Hexahydropentaleno derivatives, preparation methods and applications in medicine thereof

一种化合物、杂环基的技术，应用在六氢并环戊二烯衍生物领域，能够解决失活等问题

Active Publication Date: 2014-01-15
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, GLP-1 has not been used clinically because it can be rapidly degraded and inactivated by the widely distributed serine protease dipeptidyl peptidase-IV (DPP-IV) in the body.

Method used

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  • Hexahydropentaleno derivatives, preparation methods and applications in medicine thereof
  • Hexahydropentaleno derivatives, preparation methods and applications in medicine thereof
  • Hexahydropentaleno derivatives, preparation methods and applications in medicine thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0399] (S)-1-[2-[[5-Methoxy-2-methyl-hexahydropentalen-2-yl]amino]acetyl]-2-cyanopyrrolidine

[0400]

[0401]

[0402] Step 1) 5',5'-Dimethylspiro[hexahydropentadiene-5,2'-1,3-dioxane]-2-one

[0403] Hexahydropentacyclopentadiene-2,5-dione 1a (2.00g, 14.47mmol, Chengdu Aiertai Biotechnology Co., Ltd.), neopentyl glycol (1.51g, 14.49mmol, Aladdin), p-toluene A mixture of sulfonic acid (25 mg, 0.13 mmol, Guangzhou Huada Chemical Reagent Co., Ltd.), toluene (150 mL) was heated under reflux for 5 hours, cooled to room temperature, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=4:1) to obtain the title compound 1b (1.96 g, 60.3%) as a yellow solid.

[0404] MS m / z(ESI):225.0(M+1);

[0405] 1 H NMR (400MHz, CDCl 3 )δ:3.50(s,2H),3.45(s,2H),2.80(m,2H),2.44(m,2H),2.27(m,2H),2.15(m,2H),1.80(m,2H ),0.96(s,6H).

[0406] Step 2) 5,5-Dimethylspiro[1,3-dioxane-2,5′-hexahydropentadiene]-2′-ol

[0...

Embodiment 2

[0441] (S)-1-[2-[5-methoxy-2-methyl-hexahydropentalen-2-yl]amino]acetyl]-4-fluoro-2-cyanopyrrolidine

[0442]

[0443] N,N-dimethylformamide of the product 5-amino-5-methyl-hexahydropentalen-2-ol 2a (1.50g, 8.87mmol) prepared in step 7) of Example 1 Potassium iodide (1.62g, 9.76mmol), potassium carbonate (1.35g, 9.76mmol), (S)-1-(2-chloroacetyl )-4-fluoro-2-cyano-pyrrolidine 2b (1.86g, 9.76mmol, Chengdu Aiertai Biotechnology Co., Ltd.). The reaction was reacted at room temperature for 14 hours, then concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V)=20:1) to obtain the title compound 2 (0.87 g, 30.3%) as a yellow solid.

[0444] MS m / z(ESI):324.2(M+1);

[0445] 1 H NMR (400MHz, CDCl 3 )δ:5.22-5.49(m,1H),4.94(d,1H),3.87(m,2H),3.72(m,1H),3.33(s,2H),3.29(s,3H),2.71(m ,2H),2.63(m,1H),2.24(m,1H),1.90(m,4H),1.73(m,2H),1.59(m,2H),1.18(s,3H).

Embodiment 3

[0447] (S)-1-[2-[[5-Hydroxy-2-methyl-hexahydropentalen-2-yl]amino]acetyl]-4-fluoro-2-cyanopyrrolidine

[0448]

[0449]

[0450] Step 1) 5-Hydroxy-hexahydropentalen-2-one

[0451] To the stirred hexahydropentadiene-2,5-dione 3a (100g, 0.725mol) ethyl acetate solution (88mL) was added lithium tri-tert-butoxy aluminum hydride (184g, 0.725mol, Beijing Coupling Technology Co., Ltd. company). The resulting mixture was stirred at room temperature for 15 hours. Water (100 mL) was added dropwise, and the mixture was filtered and washed with ethyl acetate (200 mL×3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 6:1) to obtain the title compound 3b as a pale yellow oil (42g, 41.3%).

[0452] GC-MS m / z(EI):140.1(M);

[0453] 1 H NMR (400MHz, CDCl 3 )δ: 4.38(m,1H), 2.80(m,2H), 2.52(m,2H), 2.28(m,2H), 2.15(m,2H), 1.59(m,2H).

...

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Abstract

The invention relates to hexahydropentaleno derivatives, the preparation method and use in medicine thereof, and in particular to hexahydropentaleno derivatives or stereo-isomers or pharmaceutically acceptable salts thereof as shown in general formula (I), and to the preparation method therefor and pharmaceutical compositions comprising the derivatives, and to the use thereof as a therapeutical agent, especially as a DPP-IV inhibitor. The definition of each substituent in formula (I) is the same as the definition in the description.

Description

[0001] This application requires submission of a Chinese patent application submitted to the China Patent Office on June 25, 2012, with the application number 201210207680.5, and the title of the invention being "hexahydropentadiene derivatives, their preparation methods and their applications in medicine". Priority, and the request to submit to the Chinese Patent Office on April 3, 2013, the application number is 201310116954.4, the invention title is "hexahydropentadiene derivatives, its preparation method and its application in medicine" The priority of the application, the entire content of which is incorporated in this application by reference. technical field [0002] The present invention relates to a hexahydropentadiene derivative, a process for its preparation, a pharmaceutical composition containing the derivative and a therapeutic agent, especially as a dipeptidyl peptidase-IV (DPP-IV) inhibitor use. Background technique [0003] Diabetes is a disease process of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D209/52C07D405/12C07C217/52C07C213/02C07C215/44C07C255/47C07C253/30C07C219/24C07C211/41C07C209/62C07D305/14A61K31/4025A61K31/403A61K31/40A61P3/10A61P27/02A61P25/00A61P13/12A61P3/06A61P3/04A61P3/00A61P9/10A61P9/12A61P7/06
CPCC07C209/42C07C211/41C07C213/02C07C215/44C07C217/52C07C219/24C07C253/30C07C255/47C07D207/16C07D209/52C07D305/14C07D405/12C07C2602/22C07C249/08A61K31/40A61K31/4025A61K31/403A61K45/06C07C2601/02C07C2603/94A61P13/12A61P25/00A61P27/02A61P3/00A61P3/04A61P3/06A61P5/50A61P7/06A61P9/10A61P9/12A61P3/10C07C251/34A61K2300/00
Inventor 顾峥邱关鹏伍武勇康盼盼张宗远陈刚兰成生魏用刚温甲平祝国智卢泳华王鹤然王银彩原明云叶康志苏桂转邓炳初
Owner SUNSHINE LAKE PHARM CO LTD
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