitor

The present invention relates to a pharmaceutical comprising a combination of an SGLT1 inhibitor and a DPP-IV inhibitor. More specifically, 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2 , 2-dimethylpropionamide (hereinafter sometimes referred to as “compound 1”) or a pharmacologically acceptable salt thereof and a DPP-IV inhibitor.

Diabetes is a group of metabolic diseases whose main symptom is a chronically elevated blood glucose level (blood glucose level) due to insufficient insulin action. For the treatment of diabetes, dietary therapy and exercise therapy are usually performed, and when the target glycemic control cannot be achieved, drug therapy using an oral hypoglycemic drug or an insulin preparation is performed. As oral hypoglycemic drugs, sulfonylurea drugs (SU drugs), fast-acting insulin secretagogues, α-glucosidase inhibitors, insulin resistance-improving drugs such as thiazolidine drugs, and biguanides are used depending on the patient's condition. Yes. However, when these drugs are used alone, satisfactory blood glucose control may not be obtained, and various side effects have been reported depending on each drug. For example, SU drugs are reported to be secondary ineffective due to hypoglycemia or long-term use, α-glucosidase inhibitors are reported to be diarrhea, insulin resistance improvers are related to weight gain and edema, biguanides are reported to be lactic acidosis, etc. Yes. That is, although a diabetes therapeutic drug having a different mechanism of action has been proposed or put into practical use, it is not easy to select the most suitable drug for each patient because the pathology and symptoms of diabetic patients are complicated.

If continuous administration of blood glucose control cannot be achieved by single-dose administration of oral hypoglycemic drugs, it may be necessary to use oral hypoglycemic drugs in combination with insulin or in combination with insulin. From the viewpoint of safety and safety, it is required to provide a highly useful combination of drugs. That is, early establishment of a combination therapy with an effective combination that can exhibit excellent effects without increasing the occurrence of side effects such as hypoglycemia and pancreatic exhaustion is desired.

In recent years, there has been a compound that inhibits sodium-dependent glucose cotransporter 1 (SGLT1) and inhibits or delays the absorption of carbohydrates such as glucose in the small intestine, thereby exerting an inhibitory effect on the increase in blood glucose level. It has been reported and is expected as a preventive / therapeutic agent for diabetes and the like by a novel mechanism of action (see, for example, Patent Documents 1 to 4). Patent Document 1 discloses the formula (I) used for the medicament of the present invention:

Compound 1 (chemical name: 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy } Various pyrazole derivatives including propylamino) -2,2-dimethylpropionamide) have been described.

Glucagon-like peptide 1 (GLP-1) is one of the incretins (gastrointestinal hormones that promote insulin secretion during food intake) and is a potent insulin secretion enhancer, but dipeptidyl peptidase-IV ( DPP-IV) is known to be hydrolyzed (Non-patent Documents 1 and 2). Various DPP-IV inhibitors that regulate blood glucose levels in type 2 diabetes and impaired glucose tolerance by suppressing the inactivation of GLP-1 by DPP-IV and extending the duration of endogenous GLP-1 Has been developed. For example, sitagliptin is a DPP-IV inhibitor represented by the following formula (II), has an action of increasing active GLP-1, and is marketed as a therapeutic agent for type 2 diabetes.

Formula (III):

(Chemical name: 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 (compound 3)) is known (Patent Document 5).

Various combinations of these new anti-diabetic drugs with other anti-diabetic drugs have been studied. For example, the combined use of a DPP-IV inhibitor with the biguanide metformin or the PPARγ agonist pioglitazone has been reported. (For example, see Non-Patent Documents 1 and 3). In addition, for the SGLT1 inhibitor described above, Patent Document 1 has a general description of a combination with various antidiabetic drugs including a DPP-IV inhibitor. Nothing has been reported so far.

In any of the above-mentioned documents, a drug comprising a combination of an SGLT1 inhibitor such as Compound 1 or a pharmacologically acceptable salt thereof and a DPP-IV inhibitor has a remarkable blood glucose increase inhibitory effect or GLP-1 concentration. There is no description or suggestion that it is highly useful for the treatment of diseases caused by hyperglycemia.

International Publication No. 2004/018491 Pamphlet WO 02/098893 pamphlet International Publication No. 2004/014932 Pamphlet International Publication No. 2004/019958 Pamphlet International Publication No. 2006/068163 Pamphlet

The present invention provides a medicament comprising a combination of Compound 1 or a pharmacologically acceptable salt thereof and a DPP-IV inhibitor, which is useful for the treatment of diseases caused by hyperglycemia.

As a result of intensive studies in view of the above problems, the present inventors have found that SGLT1 inhibitor Compound 2 (Sebacate salt of Compound 1) and DPP-IV inhibitor Sitagliptin or Compound X (Compound 3), as described later, First monohydrochloride 1/2 hydrate) was found for the first time to significantly suppress the increase in blood glucose and enhance the action of GLP-1 compared to the case where each was used alone. Invented the invention.

