WO2009128360A1

WO2009128360A1 - Therapeutic agent for diabetes

Info

Publication number: WO2009128360A1
Application number: PCT/JP2009/057089
Authority: WO
Inventors: 道子岸野; 英仁須軽
Original assignee: 大日本住友製薬株式会社
Priority date: 2008-04-18
Filing date: 2009-04-07
Publication date: 2009-10-22

Abstract

Disclosed is a hypoglycemic agent useful for the treatment of diabetes or the like. The hypoglycemic agent comprises a combination of 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 which is a pyrrolopyrimidinedione derivative having an inhibitory activity on dipeptidyl peptidase IV (DPP-IV) or a pharmaceutical acceptable salt thereof and a therapeutic agent for diabetes.

Description

Diabetes treatment

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.

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. 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. Examples of what are called insulin secretion-type hypoglycemic agents include SU agents that bind to sulfonylurea (SU) receptors of pancreatic β cells and exhibit an insulin secretion stimulating effect, fast-acting insulin secretion promoters, and the like. In addition, as a non-insulin secretory hypoglycemic agent, it inhibits gluconeogenesis in the liver, suppresses sugar absorption from the gastrointestinal tract, and enhances insulin sensitivity in peripheral tissues, and the 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) γ, and α-glucosidase inhibitors that have a sugar absorption inhibitory effect. (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. 2006/068163 Pamphlet Deacon et al., Int J Biochem Cell Biol 2006; 38: 831-44. Joslin Diabetics 2nd Edition Medical Science International 2007; 769-794. Hermansen et al., Diabetes, Obesity and Metabolism 2007; 9 (5): 733-745. Rosenstock et al., Clin Ther. 2006; 28 (10): 1556-68.

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.

As a result of intensive studies, 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.

That is, 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.
[6] The hypoglycemic agent according to [2], wherein the non-insulin secretory hypoglycemic agent is a biguanide drug;
[7] The hypoglycemic agent according to [5], wherein the insulin sensitizer is pioglitazone or a salt thereof;
[8] The hypoglycemic agent according to [6], wherein the biguanide drug is metformin or a salt thereof;
[9] The hypoglycemic agent according to [3], wherein the insulin secretory hypoglycemic agent is a SU agent;
[10] The hypoglycemic agent according to [3], wherein the insulin secretory hypoglycemic agent is a fast-acting insulin secretagogue;
[11] 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 is 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, any one of [1] to [10] The blood sugar-lowering agent as described;
[12] Antidiabetic drug and 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2 -d] a method of lowering blood glucose in a mammal, comprising administering to the mammal pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof;
[13] A therapeutic agent for diabetes and 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3- Use of dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof;
[14] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1, for use in combination with a pharmaceutical composition containing a therapeutic agent for diabetes A hypoglycemic agent comprising 3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof;
[15] The hypoglycemic agent according to [14], wherein the antidiabetic agent is a non-insulin secretory hypoglycemic agent;
[16] The hypoglycemic agent according to [15], wherein the non-insulin secretory hypoglycemic agent is an insulin sensitizer.
[17] The hypoglycemic agent according to [15], wherein the non-insulin secretory hypoglycemic agent is a biguanide drug;
[18] The hypoglycemic agent according to [16], wherein the insulin sensitizer is pioglitazone or a salt thereof;
[19] The hypoglycemic agent according to [17], wherein the biguanide drug is metformin or a salt thereof;
[20] 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 is 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, any one of [14] to [19] The blood sugar-lowering agent as described;
[21] A 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) in a mammal, which comprises administering a therapeutic agent for diabetes to the mammal ) A method for enhancing the hypoglycemic effect of 1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof;
[22] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine An agent for enhancing blood glucose lowering effect of a therapeutic agent for diabetes, comprising -2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof;
[23] The antihyperglycemic agent according to [22], wherein the antidiabetic agent is a non-insulin secretion type hypoglycemic agent;
[24] The agent for lowering blood glucose action according to [23], wherein the non-insulin secretory blood sugar-lowering drug is an insulin resistance improving drug;
[25] The blood glucose lowering action-enhancing agent according to [23], wherein the non-insulin secretory hypoglycemic drug is a biguanide drug;
[26] The hypoglycemic effect enhancer according to [24], wherein the insulin resistance improving drug is pioglitazone or a salt thereof;
[27] The hypoglycemic effect enhancer according to [25], wherein the biguanide drug is metformin or a salt thereof;
[28] 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 is 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, any of [22] to [27] The blood glucose lowering action-enhancing agent as described;
[29] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine A method for enhancing the hypoglycemic effect of a therapeutic agent for diabetes in a mammal, which comprises administering -2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof to the mammal;
[30] 6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1, for producing an agent for increasing blood glucose lowering action of a therapeutic drug for diabetes Use of 3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof; or
[31] Antidiabetic drug 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 or a pharmaceutically acceptable salt thereof, characterized in that the mammal is synergistically compared to the administration of these drugs alone. A method for lowering blood sugar levels in animals;
About.

