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Preparation and applications for novel 1,1-cyclopropyl diamide derivative

A technology of cyclopropyl diamide and derivatives, which is applied in the direction of medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., can solve the problem of preparation and application of 1,1-cyclopropyl diamide derivatives, which has not been reported yet And other issues

Inactive Publication Date: 2018-12-04
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the preparation and application of novel 1,1-cyclopropyl diamide derivatives as shown in the present invention have not been reported yet

Method used

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  • Preparation and applications for novel 1,1-cyclopropyl diamide derivative
  • Preparation and applications for novel 1,1-cyclopropyl diamide derivative
  • Preparation and applications for novel 1,1-cyclopropyl diamide derivative

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preparation example Construction

[0018] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0019] The invention also relates to novel intermediates and / or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.

[0020] Both intermediates and final products can be worked up and / or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0021] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0022] The following examples are only used to illustrate the present invention and do not limit the present invention in any way.

Embodiment 1

[0023] Example 1 N-(4-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)-N -Synthesis of phenylcyclopropane-1,1-dicarboxamide

[0024]

[0025] Step 1.1: Preparation of 1-(phenylcarbamoyl)cyclopropane-1-carboxylic acid

[0026]

[0027] Cyclopropane-1,1-dicarboxylic acid (13.01 g, 100 mmol) was dissolved in 150 mL of isopropyl acetate and cooled to 0°C, then thionyl chloride (12.5 g, 105 mmol) was added dropwise. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 6 hours. A solution of aniline (110 mmol) and triethylamine (15.29 mL, 110 mmol) in isopropyl acetate (40 mL) was added dropwise for about 1 hour, and stirring was continued for 2 hours. The reaction solution was diluted with ethyl acetate (500 mL), washed with 1 N hydrochloric acid and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. Suspend the crude product in hept...

Embodiment 2

[0034] Example 2 N-(4-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)-N Synthesis of -(2-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0035]

[0036] Step 2.1: 1 - Synthesis of ((2-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid

[0037]

[0038] The method is the same as step 1.1, white solid, yield: 45%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.51 (s,1H), 11.27 (s, 1H), 8.15 (td, J = 8.0, 2.0 Hz, 1H), 7.27 (ddd, J = 11.4, 7.9,1.8 Hz, 1H), 7.13 (tdd, J = 13.3, 7.7, 3.7 Hz, 2H), 1.56 (h, J = 4.0 Hz, 4H).

[0039] Step 2.2: Synthesis of N-(4-aminophenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0040]

[0041] The method is the same as step 1.2, brown solid, yield: 54%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.16 (s,1H), 9.40 (s, 1H), 8.04 (td, J = 7.8, 2.4 Hz, 1H), 7.33 – 7.22 (m, 1H), 7.20– 7.09 (m, 4H), 6.53 ( d, J = 8.4 Hz, 2H), 4.99 (s, 2H), 1.66 – 1.53 (m, 4H); 13 C NMR (101 MHz, DMSO) Δ 170.14, 169.01, 152.43, 146.32...

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PUM

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Abstract

The invention discloses preparation and applications for a novel 1,1-cyclopropyl diamide derivative, and relates to a novel 1,1-cyclopropyl diamide derivative having a formula (I) and a salt thereof,including a medicinal salt, wherein R1, R2, R3, R4 and R5 and X, Z and L are defined as the description. The compound can be used for treating HIV and cancer diseases including lung cancer, liver cancer, breast cancer, lymphoma, mantle cell lymphoma, liposarcoma, melanoma, squamous cell esophageal cancer, etc. The pharmaceutical composition can be prepared to dosage forms suitable for absorption and utilization of mammal tissues and organs, and has good application prospects on treating cancers and HIV diseases. The pharmaceutical composition containing the compound is also related. The structural formula of the 1,1-cyclopropyl diamide derivative is shown as the formula (I).

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives and salts thereof, including pharmaceutically acceptable salts. Includes pharmaceutically acceptable salts. The compound of the present invention can be used for treating HIV and cancer diseases, including lung cancer, liver cancer, breast cancer, lymphoma, mantle cell lymphoma, liposarcoma, melanoma, squamous cell esophageal carcinoma and the like. The pharmaceutical composition of the invention can be made into a dosage form that is beneficial to the absorption and utilization of mammalian tissues and organs, and has good application prospects in the treatment of proliferative diseases such as HIV and cancer. The invention also relates to pharmaceutical compositions comprising the compounds of the invention. Background technique [0002] Tumor is a global problem faced by human beings, and the death rate caused by this fatal disease ranks first in the cause of human death. Chemotherap...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04A61K31/519A61P35/00A61P31/18A61P29/00
CPCC07D471/04C07D487/04
Inventor 向荣范艳李永涛郭庆祥黄志王鑫张超刘艳华
Owner NANKAI UNIV
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