That is, the present invention
Item 1: 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2, SGLT1 inhibitor which is 2-dimethylpropionamide or a pharmacologically acceptable salt thereof, sitagliptin, vildagliptin, alogliptin, saxagliptin, dutogliptin, melogliptin, carmeliptin, linagliptin and 6-[(3R) -3-aminopiperidine- 1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione and their drugs A pharmaceutical comprising a combination of a DPP-IV inhibitor selected from the group consisting of physically acceptable salts,
Item 2: The DPP-IV inhibitor is sitagliptin or 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H- Item 1. The pharmaceutical according to Item 1, which is pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione, or a pharmaceutically acceptable salt thereof.
Item 3: The pharmaceutical according to Item 1 or 2, wherein the DPP-IV inhibitor is sitagliptin or a pharmacologically acceptable salt thereof,
Item 4: The DPP-IV inhibitor is 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [ Item 3. The drug according to Item 1 or 2, which is 3,3-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmacologically acceptable salt thereof,
Item 5: The medicament according to any one of Items 1 to 4, which is used for treating a disease caused by hyperglycemia.
Item 6: The disease according to Item 5, wherein the disease caused by hyperglycemia is a disease selected from the group consisting of diabetes, impaired glucose tolerance, impaired fasting blood glucose, diabetic complications, obesity, and hyperinsulinemia. Medicine,
Item 7: The medicament according to any one of Items 1 to 4, which is a postprandial hyperglycemic agent,
Item 8: The pharmaceutical or the like according to any one of Items 1 to 4, which is a GLP-1 action potentiator.

Moreover, as one aspect, the present invention comprises a combination of Compound 1 or a pharmacologically acceptable salt thereof and a DPP-IV inhibitor, and sufficient blood glucose can be obtained by administration of an SGLT1 inhibitor or DPP-IV inhibitor. The present invention relates to a medicine or the like that can be used for treating a disease caused by hyperglycemia, improving postprandial hyperglycemia, or enhancing GLP-1 action in a patient who cannot obtain control.

The medicament of the present invention has a strong blood glucose elevation-inhibiting action and a GLP-1 enhancing action, and is extremely useful for the treatment of diseases caused by hyperglycemia. This medicine has excellent postprandial hyperglycemia improvement effect, and suppresses the progress of diabetes treatment and the progress from diabetes to diabetic complications (eg, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis) Useful for. In addition, superior effects typified by enhancing blood glucose elevation-inhibiting action, increasing active GLP-1 concentration, reducing excessive insulin secretion, etc. compared to using SGLT1 inhibitor or DPP-IV inhibitor alone Have Furthermore, by appropriately selecting the contents of both drugs, the administration method and the dosage, etc., it is useful for stable blood glucose elevation inhibiting action and side effect reduction even for long-term drug administration. In addition, compared to the administration of a DPP-IV inhibitor alone, the plasma active GLP-1 concentration is increased and sustained, but the previously known effect of suppressing the increase in insulin concentration has been demonstrated. Exerts excellent physiological effects of active GLP-1 (eg, appetite suppressive action, pancreatic β-cell protective action) Therefore, it is also useful in various pathologies associated with excessive secretion of insulin (eg, vascular complications, hypoglycemia, arteriosclerosis, obesity).

Zucker-fa / fa rats (ZF rats) were orally administered by gavage with Compound 2, Compound X and both of these agents. The diagram on the left side of FIG. 1 shows the blood glucose level change in the oral mixed carbohydrate tolerance test performed 30 minutes after drug administration (mean value ± SE). ◆ indicates solvent, ■ indicates compound 2 (0.03 mg / kg), ▲ indicates compound X (0.3 mg / kg), ● indicates compound 2 (0.03 mg / kg) + compound X (0.3 mg / kg) . The figure on the right shows the area under the increased blood glucose curve of the oral mixed carbohydrate tolerance test (mean ± SE). * P <0.05, ** P <0.01, *** P <0.001 (comparison with vehicle group); ## P <0.01 (comparison with compound 2 administration group); $$ P <0.01 (compound X administration group) Comparison with all) Student t test.

ZF rats were orally administered by gavage with Compound 2, Compound X and both of these agents. The diagram on the left side of FIG. 2 shows changes in plasma active GLP-1 concentration in the oral mixed carbohydrate tolerance test performed 30 minutes after drug administration (mean ± SE). ◆ indicates solvent, ■ indicates compound 2 (0.03 mg / kg), ▲ indicates compound X (0.3 mg / kg), ● indicates compound 2 (0.03 mg / kg) + compound X (0.3 mg / kg) . The figure on the right shows the area under the increased plasma active GLP-1 concentration curve in the oral mixed carbohydrate tolerance test (mean ± SE). ** P <0.01 (compared with solvent group), Student's t test.