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).
Moreover, since 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. For example, edema caused by increased body weight and body fat, and increased circulating plasma volume of insulin resistance-improving drugs, such as vascular complications and hypoglycemia of insulin preparations, hypoglycemia and pancreatic exhaustion of insulin secretory hypoglycemic drugs, etc. Examples thereof include heart failure, lactic acidosis possessed by biguanides, and gastrointestinal disorders possessed by α-glucosidase inhibitors. Therefore, the hypoglycemic agent of the present invention can be safely administered over a long period to patients suffering from diabetes.

Compound A, pioglitazone (PIO), or both of these agents were orally administered by gavage once a day for 15 days to db / db mice. The figure on the left side of 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), and □ 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).

A single dose of Compound A (0.03 mg / kg), metformin (Met) (300 mg / kg), or both of these was administered to Zucker fatty rats. 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).

Hereinafter, the present invention will be described in more detail.

The therapeutic agent for diabetes of the present invention means a compound that lowers blood glucose. The compound may be peptidic or non-peptidic. Moreover, as long as the antidiabetic activity is retained, 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. Furthermore, 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. Two or more of these may be used in combination at an appropriate ratio.
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, and 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, α-glucosidase inhibitors and the like.
Examples of the 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. Preferably a thiazolidinedione compound, more preferably pioglitazone or a salt thereof.
Examples of biguanides include metformin or a salt thereof, buformin or a salt thereof, or phenformin or a salt thereof. Preferably, metformin hydrochloride is used.
Examples of the α-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, 11β-hydroxysteroid dehydrogenase inhibitors, glucokinase activators, and the like.
Examples of 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. are 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. Examples of the 11β-hydroxysteroid dehydrogenase inhibitor include PF-915275 and INCB123739, and examples of the glucokinase activator include R1551, AZD6370, LY2599506, TTP355, and the like.

Examples of 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;
Further, for example, 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.

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:

Alternatively, in the pharmaceutically acceptable salt thereof, 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:

(Hereinafter abbreviated as Compound A).

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. For example, (a) a composition 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. by the same administration route, (c) (A) a therapeutic agent for diabetes, and the like (B) ) Administration of two preparations obtained by separately formulating compound A and the like at different time intervals in the same administration route (for example, (A) antidiabetic agent, (B) administration in the order of compound A, etc.) Or (d) administration in the reverse order), (d) (A) simultaneous administration of two preparations obtained by separately formulating a therapeutic agent for diabetes and (B) compound A, etc., by different administration routes, e) Administration of two preparations obtained by separately formulating (A) anti-diabetic agent and (B) compound A etc. with different administration routes (eg (A) diabetic treatment Medicine, etc. (B) administration in the order of compound A or the like, or administration in the reverse order).
In the case of administration with a time lag, both (A) anti-diabetic agent and (B) compound A etc. coexist in the body for a time sufficient to enhance blood glucose lowering action and blood insulin raising action. It is necessary to be.

