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Pyrrolopyrimidine compounds, their preparation method and use

A technology for pyrrolopyrimidine and compound, which is applied in the field of organic compound synthesis and medical application, can solve the problem of no pyrrole ring amino modification and the like, and achieves the effects of good solubility, high bioavailability and enhanced drug efficacy

Active Publication Date: 2018-05-15
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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  • Pyrrolopyrimidine compounds, their preparation method and use
  • Pyrrolopyrimidine compounds, their preparation method and use
  • Pyrrolopyrimidine compounds, their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of compound A-1

[0046]

[0047] Compound 1 (150 mg, 0.40 mmol, 1 equiv) was added to a mixed solvent of dichloromethane and acetonitrile to dissolve it, then triethylamine (140 mL, 2.5 equiv) was added, the reaction system was reacted in an ice-water bath for 15 minutes, and ethyl acetate was slowly added. Acid chloride (0.044 mL, 0.60 mmol, 1.5 equiv), slowly warmed 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-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 added to a mixed solvent of dichloromethane and acetonitrile to dissolve it, then triethylamine (140 mL, 2.5 equiv) was added, 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), slowly warmed 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 in the synthesis of Compound A-1 of Preparation Example 1 except that n-butyryl chloride was used in place of acetyl chloride in 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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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 in particular relates to pyrrolopyrimidine compounds, a preparation method and uses thereof. Background technique [0002] Prodrug refers to a class of compounds that are inactive or less active in vitro and undergo one or more steps of biotransformation of enzymes and chemical species in vivo to release active substances and produce pharmacological effects. Reversible drugs. It is usually formed by linking a biologically active drug molecule (original drug) with a non-toxic carrier (transient 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] Prodrugs are a useful method for drug design and are widely used in the design of a variety of drug molecules. Many drugs are administered in the form...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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