ZF rats were orally administered by gavage with Compound 2, Compound X and both of these agents. The graph on the left side of FIG. 3 shows changes in plasma insulin concentration in the oral mixed carbohydrate tolerance test performed 30 minutes after drug administration (mean value ± SE). ◆ indicates solvent, ■ indicates compound 2 (0.03 mg / kg), ▲ indicates compound X (0.3 mg / kg), ● indicates compound 2 (0.03 mg / kg) + compound X (0.3 mg / kg) . The figure on the right shows the area under the increased plasma insulin concentration curve for the oral mixed carbohydrate tolerance test (mean ± SE).

Hereinafter, the present invention will be described in detail.

A preferred “SGLT1 inhibitor” in the present invention includes Compound 1 or a pharmacologically acceptable salt thereof.

“Compound 1 or a pharmacologically acceptable salt thereof” can be produced by a method described in the literature, a method analogous thereto, or a method described in Reference Examples (see, for example, Patent Document 1). Examples of the “pharmacologically acceptable salt of Compound 1” include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Acid addition salts with organic acids such as sebacic acid, salts with inorganic bases such as sodium salt and potassium salt, N-methyl-D-glucamine, N, N'-dibenzylethylenediamine, 2-aminoethanol, tris ( Hydroxymethyl) Addition salts with organic bases such as aminomethane, arginine, lysine, etc. are mentioned, acid addition salts with fumaric acid or sebacic acid (decanedioic acid) are preferred, and acid addition salts with sebacic acid Even more preferred.
The compound 1 or a pharmacologically acceptable salt thereof includes a hydrate or a solvate with a pharmacologically acceptable solvent (for example, ethanol).
Examples of the “pharmacologically acceptable salt of Compound 1” include “3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazole-4- Ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethylpropionamide / 1/2 fumarate dihydrate) ”or“ bis [3- (3- {4- [3- (β- D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethylpropionamide] monosebacinate (hereinafter “compound 2”) And compound 2 is more preferable.

As the SGLT1 inhibitor, in addition to “Compound 1 or a pharmacologically acceptable salt thereof”, a compound having selective inhibitory activity on SGLT1, that is, inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) A compound having a stronger inhibitory activity against SGLT1 than the activity may be used. Specific examples thereof include, for example, the compounds described in International Publication WO2007 / 129668 pamphlet, Japanese translations of PCT publication No. 2008-501745, International Publication WO2007 / 126117 pamphlet and the like or pharmacologically acceptable salts thereof. .

Examples of the compounds described in the pamphlet of International Publication No. WO2007 / 129668 include 4- {4- [2- (benzyloxy) ethoxy] -2-methylbenzyl} -5-isopropyl-1H-pyrazol-3-yl. 5-thio-β-D-glucopyranoside (Example 1); 4- [4- (2-hydroxyethoxy) -2-methylbenzyl] -5-isopropyl-1H-pyrazol-3-yl 5-thio-β- D-glucopyranoside (Example 2); 4- [4- (2-aminoethoxy) -2-methylbenzyl] -5-isopropyl-1H-pyrazol-3-yl 5-thio-β-D-glucopyranoside (Example) 3); benzyl [imino ({2- [4-({5-isopropyl-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazole-4-i } Methyl) -3-methylphenoxy] ethyl} amino) methyl] carbamate (Example 4); N- {2- [4-({5-isopropyl-3-[(5-thio-β-D-glucopyranosyl)] Oxy] -1H-pyrazol-4-yl} methyl) -3-methylphenoxy] ethyl} guanidine (Example 5); 4- {4- [2- (N-carbamoylmethylamino) ethoxy] -2-methylbenzyl } -5-isopropyl-1H-pyrazol-3-yl 5-thio-β-D-glucopyranoside (Example 6); N- (2-hydroxy-1,1-dimethylethyl) -N ′-{2- [ 4-({5-isopropyl-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) -3-methylphenoxy] ethyl} urea 7); 4- [4- (2- {bis [2- (benzyloxy) ethyl] amino} ethoxy) -2-methylbenzyl] -5-isopropyl-1H-pyrazol-3-yl 5-thio-β- D-glucopyranoside (Example 8); N- [2-hydroxy-1- (hydroxymethyl) -1-methylethyl] -N ′-{2- [4-({5-isopropyl-3-[(5- Thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) -3-methylphenoxy] ethyl} urea (Example 9); 4- (4- {2-[(2-hydroxy- 1,1-dimethylethyl) amino] ethoxy} -2-methylbenzyl) -5-isopropyl-1H-pyrazol-3-yl 5-thio-β-D-glucopyranoside (Example 10); N- [4- ( {5-Isopro Pyr-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl] urea (Example 11); N- [4-({5-isopropyl-3 -[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl] -N '-(pyridin-3-ylmethyl) urea (Example 12); (3E)- N- (2-hydroxy-1,1-dimethylethyl) -4- [4-({5-isopropyl} -3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazole-4- Yl} methyl) phenyl] but-3-enamide (Example 13); (3E) -N- (2-amino-1,1-dimethyl-2-oxoethyl) -4- [4-({5-isopropyl} -3-[(5-thio-β-D- Lucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl] but-3-enamide (Example 14); N- (2-hydroxy-1,1-dimethylethyl) -4- [4-({ 5-isopropyl-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl] butanamide (Example 15); N- (2-amino-1,1 -Dimethyl-2-oxoethyl) -4- [4-({5-isopropyl-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl] butanamide ( Example 16); N- (2-hydroxy-1,1-bis (hydroxymethyl) ethyl) -4- [4-({5-isopropyl-3-[(5-thio-β-D-glucopyranoshi) L) oxy] -1H-pyrazol-4-yl} methyl) phenyl] butanamide (Example 17); N- [1,1-dimethyl-2- (4-methylpiperazin-1-yl) -2-oxoethyl] -4- {4-({5-isopropyl-3-[(5-thio-β-D-glucopyranosyl) oxy] -1H-pyrazol-4-yl} methyl) phenyl} butanamide (Example 18) It is done.