In the present invention, (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. A commercial package containing a description of the concomitant drug that states that it can or should be used; a pharmaceutical composition containing a therapeutic agent for diabetes, etc .; A commercial package containing a description relating to the pharmaceutical composition which can be used for or should be used for the purpose of enhancing blood insulin-elevating action; and (A) a pharmaceutical composition containing Compound A and the like And (B) the pharmaceutical composition can or should be used for the purpose of enhancing blood glucose lowering action and blood insulin raising action such as antidiabetic agent Including written matter relating to the pharmaceutical composition described bets include commercial package.

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.

When used for treatment, 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). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of 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.

EXAMPLES The present invention will be described more specifically with reference examples, examples and test examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. Note that abbreviations may be used to simplify the description, but these abbreviations have the same meanings as described above.

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. On the 7th day from the start of administration, the blood glucose level at any time after 1 hour of administration was measured, and on the 21st day, glycated hemoglobin (hereinafter, HbA1c) was measured. In addition, an oral glucose tolerance test was conducted on the 15th day from the start of administration. That is, after fasting overnight from Day 14, 30 g after administration of each drug, 2 g / kg of glucose was forcibly administered orally, and the blood glucose level was examined.

Table 1 shows the blood glucose level at any time 1 hour after administration on the seventh day from the start of administration. By using pioglitazone in combination with Compound A, a synergistic hypoglycemic effect was observed. 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. When Compound A and pioglitazone were each administered alone, there was no difference from the solvent administration group, but when both agents were used in combination, a decrease in the area under the blood glucose level curve, that is, a blood glucose lowering effect was observed. Table 4 and FIG. 2 show HbA1c before the start of administration and on the 21st day of administration. When Compound A and pioglitazone were each administered alone, there was no difference from the solvent administration group, but a synergistic HbA1c lowering effect was observed when both agents were used in combination.

** P <0.01 vs. solvent (Dunnett's test)

** P <0.01 vs. solvent, ## P <0.01 vs. Compound A, $$ P <0.01 vs. pioglitazone (Student's t-test)

** P <0.01 vs. solvent, ## P <0.01 vs. Compound A, $ P <0.05 vs. pioglitazone (Student's t-test)

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.

** P <0.01 vs. solvent, #P <0.05 vs. metformin (Student's t-test)

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. The resulting solid was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain Compound A (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 ℃

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.

Reference example 1
tert-butyl 3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -2-cyano-3- (methylthio) acrylate

To a solution of tert-butyl 2-cyano-3,3-bis (methylthio) acrylate (140.0 kg) in toluene (129.3 L), add (3R) -3-[(tert-butoxycarbonyl) amino] -3-methylpiperidine ( 114.6 kg) of toluene solution (242.5 L) was added and stirred at 42-47 ° C. After 7 hours, heptane cocoon (458.5 L) was added and stirred at 37-40 ° C for 33 hours, and then seed crystals were added. After crystal precipitation, heptane soot (458.5 L) was added. Thereafter, the mixture was stirred at -1 to 3 ° C for 2 hours, and then filtered, and the crystal was washed with a cooled mixed solvent of toluene / heptane (1: 2) (189 kg). (217.5 kg).

Reference example 2
tert-butyl 3-[(2-chloro-5-fluorobenzyl) amino] -3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -2-cyanoacrylate

Compound の (218.0 kg) of Reference Example 1 was dissolved in acetonitrile (178.5 L), and a solution of DBU (167.2 kg) and 2-chloro-5-fluorobenzylamine (105.4 kg) in acetonitrile (27.8 L) was added. Stir at ~ 58 ° C. After 5 hours, the mixture was diluted with toluene (637.6 L) and washed with water. The obtained organic layer was washed with 8.5% aqueous potassium hydrogen sulfate solution, 10% aqueous sodium hydroxide solution and water, and concentrated under reduced pressure to give the title compound (194.3 kg).

