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Piperidyl-4-carboxyl amide derivative and preparation method as well as application thereof

A technology for carboxamides and derivatives, which is applied in the field of preparation of 1-piperidine-4-carboxamide derivatives or their pharmaceutically acceptable salts, and can solve the problem of infection of the immune system, drug resistance, low oral availability, etc. question

Inactive Publication Date: 2014-05-07
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although highly active antiretroviral therapy (HAART), which is composed of reverse transcriptase inhibitors and protease inhibitors, has played an important role in the control of AIDS, although this treatment It can inhibit the replication of the virus and slow down the development of AIDS, but it cannot completely kill the virus, so the immune system will eventually be infected
In addition, the above-mentioned drugs have also exposed many shortcomings, such as large toxic and side effects, low oral availability, high cost, and drug resistance. Therefore, it is urgent to find new anti-HIV drugs with high efficiency, low toxicity and new targets.

Method used

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  • Piperidyl-4-carboxyl amide derivative and preparation method as well as application thereof
  • Piperidyl-4-carboxyl amide derivative and preparation method as well as application thereof
  • Piperidyl-4-carboxyl amide derivative and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 3-chloro-N-(3-chloropropyl)-benzamide (II)

[0047] Add 1.27g (10mmol) of compound I, 1.57g (10mmol) of 1,3-bromochloropropane, 1.63g (12mmol) of potassium carbonate, and 20ml of acetonitrile into the reaction flask, and reflux for 8-15 hours. After the reaction was completed, it was filtered, and the solvent was recovered under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: ethyl acetate:petroleum ether=1:10) to obtain 1.2 g of yellow oily liquid, yield: 60%.

[0048] 1 HNMR (δ, CDCl 3 ): 7.34-7.20 (m, 2H, Ar-H), 7.18-7.00 (m, 2H, Ar-H), 3.67-3.64 (m, 2H, CH 2 ), 3.57-3.53 (m, 2H, CH 2 ), 3.05-2.98 (m, 2H, CH 2 ).ESI-MS m / z: 204[M+H] +

Embodiment 2

[0049] Example 2 1-acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)piperidine-4-amide (IIIa)

[0050] Add 1.02g (5mmol) of compound II, 0.95g (5mmol) of 1-acetylpiperidine-4-acyl chloride, 1mL (6.9mmol) of triethylamine, and 15ml of dichloromethane into the reaction flask, stir at room temperature, and react 4- 6 hours. After the reaction was completed, the solvent was recovered under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: ethyl acetate: ethanol = 10: 1) to obtain 1.52 g of a tan solid, yield: 85%. M.p. 115-117°C.

[0051] 1 HNMR (δ, CDCl 3 ): 7.31-6.98 (m, 4H, Ar-H), 4.55-4.50 (m, 1H, piperidine-H), 3.83-3.80 (m, 1H, piperidine-H), 3.76 (t, J=7.0Hz, 2H, CH 2 ), 3.54(t, J=7.0Hz, 2H, CH 2 ), 2.94-2.81 (m, 1H, piperidine-H), 2.44-2.34 (m, 2H, piperidine-H), 2.06 (s, 3H, CH 3 ), 2.10-2.06 (m, 2H, CH 2 ), 1.87-1.62 (m, 4H, piperidine-H).ESI-MS m / z: 357[M+H] + .

Embodiment 3

[0052] Example 3 N-(3-chlorophenyl)-N-(3-chloropropyl)-4-fluorobenzamide (IIIb)

[0053] The procedure was the same as in Example 2, except that 1-acetylpiperidine-4-yl chloride was replaced by p-fluorobenzoyl chloride. A tan solid was obtained, yield: 90%. M.p.85-88°C.

[0054] 1 HNMR (δ, CDCl 3 ): 7.27-7.08(m, 4H, Ar-H), 7.03-6.93(m, 2H, Ar-H), 6.89-6.75(m, 2H, Ar-H), 4.04(t, .J=7.0Hz ,2H,CH 2 ), 3.65(t, J=7.0Hz, 2H, CH 2 ), 2.17-2.10 (m, 2H, CH 2 ).ESI-MS m / z: 326[M+H] + .

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PUM

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Abstract

The invention provides a 1-(3-amino propyl) piperidyl-4-carboxyl amide derivative, which is a highly active antagonist of a chemokine receptor CCR5. The compound has broad anti-HIV (Human Immunodeficiency Virus) application prospect, has therefore high commercial value, can be applied to preparing the CCR5 receptor antagonist and particularly to preparation of medicaments for treating diseases mediated by the CCR5, such as acquired immune deficiency syndrome, asthma, rheumatoid arthritis and autoimmune diseases, and has a structural general formula which is shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and mainly relates to a preparation method of 1-(3-aminopropyl)piperidine-4-carboxamide derivatives or pharmaceutically acceptable salts thereof with CCR5 antagonistic activity, and the preparation of the compound for the treatment of Use in medicines mediated by CCR5 such as HIV infection, autoimmune diseases and the like. Background technique [0002] AIDS (AIDS) is a fatal immunodeficiency disease caused by human immunodeficiency virus (Human immunodeficiency virus, HIV), and it is one of the major diseases that endanger human health in the world today. Although highly active antiretroviral therapy (HAART) composed of reverse transcriptase inhibitors and protease inhibitors widely used clinically plays an important role in the control of AIDS, although this treatment It can inhibit the replication of the virus and slow down the development of AIDS, but it cannot completely kill the virus, s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/62A61K31/4545A61K31/445A61P31/18A61P37/02
CPCY02P20/55
Inventor 刘滔谢欣胡永洲翁志勇魏巍
Owner ZHEJIANG UNIV
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