Examples of the compound described in JP-T-2008-501745 include compounds represented by the following table.

Examples of the compounds described in International Publication WO2007 / 126117 pamphlet include compounds represented by the following table.

In the table, Py represents pyridyl, n-Hex represents hexyl, c-Hex represents cyclohexyl, The double bond represented by “CH═CH” in the substituent Z of the compounds 23, 25-29, 33 and 34 means a trans isomer.

Examples of the “DPP-IV inhibitor” in the present invention include sitagliptin, vildagliptin, alogliptin, saxagliptin, dutogliptin, melogliptin, caregliptin, caregliptin (Cegliptin), (Teneligliptin) ", linagliptin and 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, and DPP-IV inhibitors selected from the group consisting of pharmacologically acceptable salts thereof. Preferably, sitagliptin and 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d ] A DPP-IV inhibitor selected from the group consisting of pyrimidine-2,4 (3H, 5H) -dione, and pharmacologically acceptable salts thereof. Examples of pharmacologically acceptable salts thereof include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid. Organic such as benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Examples thereof include acid addition salts with acids, organic salts such as diethanolamine salts, ethylenediamine salts and N-methylglucamine salts, and salts with inorganic bases such as calcium salts, magnesium salts, sodium salts and potassium salts.

The above DPP-IV inhibitors include hydrates thereof and solvates with pharmacologically acceptable solvents (for example, ethanol and the like).

The above-mentioned DPP-IV inhibitor can also be produced by a method described in the literature or a method according to them (for example, International Publication WO2004 / 085378 Pamphlet, International Publication WO2004 / 085661 Pamphlet, International Publication WO2006 / 033848 Pamphlet, International publication WO00 / 34241 pamphlet etc.).

“Compound 3 or a pharmacologically acceptable salt thereof” can be easily produced by a method described in the literature or a method analogous thereto (see, for example, Patent Document 5). Compound 3 or a pharmacologically acceptable salt thereof includes a hydrate or a solvate with a pharmacologically acceptable solvent (for example, ethanol). Compound 3 or a pharmacologically acceptable salt thereof includes hydrochloride thereof (compound 4; 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) is preferred, and the half hydrate of compound 4 (compound X; 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 1/2 hydrate is even more preferable.

As the pharmacologically acceptable salt of sitagliptin, phosphate or a hydrate thereof is preferable. As a pharmacologically acceptable salt of vildagliptin, hydrochloride is preferable. As the pharmacologically acceptable salt of alogliptin, benzoate is preferable.

In the present invention, the “medicament in combination” (hereinafter sometimes referred to as the medicament of the present invention) is compound 1 or a pharmacologically acceptable salt thereof, sitagliptin, vildagliptin, alogliptin, saxagliptin, dutogliptin, melogliptin , Carmegliptin, linagliptin and compound X and a DPP-IV inhibitor selected from the group consisting of pharmacologically acceptable salts thereof. These components may be combined at the time of administration, and may be combined in vivo after administration. Specifically, it may be in the form of a pharmaceutical composition containing these two active ingredients (sometimes referred to as the pharmaceutical composition of the present invention), and these two active ingredients are separated separately over a certain period of time. The form which can be combined by administering, or administering simultaneously may be sufficient.
As other embodiments of the medicament of the present invention, compound 1, a compound described in International Publication WO2007 / 129668 pamphlet, a compound described in JP 2008-501745 A, a compound described in International Publication WO2007 / 126117 pamphlet, and A pharmaceutical comprising a combination of an SGLT1 inhibitor selected from the group consisting of pharmacologically acceptable salts thereof and a DPP-IV inhibitor which is Compound 3 or a pharmacologically acceptable salt thereof. Also good.

The pharmaceutical composition of the present invention includes both a single preparation (combination agent) containing two active ingredients and a combination of separate preparations (combination kit, etc.). Including those used in the same dosage form or in different dosage forms.

In the medicament of the present invention, when the number of daily administrations of two active ingredients is different, it includes those in which simultaneous administration and single agent administration are mixed in one day.