Reference example 3
tert-butyl 3-[(2-chloro-5-fluorobenzyl) (2-ethoxy-2-oxoethyl) amino] -3-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidine-1 -Il} -2-cyanoacrylate

Compound (194. kg) of Reference Example 2 was dissolved in N, N-dimethylformamide (346.4 L), potassium carbonate (184.4 kg) was added, and the mixture was stirred at room temperature. After dropwise addition of ethyl bromoacetate (89.1 kg), the mixture was stirred at 38 to 40 ° C. for 2 hours. Ethyl bromoacetate (12.7 kg) was further added, and the mixture was stirred at 38 ° C. for 2 hours. Toluene was added, washed with water, and concentrated under reduced pressure to obtain the title compound (224.1 kg).

Reference example 4
4-tert-butyl 2-ethyl 3-amino-1- (2-chloro-5-fluorobenzyl) -5-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -1H-pyrrole-2,4-dicarboxylate

To a solution of lithium tert-butoxide (45.2 kg) in tert-butyl alcohol (621.4 L) and acetonitrile (857.2 L), add a solution of the compound of Reference Example 3 (224.1 kg) in toluene (112.0 L) to 24-28 ° C. And stirred for 2 hours. Toluene (776.3 L) was added, and the reaction mixture was washed with 20% aqueous acetic acid and concentrated under reduced pressure to give the title compound (203.5 L).

Reference Example 5
4-tert-butyl 2-ethyl 3-[(aminocarbonyl) amino] -1- (2-chloro-5-fluorobenzyl) -5-{(3R) -3-[(tert-butoxycarbonyl) amino]- Piperidin-1-yl} -1H-pyrrole-2,4-dicarboxylate

For a mixture of Compound IV (204.0 kg) in Reference Example 4 dissolved in acetic acid (1283.5 kg) and toluene (414.0 kg), a solution of potassium cyanate (64.1 kg) in water (93.8 kg) was added at 41-44 ° C. Was added dropwise and stirred. After 2 hours, the temperature was returned to room temperature, diluted with toluene (1123.4 L), and washed 3 times with water. The pH was adjusted to 7.52 with aqueous sodium hydroxide solution, washed with brine, and concentrated under reduced pressure to give the title compound (212.4 kg).

Reference Example 6
tert-butyl 5- (2-chloro-5-fluorobenzyl) -6-{(3R) -3-[(tert-butoxycarbonyl) amino] -piperidin-1-yl} -1,3-dimethyl-2, 4-Dioxo-2,3,4,5-tetrahydro-1H-pyrrolo [3,2-d] pyrimidine-7-carboxylate

After adding N, N-dimethylformamide (877.6 L) to a toluene solution of the compound of Reference Example 5 (212.0 kg), potassium carbonate (114.8 kg) and water (8.5 kg) were added and stirred at 45 to 49 ° C. . After 5 hours, the mixture was cooled to 30 ° C. and potassium carbonate (68.8 kg) was added. Methyl iodide (141.5 kg) was added dropwise and stirred. After 3 hours, the mixture was diluted with toluene, washed with water, and concentrated under reduced pressure. The obtained solid was heated to 70 ° C. in isopropanol (1620 L) and returned to room temperature. After stirring at 5 ° C. for 5 hours, the solid was collected by filtration and dried under reduced pressure to give the title compound (172.1 kg).

