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Compound and application thereof

A compound and drug technology, applied in the field of drug synthesis, can solve the problems of stimulating leukocyte adhesion, cardiovascular complications, reducing blood flow of gastric mucosa, etc., and achieve the effect of inhibiting inflammatory response

Active Publication Date: 2014-07-16
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, long-term use of non-steroidal anti-inflammatory drugs will stimulate the adhesion of white blood cells, reduce the blood flow of the gastric mucosa, and cause damage to the gastrointestinal tract
Although selective inhibition of cyclooxygenase-2 (COX-2) can reduce gastrointestinal side effects of drugs, some studies have pointed out that it may cause cardiovascular complications

Method used

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  • Compound and application thereof
  • Compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The present embodiment provides a kind of compound, and the flow process of its synthesis is as follows:

[0048]

[0049] 1) Synthesis of intermediate Ra-012-1

[0050] Cysteine ​​hydrochloride Ra-016 (2.0g, 44mmol) and Boc anhydride (3.5g, 16mmol) were dissolved in dichloromethane (20mL), and triethylamine (2.5mL, 18mmol) was slowly added in an ice-water bath, After the addition, it was raised to room temperature for 16 hours of reaction, washed with 0.5N HCl and saturated sodium chloride successively, and the organic phase was dried and spin-dried to obtain a colorless oil (2.7 g, yield 95%). The colorless oil obtained through NMR analysis is Ra-012-1. The NMR data are as follows: 1 H NMR (400MHz, CDCl 3 )δ4.93(br s,1H),3.32-3.28(m,2H),2.64(t,J=6.8Hz,2H),6.43(s,1H),6.25(d,J=8.0Hz,1H) ,1.44(s,9H).

[0051] 2) Synthesis of intermediate Ra-012-2

[0052] Under an ice-water bath, diclofenac Ra-009 (100 mg, 0.34 mmol) and Ra-012-1 were dissolved in dichloromethan...

Embodiment 2

[0056] The present embodiment provides a kind of compound, and the flow process of its synthesis is as follows:

[0057]

[0058] Synthesis of product Ra-014:

[0059] Dissolve Ra-009 (50mg, 1.7mmol) in 10mL of dichloromethane and 10mL of dioxane, add Ra-015 (770mg, 3.4mmol) and dicyclohexylcarbodiimide (420mg, 3.4mmol) under ice-cooling and 4-dimethylaminopyridine (700mg, 3.4mmol). Stir the reaction at room temperature for 24 hours, filter with diatomaceous earth, and concentrate under reduced pressure to obtain a white solid (260 mg, yield 29%) by silica gel column chromatography. The white solid was determined by NMR. After analysis, the white solid was Ra-014 . The NMR data are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.79(s,1H),9.67(s,1H),7.54(d,J=8.0Hz,2H),7.40(d,J=8.4Hz,2H),7.31 (d,J=6.8Hz,1H),7.22(t,J=8.0Hz,1H),7.13-7.06(m,2H),7.03(d,J=16.0Hz,1H),6.93-6.86(m, 2H), 6.82-6.74(m, 4H), 6.43(s, 1H), 6.25(d, J=8.0Hz, 1H), 4.07(s, 2H).

Embodiment 3

[0061] The present embodiment provides a kind of compound, and the flow process of its synthesis is as follows:

[0062]

[0063] 1) Synthesis of intermediate Ra-018-1

[0064] Dissolve Ra-009 (1.0g, 3.3mmol) in 20mL of dichloromethane and 20mL of water, add sodium bicarbonate (1.05mg, 1.25mmol) and tetrabutylammonium bisulfate (110mg, 0.33mmol), and stir for 5min, Chloromethyl chlorosulfonate (600 mg, 3.63 mmol) was dissolved in 10 mL of dichloromethane and added dropwise to the above solution, stirred at room temperature for 1 hour, extracted with dichloromethane (30 mL) and water (20 mL) for 3 Once, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, add 20 mL of acetone to dissolve, add sodium iodide (2.0 g, 13.2 mmol), stir at room temperature for 24 hours, spin off the acetone, add 20 mL of dichloromethane, Celite was filtered, and the organic layer was concentrated under reduced pressure to obtain a yellow solid (1.3 g,...

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Abstract

The invention provides a compound. The compound and pharmaceutically acceptable salt, various isotopes, various crystal forms or various isomers have the structure shown as a formula (I): A-L-B (I), wherein A is a non-steroidal anti-inflammatory drug compound monomer, B is a hydrogen sulfide releaser or an antioxidant compound, and L is a group or a functional group which connects A and B. The invention further provides an application of the compound as a medicine for inhibiting neuroinflammation as well as a combined application of the compound and other drugs as medicines for inhibiting neuroinflammation. By applying the concept of double prodrugs, the non-steroidal anti-inflammatory drug and the hydrogen sulfide releaser or the antioxidant compound are covalently connected together to form a multiple-target point compound which can effectively inhibit inflammatory response of the microglial cell induced by lipopolysaccharide, so that the compound can be used for treating or preventing various neurodegenerative diseases.

Description

technical field [0001] The invention relates to a compound and its application, in particular to a compound with the effect of inhibiting neuroinflammation and its application, and belongs to the technical field of drug synthesis. Background technique [0002] Neurodegeneration is the most important pathological feature of various neurodegenerative diseases including Parkinson's disease, multiple sclerosis and Alzheimer's disease. Although the pathogenesis of different neurodegenerative diseases is different, abnormal activation of microglia is a common feature (Block ML et al., Nat. Rev. Neurosci., 2007, 8(1):57-69). For example, in the study of Parkinson's disease, it was found that there are a large number of activated microglia in the substantia nigra area where degenerative lesions exist. [0003] Microglia is the smallest glial cell in the central nervous system, accounting for about 15% of the total glial cells, and is the most important immune defense line in the ce...

Claims

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Application Information

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IPC IPC(8): C07C327/30C07C229/42A61K31/265A61K31/216A61P25/08A61P25/28A61P25/16A61P25/00A61P9/10
Inventor 郑计岳许芝祥郑龙太马海阔镇学初张小虎
Owner SUZHOU UNIV
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