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Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor

A technology of heterocycloalkyl and cycloalkyl, which can be used in medical preparations containing active ingredients, metabolic diseases, organic active ingredients, etc., and can solve problems such as short half-life

Inactive Publication Date: 2015-11-25
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 (dipeptidylpeptidase IV, DPP-IV) in vivo, and the half-life is very short.

Method used

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  • Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor
  • Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor
  • Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0136] Synthetic route of route 1 intermediate 3a

[0137]

[0138] Preparation of the first step 4-{[(2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-pyrrolidin-2-yl]-formyl}thiomorpholine 2a

[0139] (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid 1a (5.08g, 22mmol), HOBt (2.70g, 20mmol), DIPEA (5.2mL, 30mmol) and thio Morpholine (2mL, 20mmol) was placed in a 100mL single-necked flask, and 50mL of acetonitrile was added to make the system turbid, then EDCI (4.22g, 22mmol) was added, stirred overnight at room temperature, and the system was clarified. Acetonitrile was distilled off, the system was diluted with 300 mL of ethyl acetate, and washed twice with saturated brine containing 0.5 N sodium hydroxide. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an off-white solid, which was slurried with ether and filtered to obtain Intermediate 2a, 4.79 g of a white solid, with a ...

Embodiment 1

[0336]

[0337] Compound 14-{[(2S,4S)-4-(4-cyclohexylpiperazin-1-yl)-pyrrolidin-2-yl]-formyl}-thiomorpholine trihydrochloride

[0338]

[0339] The first step 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-(4-cyclohexylpiperazin-1-yl)-pyrrolidin-2-yl]-formyl}thiomorpholine Preparation of 1c

[0340] 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-oxo-pyrrolidin-2-yl]-formyl}thiomorpholine 3a (0.112g, 0.365mmol) was mixed with commercially available 1 - Cyclohexylpiperazine 1b (57mg, 0.339mmol) was dissolved in 4mL of dichloromethane, then 1 drop of glacial acetic acid was added, and sodium triacetoxyborohydride (0.216g, 1.017mmol) was added, and stirred overnight at room temperature. Add 5 mL of saturated sodium bicarbonate solution to the reaction solution, stir for 15 minutes, add 20 mL of dichloromethane, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product was separated by sili...

Embodiment 2

[0344]

[0345] Compound 24-{[(2S,4S)-4-(4-(4-methoxyphenyl)-piperazin-1-yl)-pyrrolidin-2-yl]-formyl}-thiomorpholine trihydrochloride

[0346]

[0347] The first step 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-(4-(4-methoxyphenyl)piperazin-1-yl)-pyrrolidin-2-yl]- Preparation of formyl}thiomorpholine 2c

[0348] Using 3a (82mg, 0.263mmol) and commercially available 1-(4-methoxyphenyl)piperazine 2b (48mg, 0.25mmol) as raw materials, using the steps similar to the first step in Example 1, intermediate 2c was obtained , white solid 76mg, yield 62.3%.

[0349] The second step 4-{[(2S,4S)-4-(4-(4-methoxyphenyl)piperazin-1-yl)-pyrrolidin-2-yl]-formyl}thiomorpholine Preparation of trihydrochloride 2

[0350] Using 2c (60 mg, 0.12 mmol) as the starting material, the second step in Example 1 was used to obtain compound 2, 50 mg of white solid, with a yield of 82.0%. m.p.170-171°C, (c0.50, CH 3 OH). 1 HNMR (300MHz,D 2 O) δ: 7.43(d, J=9.0Hz, 2H, aromatic), 7.12(d, J=9.0Hz, aromat...

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Abstract

The invention discloses a nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor, a preparation method therefor and use thereof. Specifically, the invention relates to a compound shown in a formula (I), a stereisomer thereof and pharmaceutically acceptable salt thereof mentioned in the description. The invention further relates to a pharmaceutical composition comprising the compound, use of the compound in preparing drugs for treating and / or preventing diseases or illnesses associated with DDP-IV excessive activity or DPP-IV overexpression and a method of treating associated diseases by using the compound. The compound disclosed by the invention has the effect of effectively inhibiting the activity of DDP-IV. The FORMULA is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine. It relates to nitrogen-containing heterocyclic substituted pyrrolidinoylthiomorpholine DPP-IV inhibitors represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, and the preparation of such compounds, The pharmaceutical composition containing them and the application of these compounds in preventing and / or treating diabetes and non-insulin-dependent diabetes, especially the application in inhibiting DPP-IV. Background technique [0002] Diabetes Mellitus (DM) is a chronic metabolic disease with multiple etiologies. In 2013, the number of diabetic patients in the world was about 382 million, and it is estimated that the number of diabetic patients will reach 592 million by 2035. It is estimated that the number of people with diabetes in China was 98.4 million in 2013, ranking first in the world. By 2035, the number of people with diabetes will increase to 142 m...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07D401/12C07D413/12C07D403/12C07D401/14C07D401/04A61K31/541A61K31/551A61P3/10
CPCY02P20/55C07D207/16C07D401/04C07D401/12C07D401/14C07D403/12C07D413/12
Inventor 黄海洪申竹芳赵红义环奕姜茜林紫云李鹏刘泉刘率男
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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