Reference Example 7
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

Concentrated sulfuric acid (60.9 kg) was added dropwise to tetrahydrofuran (204.7 L). To the mixture was added dropwise a solution of Compound IV (181.4 kg) of Reference Example 6 IV in tetrahydrofuran (819.0 L) at 56-57 ° C. and stirred. After 2 hours, the temperature was returned to room temperature, and toluene (460.8 L) and water (634.9 L) were added to separate the layers. To the aqueous layer, NaOH (46.8 kg), water (187.2 L) and tetrahydrofuran (450.4 L) were added for liquid separation, and 2-propanol was added to the organic layer, concentrated, washed with water, and further concentrated under reduced pressure. To the residue, 2-propanol (1620.3 L) was added and the temperature was raised to 74 ° C. The title compound (172.1 kg) was obtained by cooling to 0 ° C., washing with 2-propanol, and drying under reduced pressure.

Claims

Antidiabetics and 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] A hypoglycemic agent comprising a combination of pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof.
2. The hypoglycemic agent according to claim 1, wherein the antidiabetic agent is a non-insulin secretory hypoglycemic agent.
2. The hypoglycemic agent according to claim 1, wherein the antidiabetic agent is an insulin secretory hypoglycemic agent.
2. The hypoglycemic agent according to claim 1, wherein the antidiabetic agent is an insulin preparation.
3. The hypoglycemic agent according to claim 2, wherein the non-insulin secretory hypoglycemic agent is an insulin sensitizer.
3. The hypoglycemic agent according to claim 2, wherein the non-insulin secretory hypoglycemic agent is a biguanide.
6. The hypoglycemic agent according to claim 5, wherein the insulin sensitizer is pioglitazone or a salt thereof.
The blood sugar lowering agent according to claim 6, wherein the biguanide drug is metformin or a salt thereof.
4. The hypoglycemic agent according to claim 3, wherein the insulin secretory hypoglycemic agent is a SU agent.
4. The hypoglycemic agent according to claim 3, wherein the insulin secretory hypoglycemic agent is a fast-acting insulin secretagogue.
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 is 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1 The blood glucose according to any one of claims 1 to 10, which is 1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione monohydrochloride hemihydrate. Reducing agent.
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl for use in combination with a pharmaceutical composition containing a therapeutic agent for diabetes A hypoglycemic agent comprising -1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof.
13. The hypoglycemic agent according to claim 12, wherein the antidiabetic agent is a non-insulin secretory hypoglycemic agent.
14. The hypoglycemic agent according to claim 13, wherein the non-insulin secretory hypoglycemic agent is an insulin sensitizer.
14. The hypoglycemic agent according to claim 13, wherein the non-insulin secretory hypoglycemic agent is a biguanide.
The blood glucose lowering agent according to claim 14, wherein the insulin resistance improving drug is pioglitazone or a salt thereof.
The hypoglycemic agent according to claim 15, wherein the biguanide drug is metformin or a salt thereof.
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 is 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1 The blood glucose according to any one of claims 12 to 17, which is 1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione monohydrochloride hemihydrate. Reducing agent.
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2, An agent for enhancing hypoglycemic effect of a therapeutic agent for diabetes, comprising 4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof.
20. The agent for enhancing blood glucose lowering effect according to claim 19, wherein the therapeutic agent for diabetes is a non-insulin secretory blood sugar lowering agent.
21. The blood glucose lowering action-enhancing agent according to claim 20, wherein the non-insulin secretory blood sugar lowering drug is an insulin resistance improving drug.
21. The blood glucose lowering action enhancer according to claim 20, wherein the non-insulin secretory blood sugar lowering drug is a biguanide drug.
The blood glucose-lowering effect enhancer according to claim 21, wherein the insulin resistance-improving drug is pioglitazone or a salt thereof.
23. The blood glucose lowering effect enhancer according to claim 22, wherein the biguanide drug is metformin or a salt thereof.
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 is 6-[(3R) -3-aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1 The blood glucose according to any one of claims 19 to 24, which is 1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione monohydrochloride hemihydrate. Decreasing action enhancer.
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chloro-5-fluorobenzyl) -1,3-dimethyl for the production of an antihyperglycemic agent for the treatment of diabetes Use of -1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione or a pharmaceutically acceptable salt thereof.