Deuterated acetylenic derivative, pharmaceutical composition and application thereof

A technology of deuterated acetylene and derivatives, which can be used in drug combinations, anti-tumor drugs, pharmaceutical formulations, etc., and can solve the problems of affecting clinical medication, poor pharmacokinetic properties, and large toxic and side effects.

Active Publication Date: 2015-02-11
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to provide a deuterated acetylene derivative, its Pharmaceutical composition and application

Method used

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  • Deuterated acetylenic derivative, pharmaceutical composition and application thereof
  • Deuterated acetylenic derivative, pharmaceutical composition and application thereof
  • Deuterated acetylenic derivative, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0270] Example 1: 4-Difluoromethyl-3-imidazol[1,2-b]pyridazin-3-ylethynyl-N-[4-(4-trideuteromethyl-piperazin-1-yl Methyl)-3-trifluoromethyl-phenyl]-benzamide

[0271]

[0272] The first step: methyl 3-iodo-4-bromomethylbenzoate

[0273] Dissolve methyl 3-iodo-4-methylbenzoate (200 mg, 0.7 mmol) in carbon tetrachloride (5 mL), add N-bromosuccinimide (180 mg, 1.0 mmol) and benzene peroxide in sequence Formyl (17.5mg, 0.07mmol), stirred at 100°C for 24h. After the reaction, the solvent was evaporated, the residue was adjusted to pH 9 with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried, and concentrated under reduced pressure to obtain a crude reddish-brown oil. It was directly used in the next reaction without further purification.

[0274] The second step: methyl 3-iodo-4-hydroxymethylbenzoate

[0275] The above crude 3-iodo-4-bromomethylbenzoate (300mg) was...

Embodiment 2～ Embodiment 19

[0291] Using different aryl halides and aryl acetylenes as raw materials, the compound of Example 2 to Compound 19 of Example were synthesized by general method 1, and the specific chemical structure identification data are shown in Table 1.

[0292] Table 1. Chemical Structure Identification Data of Example Compound 2~Example Compound 19

[0293]

[0294]

[0295]

[0296]

[0297]

Embodiment 20～ Embodiment 25

[0299] Using Example Compounds 5, 6, 10, 11, 12, and 19 in Table 1 as raw materials, Example Compound 20 to Example Compound 25 were synthesized by General Method 2. The specific chemical structure identification data are shown in Table 2.

[0300] Table 2. The chemical structure identification data of Example Compound 20~Example Compound 25

[0301]

[0302]

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PUM

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Abstract

The invention discloses a deuterated acetylenic derivative, a pharmaceutical composition and application thereof. The deuterated acetylenic derivative comprises one or more of the deuterated acetylenic derivative (I) with curative effective dose, pharmaceutically-acceptable salt, a stereoisomer, solvate, a polymorphic substance, tautomer, metabolite and prodrugs thereof and at least one pharmaceutically-acceptable auxiliary material. The invention also provides the deuterated acetylenic derivative (I), the pharmaceutically-acceptable salt, the stereoisomer, the solvate, the polymorphic substance, the tautomer, the metabolite or the prodrug thereof, or application of the pharmaceutical composition in preparing one or more protein kinase inhibitors and application in preparing drugs for treating and / or preventing tumors. The deuterated acetylenic derivative (I) disclosed by the invention has the advantages that the activity of protein kinase and the growth of tumor cells can be effectively inhibited, and excellent pharmacokinetic properties and in-vitro and in-vivo pharmaceutical effect are expressed. The formula (I) is as shown in the specification.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a class of deuterated acetylene derivatives, pharmaceutical compositions and applications thereof. Background technique [0002] At present, diaryl-substituted acetylene compounds have been widely accepted as a class of protein kinase inhibitors for the treatment of imatinib-resistant chronic myelogenous leukemia, such as AP24534 and GDZ824, which have similar ability to inhibit one or A variety of protein kinase activities closely related to the occurrence and development of tumors and / or the activity of inhibiting the growth of tumor cells. AP24534, namely Ponatinib, a potent protein kinase inhibitor developed by Ariad Pharmaceuticals of the United States, has been approved by the FDA in December 2012 for the treatment of Philadelphia chromosome-positive drug-resistant chronic myelogenous leukemia. However, this type of drug still has some unavoidable shortcomings, such a...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04A61K31/5025A61K31/496A61K31/4985A61P35/00A61P35/02
CPCC07D471/04C07D487/04
Inventor 万惠新李春丽石辰刘海燕李萍沈竞康
Owner SHANGAI PHARMA GRP CO LTD
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