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Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor

A compound and solvate technology, applied in the field of thiadiazole derivative DPP-IV inhibitors, can solve the problem of low metabolism of linagliptin

Active Publication Date: 2012-12-05
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, Linagliptin, which has a better effect, has been listed recently, but it has been reported in the literature that the metabolism level of Linagliptin in vivo is low. In rats, mice and humans, about 80% of Linagliptin in plasma is Existing as a prototype

Method used

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  • Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor
  • Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor
  • Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: 8-((R)-3-amino-piperidin-1-yl)-1-(benzo[1,2,5]thiadiazole-5-methyl)-7-(2- Butyn-1-yl)-3-methyl-xanthine

[0217]

[0218] General synthesis method:

[0219]

[0220] Step 1: 8-Bromo-7-(2-butyn-1-yl)-3-methyl-xanthine

[0221]

[0222] Under stirring conditions, 1-bromo-2-butyne ( 2.0g, 15mmol) and diisopropylethylamine (1.9g, 14.7mmol), reacted at 40°C for 4 hours, poured into water after cooling to room temperature, precipitated solid, filtered, washed with water, and dried in vacuum to obtain 8-Bromo-7-(2-butyn-1-yl)-3-methyl-xanthine (3.1 g, white solid), yield: 84.3%. 1 H NMR (400MHz, DMSO-d6): δ=11.31(s, 1H), 5.036-5.030(d, J=2.4Hz, 2H), 3.31(s, 3H), 1.785-1.773(t, J=2.4Hz , 3H).

[0223] Step 2: 1-(Benzo[1,2,5]thiadiazol-5-methyl)-8-bromo-7-(2-butyn-1-yl)-3-methyl-xanthine

[0224]

[0225] Under stirring conditions, 8-bromo-7-(2-butyn-1-yl)-3-methyl-xanthine (1.1g, 3.7mmol) in N,N-dimethylformamide (50mL) Add 5-bromomethylbenzo[1,...

Embodiment 2

[0232] Example 2: 8-((R)-3-Amino-piperidin-1-yl)-1-(7-fluorobenzo[1,2,5]thiadiazole-5-methyl)-7- (2-Butyn-1-yl)-3-methyl-xanthine

[0233]

[0234] Step 1: 1-(7-Fluorobenzo[1,2,5]thiadiazol-5-methyl)-8-bromo-7-(2-butyn-1-yl)-3-methyl- Xanthine

[0235]

[0236] Referring to the method of step 2 in Example 1, replace 5-bromomethylbenzo[1,2,5]thiadiazole with 6-bromomethyl-4-fluorobenzo[1,2,5]thiadiazole , to obtain the target compound, yield: 80.5%. 1 H NMR (400MHz, CDCl3-d3): δ=7.865(s, 1H), 7.421-7.394(dd, J=1.2Hz, 10.8Hz, 1H), 5.340(s, 2H), 5.128-5.117(q, J = 2.4, 2H), 3.570 (s, 3H), 1.822-1.811 (t, J = 2.4Hz, 3H).

[0237] Step 2: 8-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1-(7-fluorobenzo[1,2,5]thiadiazole-5-methyl) -7-(2-Butyn-1-yl)-3-methyl-xanthine

[0238]

[0239] Referring to the method of step 3 in Example 1, use 1-(7-fluorobenzo[1,2,5]thiadiazole-5-methyl)-8-bromo-7-(2-butyne-1- Base)-3-methyl-xanthine instead of 1-(benzo[1,2,5]thiadiazol-...

Embodiment 3

[0243] Example 3: 8-((R)-3-amino-piperidin-1-yl)-1-(7-chlorobenzo[1,2,5]thiadiazole-5-methyl)-7- (2-Butyn-1-yl)-3-methyl-xanthine

[0244]

[0245] Step 1: 1-(7-Chlorobenzo[1,2,5]thiadiazol-5-methyl)-8-bromo-7-(2-butyn-1-yl)-3-methyl- Xanthine

[0246]

[0247] With reference to the method of step 2 in Example 1, replace 5-bromomethylbenzo[1,2,5]thiadiazole with 6-bromomethyl-4-chlorobenzo[1,2,5]thiadiazole , to obtain the target compound, yield: 60.5%. 1 H NMR (400MHz, CDCl3-d3): δ=7.977-7.974(d, J=1.2Hz, 1H), 7.797-7.794(d, J=1.2Hz, 1H), 5.334(s, 2H), 5.131-5.113 (q, J = 2.4, 2H), 3.572 (s, 3H), 1.824-1.812 (t, J = 2.4Hz, 3H).

[0248] Step 2: 8-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1-(7-chlorobenzo[1,2,5]thiadiazole-5-methyl) -7-(2-Butyn-1-yl)-3-methyl-xanthine

[0249]

[0250] With reference to the method of step 3 in Example 1, use 1-(7-chlorobenzo[1,2,5]thiadiazole-5-methyl)-8-bromo-7-(2-butyne-1- Base)-3-methyl-xanthine instead of 1-(benzo[...

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Abstract

The invention relates to thiadiazole derivatives which are shown as a formula I and have DPP-IV (dipeptidyl peptidase IV) inhibition activity, a preparation method of the thiadiazole derivatives and drug compositions of the thiadiazole derivatives, and application of the thiadiazole derivatives to treatment of diseases beneficial from DPP-IV inhibition, especially application to treatment of diabetes mellitus type 2. The thiadiazole derivatives provided by the invention have very good DPP-IV inhibition activity, have a very good in-vivo metabolic level and a very proper in-vivo half-life period and are expected to be used as proper DPP-IV inhibitor drugs.

Description

technical field [0001] The present invention relates to a new thiadiazole derivative with DPP-IV inhibitory activity, its preparation method, its pharmaceutical composition, and its use in treating diseases benefited from DPP-IV inhibition, especially for the treatment of type II diabetes use. Background technique [0002] Diabetes mellitus is a multi-etiological disease manifested by elevated blood glucose levels or hyperglycemia in the fasting state or after administration of glucose in an oral glucose tolerance test. Persistent uncontrolled hyperglycemia increases early morbidity and mortality and is therefore a significant public health problem. [0003] There are two main types of diabetes. Type 1 diabetes is also called insulin-dependent diabetes. The patient's own body can hardly produce insulin. Type II diabetes is also called non-insulin-dependent diabetes. The insulin level in these patients is comparable to or even higher than that of normal people. However, ins...

Claims

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Application Information

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IPC IPC(8): C07D473/04C07D519/00C07D417/14C07D487/04C07D285/14C07D513/04A61K31/522A61K31/513A61K31/519A61P3/10A61P3/06A61P3/08A61P3/00A61P3/04A61P35/00A61P25/00A61P37/00
Inventor 刘希杰胡远东许新合沈宇王树龙刘志华于洪灏李根孙颖慧孔凡胜罗鸿彭勇校登明杨玲张喜全韩永信
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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