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Substituted-pyrrolidinyl-contained thiomorpholine compounds

A technology of compound and alkyl, applied in the field of medicine, can solve problems such as short half-life

Inactive Publication Date: 2013-12-04
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, endogenous GLP-1 and GIP can be rapidly degraded and inactivated by dipeptidyl peptidase IV (DPP-IV) in vivo, and the half-life is very short.

Method used

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  • Substituted-pyrrolidinyl-contained thiomorpholine compounds
  • Substituted-pyrrolidinyl-contained thiomorpholine compounds
  • Substituted-pyrrolidinyl-contained thiomorpholine compounds

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0105] Synthetic route of Scheme 1 intermediate 6a

[0106]

[0107] Preparation of the first step (2S, 4R)-N-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid 2a

[0108] Dissolve 4-OH-L-proline (3.95g, 30.1mmol) in 50mL 1,4-dioxane and 50mL 1mol·L -1 Add (Boc) to the mixed solution of sodium hydroxide solution at 0°C 2 O (7.85g, 36.0mmol), stirred at low temperature for 0.5h, then raised to room temperature and stirred overnight. Concentrate under reduced pressure and evaporate to near dryness, add 50mL water to dissolve, and use 1mol·L -1 Adjust the pH of the HCl solution to 2~3, extract with ethyl acetate, combine the organic layers, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate 2a, white solid 6.68g, yield About 96.3%. 1 H NMR (D 2 O,300MHz)δ:4.53(br,1H, CH -OH in pyrrolidine),4.42-4.36(m,1H,CHC=O),3.60-3.47(m,2H,CH 2 N in pyrrolidine),2.42-2.35&2.19...

Embodiment 1

[0123]

[0124] Compound 1 4-{[(2S,4S)-4-(piperidin-4-yl-amino)-pyrrol-2-yl]-formyl}thiomorpholine trihydrochloride

[0125]

[0126] Preparation of the first step 4-{[(2S, S)-N-tert-butoxycarbonyl-4-(piperidin-4-yl)amino-pyrrol-2-yl]-formyl}thiomorpholine 1b

[0127] 4-{[(2S,4S)-4-amino-N-tert-butoxycarbonyl-pyrrol-2-yl]-formyl}thiomorpholine 6a (0.15g, 0.48mmol) was mixed with N-Boc-4 -Piperidone (0.098g, 0.49mmol) was dissolved in 10mL of dichloromethane, then a small amount of AcOH was added to adjust the pH of the reaction system to 3-5, stirred at room temperature for 3 hours, the temperature of the reaction system was lowered to below 0°C, and triacetylboron was added Sodium hydride (0.317g, 1.50mmol), raised to room temperature and stirred for 6 hours until the reaction was complete. Add 20 mL of water to the reaction solution, extract with dichloromethane, combine the organic layers, wash with saturated sodium bicarbonate solution and saturated brine, respectiv...

Embodiment 2

[0132]

[0133] Compound 24-{[(2S,4S)-4-(3-Hydroxy-2,2-dimethyl-propylamino)-pyrrol-2-yl]-formyl}thiomorpholine dihydrochloride

[0134]

[0135] The first step 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-(3-hydroxy-2,2-dimethylpropylamino)-pyrrol-2-yl]-formyl}thio Preparation of Morpholine 2b

[0136] 4-{[(2S,4S)-4-Amino-N-tert-butoxycarbonyl-pyrrol-2-yl]-formyl}thiomorpholine 6a (0.15g, 0.48mmol) was mixed with 2,2-bis Methyl-3-hydroxypropanal (0.051g, 0.50mmol) was dissolved in 10mL of dichloromethane, after complete dissolution, a small amount of acetic acid was added to make the reaction system pH=3-5, stirred at room temperature for 3 hours, and the reaction system was cooled to 0°C Next, sodium triacetylborohydride (0.317 g, 1.50 mmol) was added, raised to room temperature and stirred for 6 hours until the reaction was complete. Add 20 mL of water to the reaction solution, extract with dichloromethane and combine the organic layers, wash with saturated sodium bicarbonat...

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Abstract

The invention discloses substituted-pyrrolidinyl-contained thiomorpholine compounds, a preparation method thereof and applications thereof. In concrete, the invention relates to compounds having a general formula (I), stereoisomers of the compounds and pharmaceutical acceptable salts of the compounds, wherein R is shown in the specification. The invention also relates to pharmaceutical compositions comprising the compounds, and the applications of the compounds in preparing medicines used for treating and / or preventing a disease or a symptom which are related to over-high activity of DPP-IV or over-expression of the DPP-IV, and also relates to a method of using the compounds for treating related diseases. The compounds have activity for effectively inhibiting the DPP-IV.

Description

technical field [0001] The invention belongs to the technical field of medicine. It relates to thiomorpholine compounds containing substituted pyrrolidinyl represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, preparation of such compounds, pharmaceutical compositions containing them and the Application of compounds in preventing and / or treating diabetes and non-insulin-dependent diabetes, especially in inhibiting DPP-IV. Background technique [0002] Diabetes is a chronic metabolic disease characterized by hyperglycemia. Sustained hyperglycemia can lead to many complications, such as retinal, renal, nervous system and microvascular complications. At present, there are about 246 million people in the world suffering from type 2 diabetes, and the number of patients is expected to reach 380 million within 20 years [Xu Sisheng. Research progress of new antidiabetic drugs. Journal of China Pharmaceutical University. 2011,42(2):97 -106]. D...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D207/16C07D401/14A61K31/541A61K31/635A61P3/10
Inventor 黄海洪申竹芳吴琪刘景龙环奕林紫云李鹏
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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