Pyrimido-pyrrolopyridazine derivative as well as intermediate, preparation method, pharmaceutical composition and application

A technology of pyridazine derivatives and pyrimidines, which is applied in the field of pyrimidopyrrolopyridazine derivatives, and can solve the problems of long synthetic route and low total yield, etc.

Active Publication Date: 2020-02-07
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The problem to be solved by the present invention is to provide a kind of pyrimidopyrrolopyridazine derivatives, intermediate , preparation method, pharmaceutical composition and application

Method used

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  • Pyrimido-pyrrolopyridazine derivative as well as intermediate, preparation method, pharmaceutical composition and application
  • Pyrimido-pyrrolopyridazine derivative as well as intermediate, preparation method, pharmaceutical composition and application
  • Pyrimido-pyrrolopyridazine derivative as well as intermediate, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Preparation of Compound II-1

[0088] Refer to Huang, Z.-T.; Wang, M.-X., Synthesis 1992, 12, 1273-1276 and Li, Z.-J.; Smith, C.D., Synthetic Communications 2001, 31, 527-533 for specific synthesis The route looks like this:

[0089]

[0090] Dissolve acetophenone (10.0mmol) in THF (50ml) under ice-cooling, add NaH (20.0mmol) and stir for half an hour, then CS 2 (10.0mmol) was added dropwise to the above reaction solution, kept in the ice bath and continued to stir for two hours, and finally MeI (20.0mmol) was dropped into the reaction solution, kept in the ice bath for half an hour, then the temperature was slowly raised to room temperature, and stirred overnight. The reaction was evaporated to dryness under reduced pressure and diluted with EtOAc (100 mL). The organic phase was washed with water (50mL) and saturated brine (50mL) successively, washed with Na 2 SO 4 After drying, the solution was evaporated to dryness under reduced pressure and used directly in t...

Embodiment 2

[0102] Example 2: Preparation of pyrimidopyrrolopyridazine derivative I-1

[0103]

[0104] in CH 3 CN (5ml) was added HKAs (0.2mmol) shown in formula II-1 and DDs (0.2mmol) shown in formula III-1, stirred at room temperature, TLC (thin layer chromatography using silica gel GF254) followed the reaction, Until HKAs and DDs are completely consumed, the compound represented by formula IV-1 is obtained, and the compound is directly subjected to subsequent reactions without isolation.

[0105] Add CuCl to the reactant 2 (0.02 mmol), the resulting mixture was stirred at 50° C. until the compound represented by formula IV-1 was completely converted into product I-1 (monitored by thin-layer chromatography using silica gel GF254). The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic phase was washed with saturated NH 4 Cl solution (20mL) and water (20mL) washed with Na 2 SO 4 After drying, the solution was evaporated to dryness on a rotary eva...

Embodiment 3

[0108] Example 3: Preparation of pyrimidopyrrolopyridazine derivatives I-2

[0109]

[0110] The preparation process of pyrimidopyrrolopyridazine derivative I-2 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed to finally obtain yellow solid I-2, melting point: 174.6-175.3 ° C, yield: 65% ,

[0111]

[0112] 1 H NMR (500MHz, CDCl 3 )δ7.96(d, J=8.2Hz, 2H), 7.30(d, J=7.9Hz, 2H), 3.83(q, J=5.6Hz, 4H), 3.11(s, 3H), 2.46–2.41( m,3H),1.97-1.92(m,2H); 13 C NMR (126MHz, CDCl 3 )δ165.21, 155.47, 154.52, 148.65, 140.37, 131.38, 130.48, 128.60, 128.33, 126.31, 47.15, 37.73, 21.52, 19.81, 18.60; HRMS (TOF ES + ):C 17 h 17 N 4 O[(M+H) + ] The predicted value is 293.1397, and the measured value is 293.1398.

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Abstract

The invention discloses a pyrimido-pyrrolopyridazine derivative as well as an intermediate, a preparation method, a pharmaceutical composition and application thereof. The preparation method of the pyrimido-pyrrolopyridazine derivative of a formula I shown in the description comprises the following step: in a solvent, under the action of additives, performing a reaction shown in the description onthe compound of a formula IV shown in the description. By adopting the preparation method disclosed by the invention, defects such as multi-step synthesis and low separation yields in a traditional method can be overcome, and various novel heterocyclic compounds with important biological activity can be rapidly synthesized. The pyrimido-pyrrolopyridazine derivative disclosed by the invention hasgood activity of inhibiting production of NO by macrophage RAW264.7.

Description

technical field [0001] The invention relates to a pyrimidopyrrolopyridazine derivative, its intermediate, preparation method, pharmaceutical composition and use. Background technique [0002] Nitrogen-containing heterocycles are an important core of a class of biologically active compounds (Chem.Heterocycle.Compd.2016,52,651-657; Curr.Org.Chem.2017,21,1265-1291). Among them, pyridazine fused heterocycles have attracted extensive attention due to their remarkable broad-spectrum biological activities, including diuretic activity (J.Med.Chem.1999,42,779-783), anti-HIV-1 (J.Med.Chem.2000 , 43, 2457-2463), psychoactive effect (J.Med.Chem.2005, 48, 1367-1383) and platelet aggregation activity (J.Med.Chem.1986, 29, 2191-2194), etc. Multi-step synthesis and low isolated yields limit the development of such scaffolds (Heterocycles 1993, 35.; J. Heterocycle. Chem. 2005, 42, 361-373). [0003] The construction of some nitrogen-containing heterocyclic ring systems that have been repor...

Claims

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Application Information

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IPC IPC(8): C07D487/14C07D487/04A61K31/519A61P29/00A61P7/10
CPCC07D487/14C07D487/04A61P29/00A61P7/10
Inventor 孙青张卫东赵蒙浩李霞
Owner SHANGHAI INST OF PHARMA IND
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