Examples of the “disease caused by hyperglycemia” in the present invention include type 1 and type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, diabetic complications (for example, retinopathy, neuropathy, nephropathy, ulcer, Angiopathy), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, Gout etc. are mentioned. Further, the medicament of the present invention enhances GLP-1 action, thereby suppressing glucagon secretion, suppressing gastric emptying, promoting pancreatic β-cell differentiation / proliferation and suppressing apoptosis, improving myocardial and endothelial function, gastric acid / pancreatic juice Suppression of secretion, suppression of feeding, weight loss, increased insulin sensitivity, increased glucose uptake / accumulation in muscle / adipose tissue, suppression of glucose synthesis in liver, suppression of stomach movement, decreased postprandial / fasting blood glucose, decreased HbA _1C , fructosamine Normalization of concentration, cranial nerve protection, cardioprotective effect, etc. can be expected, especially type 1 and type 2 diabetes, impaired glucose tolerance, fasting blood glucose abnormality, diabetic complications, obesity, hyperinsulinemia, etc. It is extremely useful in the treatment of

In the present invention, treatment of a disease caused by hyperglycemia includes prevention of transition to diabetes (prophylactic treatment) of a person with impaired glucose tolerance or an impaired fasting blood glucose obtained by correcting hyperglycemia. It is.

In the present invention, the “GLP-1 action enhancer” means a drug that enhances the action of GLP-1 by increasing and maintaining the endogenous active GLP-1 concentration.

When the medicament of the present invention is used for actual treatment, preparations of various dosage forms are used depending on the drug and usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids and the like, which are administered orally or parenterally. Each formulation can be produced by formulating each active ingredient simultaneously or separately. When administered as separate formulations, the dosage forms of both may be the same or different, and each available single formulation may be used.

The medicament of the present invention is prepared by an appropriate excipient, disintegrant, binder, lubricant, diluent, buffering agent, isotonic agent, preservative, wetting agent according to the method used in pharmacology depending on the dosage form. It can also be produced by mixing or diluting / dissolving appropriately with pharmaceutical additives such as agents, emulsifiers, dispersants, stabilizers, solubilizers, etc., and dispensing according to conventional methods.

For example, a tablet can be easily produced by a method described in the literature or a method analogous thereto. If necessary, the tablets may be coated to form film-coated tablets, sugar-coated tablets, enteric-coated tablets, and the like. Capsules may be prepared by adding appropriate excipients, lubricants, and the like to the active ingredient as necessary and mixing well, and then filling the appropriate capsules into capsules. Further, it may be filled after granulation or fine granulation by a conventional method.

When the medicament of the present invention is used for actual treatment, the dose of each active ingredient is appropriately determined depending on the patient's age, sex, body weight, disease and degree of treatment, drug, dosage form, administration method, drug combination, etc. The The SGLT1 inhibitor is, for example, a compound 1 or a pharmacologically acceptable salt thereof in the range of about 0.1 to 1000 mg per day for an adult when administered orally, and about 0.01 to about a day for an adult when administered parenterally. In the range of 300 mg, it can be appropriately administered in one or several divided doses. When administered orally, DPP-IV inhibitors can be administered in an amount of approximately 0.01 to 3000 mg per day for adults once or in several divided doses. For example, sitagliptin is 1 to 400 mg / day, vildagliptin is 1 -100 mg / day, alogliptin 1-400 mg / day, saxagliptin 1-400 mg / day, etc. can be administered in one or several divided doses.

The contents of the present invention will be described in more detail with reference to the following reference examples, test examples and examples, but the present invention is not limited to the contents.

Reference example 1:
Bis [3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2 -Dimethylpropionamide] monosebacate 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} Propylamino) -2,2-dimethylpropionamide (1.00 g) and sebacic acid (0.18 g) were suspended in ethanol (10 mL) and dissolved by heating and stirring at 70 ° C. for 5 minutes. Diisopropyl ether (5 mL) was added at 70 ° C., and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried at 50 ° C. under reduced pressure to give the title compound (1.05 g). Further, the compound was dissolved in ethanol (10 mL) by heating under reflux, diisopropyl ether (5 mL) was added, and the mixture was cooled to room temperature and stirred overnight. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure to obtain purified crystals of the title compound (0.96 g).
¹ H-NMR (DMSO-d ₆ ) (δ (ppm)): 1.00-1.10 (12H, m), 1.24 (4H, s), 1.40-1.50 (2H, m), 1.70-1.90 (2H, m) , 2.17 (2H, t, J = 7.0Hz), 2.26 (3H, s), 2.64 (2H, t, J = 6.5Hz), 2.70-2.80 (1H, m), 3.00-3.20 (4H, m), 3.40-3.50 (3H, m), 3.62 (1H, d, J = 11.5Hz), 3.93 (2H, t, J = 6.0Hz), 4.20-4.80 (1H, br), 5.18 (1H, d, J = 8.0Hz), 6.60 (1H, d, J = 8.0Hz), 6.69 (2H, s), 6.82 (1H, d, J = 8.5Hz), 7.47 (1H, s)

