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4-substituted pyrrolidine formyl thiomorpholine DPP-IV (Dipeptidyl Peptidase IV) inhibitor

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

Inactive Publication Date: 2015-11-25
INST OF MATERIA MEDICA 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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  • 4-substituted pyrrolidine formyl thiomorpholine DPP-IV (Dipeptidyl Peptidase IV) inhibitor
  • 4-substituted pyrrolidine formyl thiomorpholine DPP-IV (Dipeptidyl Peptidase IV) inhibitor
  • 4-substituted pyrrolidine formyl thiomorpholine DPP-IV (Dipeptidyl Peptidase IV) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0120] Synthetic route of Scheme1 intermediate 5a

[0121]

[0122] Preparation of the first step 4-{[(2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-pyrrolidin-2-yl]-formyl}thiomorpholine 2a

[0123] (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid 1a (5.08g, 22mmol), HOBt (2.70g, 20mmol), diisopropylethylamine (5.2mL , 30mmol) and thiomorpholine (2mL, 20mmol) were placed in a 100mL single-necked bottle, 50mL of acetonitrile was added, the system was cloudy, 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 sol...

Embodiment 1

[0150]

[0151] Compound 14-{[(2S,4S)-4-(N-Methyl-N-ethylamino)-pyrrolidin-2-yl]-formyl}-thiomorpholine dihydrochloride

[0152]

[0153] The first step 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-(N-methyl-N-ethylamino)-pyrrolidin-2-yl]-formyl}thiomorpholine Preparation of 1c

[0154] 4-{[(2S,4S)-4-Methylamino-N-tert-butoxycarbonyl-pyrrolidin-2-yl]-formyl}thiomorpholine 6a (100 mg, 0.304 mmol) was dissolved in 4 mL 1,2 -Dichloroethane, add 2 drops of acetic acid dropwise, and add sodium triacetoxyborohydride (193mg, 0.912mmol) and acetaldehyde (0.11mL, 0.608mmol). Stir at room temperature for 1 h, add saturated sodium bicarbonate solution and stir for 5 min, and extract with dichloromethane three times. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. ) mixture is the eluent. Intermediate 1c was obtained, white solid 94mg, yield 87.0%.

[0155] The second step of 4-{[(2S,4S)-4-(N-methyl-N-ethylamino)-py...

Embodiment 2

[0158]

[0159] Compound 24-{[(2S,4S)-4-(N-(4-trifluoromethylphenyl)-N-methylamino)-pyrrolidin-2-yl]-formyl}-thiomorpholine Dihydrochloride

[0160]

[0161] The first step 4-{[(2S,4S)-N-tert-butoxycarbonyl-4-(N-(4-trifluoromethylphenyl)-N-ethylamino)-pyrrolidin-2-yl] Preparation of -formyl}thiomorpholine 2c

[0162] 4-{[(2S,4S)-4-Methylamino-N-tert-butoxycarbonyl-pyrrolidin-2-yl]-formyl}thiomorpholine 6a (42mg, 0.128mmol) and 4-bromotri Fluorotoluene (32mg, 0.140mmol) was dissolved in 1mL of anhydrous toluene, cesium carbonate (58mg, 0.179mmol) was added, Pd(AcO) 2 (0.1%) and (±)-BINAP (0.3%), reacted at 100°C for 22 hours under the protection of argon, and then cooled to room temperature, filtered out the insoluble matter in the reaction system, and concentrated under reduced pressure. The obtained crude product was separated by column chromatography, using a dichloromethane:methanol (V:V=100:1.2) mixture as the eluent, to obtain intermediate 2c, 55 mg of white soli...

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Abstract

The invention discloses a 4-substituted pyrrolidine formyl thiomorpholine DPP-IV (Dipeptidyl Peptidase IV) inhibitor and a preparation method therefor and use thereof. Specifically, the invention relates to a compound represented by a formula (I) shown in the description, a stereoisomer thereof and pharmaceutically-acceptable salts thereof, wherein R1 and R2 are as defined in the description. The invention also relates to a pharmaceutical composition containing the compound disclosed by the invention, use of the compound disclosed by the invention in preparation of drugs for methods for treating and / or preventing too-high DPP-IV activity or DPP-IV overexpression related diseases or disease symptoms, and a method for treating related diseases by using the compound disclosed by the invention. The compound disclosed by the invention has effective DPP-IV inhibiting activity.

Description

technical field [0001] The invention belongs to the technical field of medicine. It relates to 4-substituted pyrrolidinoformylthiomorpholine DPP-IV inhibitors represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, the preparation of such compounds, and their The pharmaceutical composition and the application of this type of compound 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 million (International Diabetes ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D401/12C07D401/14A61K31/541A61P3/10
CPCY02P20/55C07D207/16C07D401/12C07D401/14
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 CHINESE ACAD OF MEDICAL SCI
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