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Pyrrolomiazine compound and preparation method and application thereof

A pyrrolopyrimidine and compound technology, which is applied in the fields of organic compound synthesis and pharmaceutical application, can solve the problem of no modification of pyrrole ring amino group, achieve good solubility, high bioavailability, and enhance drug efficacy

Active Publication Date: 2017-03-15
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Baricitinib is disclosed in the patent WO2009114512, but there is no report on the modification of the amino group on the pyrrole ring in the prior art

Method used

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  • Pyrrolomiazine compound and preparation method and application thereof
  • Pyrrolomiazine compound and preparation method and application thereof
  • Pyrrolomiazine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of Compound A-1

[0046]

[0047] Add compound 1 (150 mg, 0.40 mmol, 1 equiv) into a mixed solvent of dichloromethane and acetonitrile to dissolve it, then add triethylamine (140 mL, 2.5 equiv), react the reaction system in an ice-water bath for 15 minutes, and slowly add ethyl Acyl chloride (0.044mL, 0.60mmol, 1.5equiv), slowly warmed up to room temperature, stirred overnight. The filtrate was concentrated, mixed with silica gel, and subjected to direct column chromatography (dichloromethane:methanol=50:1) to obtain compound A-1 (106 mg), with a yield of 64%. l H-NMR (300MHz, DMSO-d6) δ: 9.01 (s, 1H), 8.96 (d, J = 5.3, 1H), 8.52 (s, 1H), 8.13 (d, J = 4.1, 1H), 7.43 ( m,J=5.1,1H),4.61(d,J=9.2,2H),4.25(d,J=9.2,2H),3.69(s,1H),3.25(m,J=8.6,2H),3.00 (s,3H),1.24(m,J=4.9,3H)

Embodiment 2

[0048] Example 2 Preparation of Compound A-2

[0049]

[0050] Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved by adding a mixed solvent of dichloromethane and acetonitrile, then triethylamine (140 mL, 2.5 equiv) was added, and the reaction system was reacted in an ice-water bath for 15 minutes, and slowly added Isobutyryl chloride (0.084 mL, 0.60 mmol, 1.5 equiv), warmed up slowly to room temperature, and stirred overnight. The filtrate was concentrated, mixed with silica gel, and subjected to direct column chromatography (dichloromethane:methanol=50:1) to obtain compound A-2 (128 mg), with a yield of 72%. l H-NMR (300MHz, DMSO-d6) δ: 8.93(s, 1H), 8.44(s, 1H), 8.31(s, 1H), 8.01(d, J=4.1, 1H), 6.87(d, J= 4.1,1H),4.62(m,J=6.1,2H),4.25(d,J=9.4,2H),3.41(s,2H),3.09(m,J=7.4,2H),1.41(d,J =7.4,3H),1.38(t,J=4.9,6H)

Embodiment 3

[0051] Example 3 Preparation of Compound A-3

[0052]

[0053] Compound A-3 (125 mg) was synthesized in the same manner as compound A-1 in Preparation Example 1 except that n-butyryl chloride was used instead of acetyl chloride, with a yield of 70%. l H-NMR (300MHz, CDCL3) δ: 8.93(s, 1H), 8.44(s, 1H), 8.31(s, 1H), 8.06(d, J=4.1, 1H), 6.86(d, J=4.2, 1H), 4.64(d, J=9.5, 2H), 4.25(d, J=9.5, 2H), 3.53(t, J=7.3, 2H), 3.41(s, 2H), 3.09(m, J=7.4 ,2H),1.88(m,J=7.4,2H),1.42(t,J=7.4,3H),1.11(t,J=7.4,3H)

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PUM

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Abstract

The invention discloses a pyrrolomiazine compound shown as the general formula I (please see the formula in the description) and pharmaceutically-acceptable salt or solvate of the pyrrolomiazine compound, and further discloses preparation methods and application of the pyrrolomiazine compound shown as the general formula I and the pharmaceutically-acceptable salt or solvate of the pyrrolomiazine compound. The prepared pyrrolomiazine compound can be quickly converted into a stock drug baricitinib in plasma and has the better solubility, the higher bioavailability and the enhanced drug efficacy compared with the stock drug.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to pyrrolopyrimidine compounds, their preparation method and application. Background technique [0002] Prodrug (Prodrug) refers to a class of inactive or less active in vitro, in vivo through one or more steps of enzymes and biotransformation of chemical species, releasing active substances and producing pharmacological effects of compounds, also known as biological reversible drugs. It is usually formed by connecting a biologically active drug molecule (original drug) with a non-toxic carrier (temporary transport group). According to the chemical structure, prodrugs can be divided into four categories: carrier-linked prodrugs, biological prodrugs, macromolecular prodrugs, and drug-antibody conjugates. [0003] Prodrug is a very useful drug design method, which is widely used in the design of various drug molecules. Many drug...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F9/6561A61K31/519A61K31/675A61P19/02A61P29/00
CPCC07D487/04C07F9/6561
Inventor 吉民王鹏许娇娇蔡进
Owner SOUTHEAST UNIV
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