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NK1 receptor-targeting antagonist and application of same to chemotherapy-induced nausea and vomiting

A technology of compounds and racemates, applied in medical preparations containing active ingredients, digestive system, organic chemistry, etc., can solve problems such as lack of drugs and large side effects

Active Publication Date: 2019-02-26
北京宽厚医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still a lack of effective drugs for delayed nausea and vomiting caused by chemotherapy, and the side effects of existing drugs are relatively large

Method used

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  • NK1 receptor-targeting antagonist and application of same to chemotherapy-induced nausea and vomiting
  • NK1 receptor-targeting antagonist and application of same to chemotherapy-induced nausea and vomiting
  • NK1 receptor-targeting antagonist and application of same to chemotherapy-induced nausea and vomiting

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] The synthesis of embodiment 1 compound A1-A18

[0108] Compounds A1-A18 can be synthesized using the following reaction formula:

[0109]

[0110] Reagents and conditions: (i-A) a. Thionyl chloride, reflux for 3 hours; b. Dichloromethane, DIEA (N,N-diisopropylethylamine); (ii-A) o-tolylmagnesium chloride (O- tolyl magnesium chloride), tetrahydrofuran, dichlorodicyanobenzoquinone or manganese acetate; (iii-A) isopropanol, nitrogen methylpiperazine; (iv-A) methanesulfonic acid; (v-A) N-bromobutyl Diimide, sodium methoxide, methanol; (vi-A) red aluminum, toluene; (vii-A) N,N-diisopropylethylamine, dichloromethane;

[0111] Preparation of Intermediate A-1

[0112] The raw material 5-carboxy-2-chloropyridine (1eq) was dissolved in 10ml of thionyl chloride, and refluxed for 2h. After cooling to room temperature, the solvent was spin-dried and dissolved with an appropriate amount of dry dichloromethane to obtain a yellow solution for use. Then tert-butylamine (1.1eq) an...

Embodiment 2

[0154] Embodiment 2 compound B1-B15 is synthesized

[0155]

[0156] Reaction reagents and conditions: (i-B) concentrated sulfuric acid and methanol (ii-B) isopropanol, nitrogen methyl piperazine; (iii-B) lithium hydroxide and water; (iv-B) 2-(7-azo Benzotriazole)-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, amine derivatives;

[0157] Intermediate B-8 Synthesis

[0158] Dissolve 1 mmol of intermediate B-7 in 15 ml of methanol, add two drops of concentrated sulfuric acid, react at room temperature for 10 h, concentrate and dissolve in ethyl acetate, wash with saturated sodium bicarbonate, water, saturated brine, and anhydrous sodium sulfate Dry and concentrate to obtain intermediate B-8, which is used directly without purification. 1 H-NMR (DMSO-d 6 ,400MHz),δ(ppm):8.88(1H,s),7.53(3H,m),7.39(1H,m),7.23(1H,m),3.84(3H,s),2.61(3H,s) .

[0159] Intermediate B-9 Synthesis

[0160] Intermediate 8 (1 mmol) was dissolved in 10 ml of isopropanol, and nitr...

Embodiment 3

[0180] Example 3 Synthesis of Compound C1-C9

[0181] Compound C-1 was prepared by referring to the method of Example 2. Compound C-1 was reacted with different amine derivatives to obtain the target compound. The reaction scheme is as follows:

[0182]

[0183] Reagents and conditions: 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, amine derivatives.

[0184] Take the above-mentioned intermediate C-1 (1mmol) and dissolve it in 10ml DMF (N,N-dimethylformamide), add DIEA (N,N-diisopropylethylamine) (2mmol), and derivatize with different amines (1 mmol) and HBTU (2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate) (1 mmol) were reacted overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layers were combined, washed 3 times with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, it was purified by silica ge...

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Abstract

The invention relates to a NK1 receptor-targeting antagonist and application of the same to chemotherapy-induced nausea and vomiting, belonging to the technical field of adjuvant therapeutics for tumor chemotherapy. The invention provides a compound as shown in a formula I which is described in the specification, or a racemate, stereoisomer, tautomer, isotopic label, oxynitride or pharmaceutically-acceptable salt thereof. The invention also provides a preparation method for the compound, a pharmaceutical compositions and the application of the compound or the racemate, stereoisomer, tautomer,isotopic label, oxynitride or pharmaceutically-acceptable salt thereof.

Description

[0001] This application claims the patent application number 201710691601.5 submitted to the State Intellectual Property Office on August 14, 2017, and the title of the invention is "Targeted NK1 receptor antagonist and its application in the treatment of nausea and vomiting caused by chemotherapy". Priority right to an earlier application for a patent for invention, which is hereby incorporated by reference in its entirety. technical field [0002] The invention relates to a targeted NK1 receptor antagonist and its application in the treatment of nausea and vomiting caused by chemotherapy, and belongs to the technical field of drugs for adjuvant chemotherapy of tumors. Background technique [0003] Nausea and vomiting caused by chemotherapy are one of the most common adverse reactions in cancer patients and are the main factors affecting the efficacy of anticancer drugs. Nausea and vomiting after chemotherapy not only directly cause nutritional and metabolic disorders and e...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07D213/76C07D213/87A61K31/496A61K31/5377A61K31/4439A61K31/44A61P1/08
CPCA61P1/08C07D213/75C07D213/76C07D213/87
Inventor 崔一民和龙欧阳亮苟马玲王玲
Owner 北京宽厚医药科技有限公司
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