Reference example 2:
3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethyl Propionamide 1/2 fumarate dihydrate 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3 -Methylphenoxy} propylamino) -2,2-dimethylpropionamide (17 g) was dissolved in ethanol (150 mL) by heating at 40 ° C., and 1/2 equivalent of fumaric acid (1.75 g) and ethanol (105 mL) were added. And stirred under heating at 70 ° C. After cooling to room temperature, the mixture was stirred for 2 hours. The precipitate was collected by filtration and dried under reduced pressure at 70 ° C. for 12 hours to obtain ½ fumarate ethanol hydrate crystals (18.5 g).
The crystals of ½ fumarate ethanolate (6.4 g) were dissolved in a mixed solvent of ethanol (64 mL) and water (3.2 mL) with heating at 60 ° C. Insoluble matter was filtered, and the filtrate was stirred at room temperature for 15 hours. The precipitated crystals were collected by filtration and dried at 50 ° C. under reduced pressure. The obtained crystals were allowed to stand at 25 ° C./60% relative humidity for 2 days, and further allowed to stand at 40 ° C./75% relative humidity for 7 days to obtain crystals of 1/2 fumarate dihydrate (5 .3 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) (δ (ppm)): 1.00-1.10 (12H, m), 1.88 (2H, t, J = 6.5 Hz), 2.26 (3H, s), 2.64 (2H, s ), 2.70-2.80 (3H, m), 3.10-3.30 (4H, m), 3.40-3.60 (3H, m), 3.62 (1H, d, J = 11.0Hz), 3.95 (2H, t, J = 6.0 Hz), 4.40-4.60 (1H, br), 5.18 (1H, d, J = 7.5Hz), 6.47 (1H, s), 6.61 (1H, d, J = 7.5Hz), 6.70 (1H, s), 6.82 (1H, d, J = 8.5Hz), 6.89 (1H, s), 7.50 (1H, s), 11.00-12.00 (1H, br)

Reference Example 3:
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 1/2 hydrate

(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 can be synthesized by the method described in International Publication WO2006 / 068163 Pamphlet.
(2)
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, To a mixture of 4 (3H, 5H) -dione (1.02 kg) and water (7.80 kg), 1N hydrochloric acid (2.67 kg) was added dropwise and stirred at room temperature. After 1 hour, toluene was added and the solution was concentrated under reduced pressure three times. Isopropanol (4.49 kg) containing 15% water was added to the resulting residue 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. The resulting solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (721.8 g) as white crystals.
¹ H 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 ℃

Test Example 1: Blood glucose elevation inhibitory effect test example 1A:
ZF rats (10 weeks old, male, Japan SLC), which is a type 2 diabetes model, were used. The anti-diabetic effect obtained by the combination of Compound 2 and Compound X was examined using as an index the anti-diabetic effect after loading with a mixed carbohydrate. After ZF rats were divided into 4 groups (8 rats each) and fasted overnight, 1 group contained only the solvent, 2 groups contained 0.03 mg / kg of compound 2 (solvent: distilled water) as compound 1, Group 3 received 0.3 mg / kg of Compound X (solvent: 0.5% methylcellulose solution), and Group 4 received 0.03 mg / kg of Compound 2 and 0.3 mg / kg of Compound X as Compound 1 by gavage (Table). 3). For carbohydrate loading, 2 g / kg of mixed carbohydrate (soluble starch: sucrose: lactose monohydrate = 6: 3: 1) was orally administered by gavage. Compound X was administered 30 minutes prior to mixed carbohydrate loading and Compound 2 was administered immediately prior to mixed carbohydrate loading. Blood was collected from the tail vein over time, EDTA was added as an anticoagulant to a final concentration of 1 mg / mL, and 1/100 amount of DPP-IV inhibitor (Millipore) was added. Plasma was centrifuged and the glucose concentration was measured with a commercially available kit (Glucose CII-Test Wako, Wako Pure Chemical Industries, Ltd.). The blood glucose level (plasma glucose concentration) at each time point was expressed as the mean ± standard error of each group (N = 8) (Table 4). The area under the blood glucose level increase curve (ΔAUC _{0-1 hr} and ΔAUC _{0-2 hr} ) 0 to 1 hour and 0 to 2 hours after the mixed carbohydrate loading was calculated by the trapezoidal method. The results of each group were expressed as mean ± standard error, and Student's t test was performed (Table 5). Also, a risk rate of less than 5% was considered significant.

As shown in Table 4, Table 5 and FIG. 1, the group administered with Compound 2 which is an SGLT1 inhibitor and the compound X which is a DPP-IV inhibitor showed an increase in blood glucose after mixed carbohydrate loading as compared with the solvent group. It was suppressed by 37% and 50% from 0 to 1 hour, respectively. When both compounds were used in combination, the blood glucose elevation-inhibiting action was even stronger, with a marked suppression of 83%. That is, in the case of combined use, a significant difference was recognized as compared with the solvent or each administration alone. Similarly, it was suppressed by 12% and 42% when administered alone at 0 to 2 hours, respectively, and when combined, 68% was further markedly suppressed.

