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Substituted azaindole compounds and their salts, compositions and uses

A compound and composition technology, which is applied in the direction of drug combination, compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, etc., can solve the problems of low water solubility, low bioavailability, poor stability, etc.

Active Publication Date: 2016-08-10
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, prodrugs improve the therapeutic effect by improving the pharmacokinetic properties of the original drug in one or more aspects, which can overcome various difficulties in the dosage form and metabolism of the original drug, such as low water solubility, poor stability, Insufficient oral bioavailability, obvious first-pass effect and toxicity
[0011] The defect of vemurafenib is low bioavailability and large oral dose (the approved dose of MBP dosage form is 960 mg twice a day, each time), but its remarkable curative effect on melanoma makes it a highly sought-after drug. Concerned about drug substrates, researchers expect to improve oral bioavailability by synthesizing vemurafenib analogs

Method used

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  • Substituted azaindole compounds and their salts, compositions and uses
  • Substituted azaindole compounds and their salts, compositions and uses
  • Substituted azaindole compounds and their salts, compositions and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0332] Example 1: 3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl (propane Sulfonyl) urethane

[0333]

[0334] N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2g, 0.41mmol) was suspended in 1,4-dioxane (15mL), and ethyl chloroformate (EtOCOCl, 44mg, 0.41mmol) and triethylamine (0.14g, 1.38mmol) were sequentially added thereto . After the reaction solution was stirred at room temperature for 1.5 hours, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate (v / v)=4 / 1) to obtain the title compound as a white solid (0.12 g, 50%).

[0335] LC-MS(ESI,pos.ion)m / z562.1[M+H] + ;

[0336] 1 H NMR (400MHz, CDCl 3 )δ1.08(t,J=7.2Hz,3H),1.29(t,J=7.2Hz,3H),1.92-2.05(m,2H),3.61(br,1H),3.70(br,1H), 4.27-4.32(q,J=7.2Hz,2H),7.08-7.13(m,1H),7.45-7.51(m,3H),7.78(d,J=8.4Hz,2H),7.98(d,J= 2.0Hz, 1H), 8.65(d, J=1.9Hz, 1...

Embodiment 2

[0337] Example 2: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorobenzene base)-N-(propanesulfonyl)benzamide

[0338]

[0339] N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2g, 0.41mmol) was suspended in dioxane (15mL), and benzoyl chloride (57mg, 0.41mmol) and triethylamine (0.14g, 1.38mmol) were added thereto. The reaction solution was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate (v / v)=4 / 1) to obtain the title compound as a white solid (0.14 g, 55%).

[0340] LC-MS(ESI,pos.ion)m / z594.1[M+H] + ;

[0341] 1 H NMR (400MHz, CDCl 3 )δ1.10(t,J=7.4Hz,3H),1.92-2.05(m,2H),3.74(t,J=7.6Hz,2H),6.27-6.32(q,J=7.2Hz,2H), 7.06-7.10(m,1H),7.39(t,J=7.6Hz,2H),7.46-7.63(m,6H),8.16(d,J=7.0Hz,1H),8.65(d,J=2.1Hz ,1H), 8.84(d,J=2.0Hz,1H),10.08(s,1H).

Embodiment 3

[0342] Example 3: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorobenzene base)-N-(propanesulfonyl)isobutyramide

[0343]

[0344] At room temperature, N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane- 1-Sulphonamide (0.2 g, 0.41 mmol) and triethylamine (2 mL) were suspended in chloroform (10 mL), and isobutyryl chloride (173 μL, 1.64 mmol) was added thereto. After the reaction solution was stirred at room temperature for 16 hours, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=1 / 1 to 1 / 2) to obtain the title compound as a white solid ( 2mg, 0.8%).

[0345] LC-MS(ESI,pos.ion)m / z560.1[M+H] + ;

[0346] 1 H NMR (400MHz, CDCl 3 )δ1.04-1.15(t,J=7.4Hz,3H),1.12(s,3H),1.13(s,3H),1.88-1.99(m,2H),2.46-2.54(m,1H),3.55 -3.80(m,2H),7.14-7.20(m,1H),7.46-7.55(m,3H),7.60-7.45(d,J=8.4Hz,2H),7.77(s,1H),8.64-8.68 (d...

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Abstract

The invention provides a substituted azaindole compound having a structure as represented by a formula (I) and a pharmaceutically acceptable salt and a medicinal preparation thereof. The compound is used for adjusting activity of protein kinase and adjusting intercellular or intracellular signal response. The invention further relates to a pharmaceutical composition including the compound and a method of applying the pharmaceutical composition to treatment of highly proliferative diseases of mammals, especially of mankind.

Description

[0001] This application requires a Chinese patent application submitted to the China Patent Office on August 27, 2012, with the application number 201210307104.8, and the invention title is "Substituted azaindole compounds and their salts and methods of use" and filed on April 3, 2013 The priority of the Chinese patent application with the application number 201310116870.0 and the invention title "Substituted azaindole compounds and their salts and methods of use" filed with the China Patent Office, the entire contents of which are incorporated by reference in this application. technical field [0002] The invention belongs to the technical field of medicines, and specifically relates to a substituted azaindole compound and its salt, composition and application. Background technique [0003] Kinases, as a large family of proteins, have become a major class of targets in drug research. Human gene sequencing has confirmed that there are more than 500 protein kinases present in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07F9/6561A61K31/437A61K31/444A61K31/4545A61K31/675A61P35/00A61P35/04A61P9/10A61P11/00A61P35/02A61P27/02A61P3/10A61P27/06A61P1/04A61P15/00A61P7/10
CPCC07D471/04C07F9/6561
Inventor 习宁王婷瑾唐胤孙明明王茜
Owner SUNSHINE LAKE PHARM CO LTD