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Benzocyclodirivative

A compound and alkyl technology, applied in the field of medicine, can solve the problems of not meeting clinical needs and limited varieties of drugs

Active Publication Date: 2011-08-17
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the variety of drugs is limited and cannot meet the clinical needs. There is an urgent need to develop more DPP-IV inhibitor drugs to meet the clinical needs.

Method used

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  • Benzocyclodirivative
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  • Benzocyclodirivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1 (R)-2-[[7-(3-aminopiperidin-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl]methyl]benzene formyl nitrile Compound 1) preparation of hydrochloride

[0193]

[0194] (1) Preparation of 1,3-dibromo-2-nitrosobenzene

[0195]

[0196] 9.8g (39mmol) of 2,6-dibromoaniline and 30g (139mmol) of 80% m-chloroperoxybenzoic acid were added to 500mL of dichloromethane, and reacted at room temperature for 3 hours to obtain 7.24g of the product, yield: 70.0 %.

[0197] (2) Preparation of 1,3-dibromo-2-nitrobenzene

[0198]

[0199] At room temperature, 1.23 g (4.64 mmol) of 1,3-dibromo-2-nitrosobenzene was dissolved in glacial acetic acid (25 mL) and H 2 o 2 (25mL), add HNO 3 (0.83mL), heated to 90°C, reacted for 2h, added 50mL of water, filtered to obtain 0.67g of product, yield: 51.4%.

[0200] (3) Preparation of (R)-1-(3-bromo-2-nitrophenyl)piperidin-3-ylcarbamate tert-butyl ester

[0201]

[0202] Dissolve 1,3-dibromo-2-nitrobenzene 8.4g (30.0mmol), (R)-piperi...

Embodiment 2

[0220] Example 2 (R)-2-[[7'-(3-aminopiperidin-1-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base]methyl]benzene Preparation of forminonitrile (compound 2) hydrochloride

[0221]

[0222] (1) Preparation of 2-(3-fluoro-2-nitrophenyl) diethyl malonate

[0223]

[0224] Add K 2 CO 3 26.7g (0.193mol), stirred and reacted overnight at 60°C. After the reaction was completed, it was cooled to room temperature, and ice water was added. The reaction mixture was extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with brine (2×100 mL), MgSO 4 After drying, filtering and concentrating in vacuo, 26.8 g of a light yellow oily product was obtained, with a yield of 83.8%, which was directly used in the next reaction without further purification.

[0225] (2) Preparation of 2-(3-fluoro-2-nitrophenyl)acetic acid

[0226]

[0227] A mixture of 26.8 g (0.896 mol) of diethyl 2-(3-fluoro-2-nitrophenyl) malonate and 200 mL (6N) of HCl was refluxed...

Embodiment 3

[0254] Example 3 (R)-2-[[7-(3-aminopiperidin-1-yl)-3-methyl-2-oxo-2,3-dioxo-1H-benzo[d]imidazole -1-yl] A The preparation of base] benzonitrile (compound 5) trifluoroacetate

[0255]

[0256] (1) Preparation of (R)-1-(3-fluoro-2-nitrophenyl)piperidin-3-ylcarbamate tert-butyl ester

[0257]

[0258] Add 6 mL of ethanol, 0.21 mL (2.0 mmol) of 1,3-difluoro-2-nitrobenzene, 480 mg (2.4 mmol) of tert-butyl (R)-piperidin-3-ylcarbamate into the dry reaction flask, 0.5 mL of triethylamine was heated to 100° C. and stirred for 12 hours, the reaction solution was decompressed, and a yellow liquid was precipitated to obtain 0.7 g of crude product, which was directly used in the next reaction.

[0259] (2) Preparation of (R)-1-[3-(methylamino)-2-nitrophenyl]piperidin-3-ylcarbamate tert-butyl ester

[0260]

[0261] In the dry reaction bottle, add (R)-1-(3-fluoro-2-nitrophenyl)piperidin-3-ylcarbamate tert-butyl 0.7g (2.1mmol), dissolve in 8mL butanol, Add 6 mL of 27% methyla...

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Abstract

The invention belongs to the technical field of medicaments, in particular relates to a benzocyclodirivative as shown in a general formula (I) as well as pharmaceutically acceptable salts, a hydras and an isomer thereof, wherein R1, R2, R3, R4, Q, X and Y are defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating and / or preventing non-insulin-dependent diabetes mellitus.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to benzocyclic derivatives, pharmaceutically acceptable salts thereof, stereoisomers or solvates thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and these compounds Application in preparation of medicine for treating and / or preventing non-insulin dependent diabetes. 2. Background technology [0002] Diabetes is a systemic chronic metabolic disease caused by uncontrolled blood sugar levels higher than normal. Basically divided into four categories, including: type I (insulin-dependent), type II (non-insulin-dependent), other types and gestational diabetes. Type 1 and type 2 diabetes belong to primary diabetes, the two most common forms, caused by the interaction of genetic and environmental factors. The etiology of diabetes is very complex, but in the final analysis is due to absolute or relative lack of insuli...

Claims

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Application Information

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IPC IPC(8): A61K31/423A61K31/4155A61P25/00A61P35/00A61P13/12A61P37/02C07D235/26C07D417/04A61K31/5377A61K31/4196A61K31/4178A61P3/00A61P31/18A61P27/02A61P9/10A61P9/14A61P1/00C07D401/04A61P5/26A61K31/496A61K31/428A61P3/10A61P3/06C07D209/40A61K31/454C07D413/04A61P7/00A61K31/5355A61P15/08A61K31/404A61P19/10C07D263/58
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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