From the above, it has been clarified that the combined administration of both agents shows a very strong inhibitory effect on the increase in blood glucose level compared to the single administration of each agent.

Test Example 1B:
C57BL / 6J mice (9 weeks old, male, CLEA Japan), which are normal mice, were used. The anti-diabetic effect obtained by the combination of Compound 2 and sitagliptin phosphate was examined using as an index the effect of suppressing the increase in blood glucose after glucose loading. C57BL / 6J mice were divided into 4 groups (3-4 mice each), and after overnight fasting, 1 group contained only solvent, 2 group contained 0.1 mg / kg of compound 2 (solvent: distilled water) In group 3, 1 mg / kg sitagliptin phosphate (solvent: 0.25% methylcellulose solution) was forcibly orally administered to group 4 (Table 6). For glucose loading, a 0.4 g / mL glucose solution was orally administered by gavage at 5 mL / kg. Sitagliptin phosphate was administered 30 minutes prior to glucose loading and Compound 2 was administered immediately prior to glucose loading. Blood was collected from the tail vein over time, and the plasma glucose concentration (mg / dL) was measured using a small electrode blood glucose measurement device Antsense II.
Area under the curve (AUC _0-1hr ) (mg · hr / dL) and increase AUC (ΔAUC _0-1hr ) (mg · hr / dL) for _0-1 hour after glucose loading Was calculated by the trapezoidal method. The results of each group were expressed as mean ± standard error, and the Student t test was performed and shown in Table 6. Also, a risk rate of less than 5% was considered significant.

As shown in Table 6, Compound 2 and sitagliptin phosphate inhibited the increase in blood glucose after glucose loading by 19% and 27%, respectively, in the 0 to 1 hour period compared to group 1 (solvent group). When both compounds were used in combination, it was further strongly suppressed by 57%. Therefore, it was found that, by using both compounds in combination as compared with single administration, a remarkable blood glucose increase inhibitory effect after glucose load can be obtained.

As described above, from the results of Test Example 1, the medicament of the present invention enhances the blood glucose elevation-inhibiting action of the DPP-IV inhibitor without inducing side effects such as hypoglycemia, and is extremely useful for the treatment of diseases caused by hyperglycemia. Useful.

Test Example 2: GLP-1 action enhancing effect test example 2A:
Using the plasma obtained from the mixed carbohydrate loading test shown in Test Example 1A, the active GLP-1 concentration was measured by a commercially available kit GLP-1 (7-36) Active ELISA Kit (Millipore). The active GLP-1 concentration at each time point was expressed as the mean ± standard error of each group (N = 8) (Table 7). Active GLP-1 concentrations ΔAUC _{0-1 hr} and ΔAUC _0-2 hr at 0 to 1 hour and 0 to 2 hours after mixed carbohydrate loading were calculated by the trapezoidal method. The results of each group were expressed as mean ± standard error, and Student's t test was performed (Table 8). Also, a risk rate of less than 5% was considered significant.

As shown in Table 7, Table 8, and FIG. 2, the group administered with Compound 2 and Compound X alone had an active GLP-1 concentration ΔAUC at 0 to 1 hour after the mixed carbohydrate loading, as compared with the solvent group, respectively. Increased by 1.32 (pM · hr) and 2.85 (pM · hr). When Compound 2 and Compound X were used in combination, they were more potent and showed a significant increase of 5.77 (pM · hr). Similarly, it increases by 2.25 (pM · hr) and 2.39 (pM · hr), respectively, 0 to 2 hours after mixed carbohydrate loading, and in the case of combined use, it is further significantly and markedly 7.40 (pM · hr). Showed an increase.

Compound X administration increased plasma active GLP-1 concentration after loading with mixed carbohydrates. In the administration of Compound 2, the maximum increase in plasma active GLP-1 concentration was similar to that in the solvent group, but unlike the control group, it was higher than that in the control group until 90 minutes after loading with mixed carbohydrates. Indicated. Further, the combined administration of both drugs increased the maximum value of the increase in the plasma active GLP-1 concentration compared to the administration of Compound X alone, while extending the duration of the concentration to 90 minutes. This can also be understood from the fact that ΔAUC of plasma active GLP-1 concentration at 0-2 hours was significantly higher in the combination administration group.

Test Example 2B:
Normal Wistar rats were divided into 4 groups (5 each), and after overnight fasting, 1 group contained only solvent, 2 group contained 0.03 mg / kg of compound 2 (solvent: distilled water), 3 30 mg / kg sitagliptin phosphate (solvent: 0.25% methylcellulose solution) was administered to the group, and both compounds were forcibly administered orally to group 4. For glucose loading, a 0.4 g / mL glucose solution was orally administered by gavage at 5 mL / kg. Sitagliptin phosphate was administered 30 minutes prior to glucose loading and Compound 2 was administered immediately prior to glucose loading. One hour after glucose administration, the abdomen was opened under diethyl ether anesthesia, and blood was collected from the portal vein. The concentration of active GLP-1 in portal vein plasma was measured using a commercially available kit GLP-1 (7-36) Active ELISA Kit (Millipore). The results of each group were expressed as mean ± standard error, and Student's t-test was performed (Table 9). Also, a risk rate of less than 5% was considered significant.

As shown in Table 9, Compound 2 and sitagliptin phosphate increased the active GLP-1 concentration for 1 hour after glucose loading by 8.8 pmol / L and 5.2 pmol / L, respectively, as compared with the solvent group. When both compounds were used in combination, it was more potent and showed a significant increase of 30.0 pmol / L.

From the results of Test Examples 2A and 2B, it was found that the combined use of SGLT1 inhibitor and DPP-IV inhibitor synergistically increased the active GLP-1 concentration.

Test Example 3: Insulin Concentration Inhibitory Effect Using the plasma obtained from the mixed carbohydrate loading test shown in Test Example 1A, the insulin concentration was measured with a commercially available kit (for Levis Insulin Rat, Shiba Goat Co., Ltd.). The insulin concentration at each time point was expressed as the mean ± standard error of each group (N = 8) (Table 10). Insulin concentrations ΔAUC _{0-1 hr} and ΔAUC _0-2 hr at 0 to 1 hour and 0 to 2 hours after mixed carbohydrate loading were calculated by the trapezoidal method. The results of each group were expressed as mean ± standard error, and Student's t test was performed (Table 11). Also, a risk rate of less than 5% was considered significant.

As shown in Tables 10 and 11 and FIG. 3, the ΔAUC of the insulin concentration slightly increased in the compound X administration group and decreased in the compound 2 administration group. The combination administration group showed a decrease compared to the compound X administration group and an increase compared to the compound 2 administration group, and as a result, the area under the insulin concentration increase curve was almost the same as that of the control group. That is, it is shown that glycemic control is possible by administering both compounds in combination with a smaller amount of insulin secretion compared to administration of Compound X alone.

The blood glucose level decreased synergistically with the combined administration of SGLT1 inhibitor and DPP-IV inhibitor, and compound 2, which is an SGLT1 inhibitor, significantly enhanced the blood glucose elevation-inhibiting action of DPP-IV inhibitor (Test Example) 1). This effect was not due to the promotion of insulin secretion (Test Example 3). In addition, when both drugs were administered in combination, the active GLP-1 concentration, which is known to protect pancreatic β cells, etc., increased synergistically, and the increase was sustained (Test Example 2). That is, Compound 2, which is an SGLT1 inhibitor, supplements the effects of DPP-IV inhibitors on blood glucose levels in a manner that does not depend on insulin secretion, and at the same time increases the concentration of GLP-1, which is known to protect pancreatic β cells. It was confirmed to show the combined effect such as increasing.

Examples 1 to 3:
According to the formulations of Formulation Examples 1 to 3, 300 mg tablets are obtained by mixing, granulating and tableting the following components 1-6.

Example 4:
In accordance with the formulation of Formulation Example 4, the following components 1-5 are mixed, wet granulated using an aqueous solution of component 6, and mixed with component 7. The resulting mixture is tableted to obtain 300 mg tablets.

The medicament of the present invention has a strong blood glucose elevation-inhibiting action and a GLP-1 enhancing action, and is extremely useful for the treatment of diseases caused by hyperglycemia.

Claims

3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethyl SGLT1 inhibitor which is propionamide or a pharmacologically acceptable salt thereof, sitagliptin, vildagliptin, alogliptin, saxagliptin, dutogliptin, melogliptin, carmeliptin, linagliptin and 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 and their pharmacological properties A pharmaceutical comprising a combination with a DPP-IV inhibitor selected from the group consisting of acceptable salts.
The DPP-IV inhibitor is sitagliptin or 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3 2. The pharmaceutical according to claim 1, which is 2,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmacologically acceptable salt thereof.
The medicament according to claim 1 or 2, wherein the DPP-IV inhibitor is sitagliptin or a pharmacologically acceptable salt thereof.
The DPP-IV inhibitor is 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2 The pharmaceutical according to claim 1 or 2, which is -d] pyrimidine-2,4 (3H, 5H) -dione or a pharmacologically acceptable salt thereof.
The medicament according to any one of claims 1 to 4, which is used for treatment of a disease caused by hyperglycemia.
The medicament according to claim 5, wherein the disease caused by hyperglycemia is a disease selected from the group consisting of diabetes, impaired glucose tolerance, fasting glucose abnormalities, diabetic complications, obesity and hyperinsulinemia.
The medicament according to any one of claims 1 to 4, which is a postprandial hyperglycemic agent.
The medicament according to any one of claims 1 to 4, which is a GLP-1 action potentiator.