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1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole transient receptor potential vanilloid 1 (TRPV1) antagonist and application thereof

A 4-b, antagonist technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as obvious side effects and inability to be effectively controlled

Active Publication Date: 2019-05-17
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these drugs have good clinical effects, their side effects are also obvious, such as the addiction of opioids, the gastrointestinal side effects of non-steroidal anti-inflammatory drugs, etc.
In addition, a significant number of pain types such as chronic and neuropathic pain cannot be effectively controlled with existing medications

Method used

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  • 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole transient receptor potential vanilloid 1 (TRPV1) antagonist and application thereof
  • 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole transient receptor potential vanilloid 1 (TRPV1) antagonist and application thereof
  • 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole transient receptor potential vanilloid 1 (TRPV1) antagonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 2-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3 , Preparation of 4-b]indole (1)

[0045]

[0046] (a) Preparation of 1-azido-4-chlorobenzene

[0047] Under ice-cooling, p-chloroaniline (1.27g, 10mmol) was dissolved in 6mol / L HCl (10ml) in a round bottom flask, and NaNO 2 (0.69g, 10mmol) was dissolved in 25ml of water and added dropwise to the above reaction system. The mixture was stirred for 20 min, NaN 3 (1.95g, 30mmol) was dissolved in 40ml of water and added dropwise. Stir at room temperature for 2-4h, extract with ethyl acetate (30ml×2), combine the organic phases and wash with water (30ml×3), evaporate the solvent under reduced pressure to obtain 1-azido-4-chlorobenzene;

[0048] (b) Preparation of 2-(prop-2-yn-1-yl)-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole

[0049] 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (1.72g, 10mmol), K 2 CO 3 (0.69g, 0.5mmol) was dissolved in acetone (10ml) to obtain solution A. Propylene brom...

Embodiment 2

[0054] 2-((1-(isoquinolin-5-yl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido Preparation of [3,4-b]indole (2)

[0055]

[0056] Referring to the preparation method in Example 1, wherein p-chloroaniline was replaced with pentaaminoisoquinoline, compound 2 was obtained as a brownish yellow solid with a yield of 87%. The experimental data are as follows:

[0057] C 23 h 20 N 6 , yield 87%, brown yellow solid, m.p=147.2-149.6℃; 1 H NMR (CDCl 3 ,400MHz): δppm 9.33(s,1H,NH),8.70(s,1H,C=CH),8.54(s,1H,Ar-H),8.09(d,1H,J=12.0Hz,Ar-H ),7.91(s,1H,Ar-H),7.73-7.63(m,2H,Ar-H),7.54(d,1H,J=8.0Hz,Ar-H),7.44(d,1H,J= 12.0Hz, Ar-H), 7.24(t, 1H, J=8.0Hz, Ar-H), 7.10-7.01(m, 2H, Ar-H), 4.05(s, 2H, CH 2 ),3.79(s,2H,CH 2 ),3.02(t,2H,J=6.0Hz,CH 2 ),2.86(t,2H,J=6.0Hz,CH 2 ); HRMSm / z:[M+H] + 381.1819 (calcd. 381.1822).

Embodiment 3

[0059] 2-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3 , Preparation of 4-b]indole (3)

[0060]

[0061] Referring to the preparation method in Example 1, wherein o-chloroaniline was used instead of p-chloroaniline, light yellow solid compound 3 was obtained with a yield of 91.6%. The experimental data are as follows:

[0062] C 20 h 18 ClN 5 , yield 91.6%, pale yellow solid, m.p=143.6-145.0℃; 1 H NMR (DMSO, 400MHz): δppm 10.62(s, 1H, NH), 8.42(s, 1H, C=CH), 7.68(d, 1H, J=8.0Hz, Ar-H), 7.62(d, 1H ,J=12.0Hz,Ar-H),7.52(t,2H,J=10.0Hz,Ar-H),7.27(d,1H,J=8.0Hz,Ar-H),7.18(t,1H,J =12.0Hz, Ar-H), 6.94-6.82(m, 2H, Ar-H), 3.87(s, 2H, CH 2 ),3.60(s,2H,CH 2 ),2.79(t,2H,J=8.0Hz,CH 2 ),2.65(t,2H,J=14.0Hz,CH 2 ); HRMS m / z: [M+H] + 364.1319 (calcd. 364.1323).

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Abstract

The invention relates to a 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole transient receptor potential vanilloid 1 (TRPV1) antagonist or a pharmaceutically-acceptable salt thereof. The structure generalformula is shown in the specifications, in the formula, R is H, or F, or Cl, or Br, or I, or CF3, or methyl, or isopropyl, or tertiary butyl, or cyclopropyl, or propenyl, or acetenyl, or hydroxyl, orphenoxyl, or acetyl or phenyl; n is 1, or 2 or 3; L is triazole, or tetrazole, or carbamido or thioureido; Ar is phenyl, or pyridyl, or isoquinolyl, or quinolyl or pyrimidyl. Through tests, it is found that 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole compounds have good TRPV1 inhibitory activity, and the activity of part of the compounds is far higher than that of a TRPV1 receptor antagonist BCTC;compared with the BCTC, the side effect of body temperature increasing is almost avoided. Therefore, the 1,2,3,4-tetrahydro-9H-pyridino[3,4-b]indole compounds as shown in the general formula and medicinal salts thereof are safe and effective and have a high analgesic effect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole TRPV1 antagonists, and a drug containing such compounds as active ingredients Preparations, and their application in the preparation of medicines for the treatment of pain. Background technique [0002] Pain is a common symptom of many diseases, and about 500 million people suffer from various pains every year. At present, the most clinically used analgesics are mainly divided into two categories: one is narcotic analgesics that directly activate opioid receptors, and the other is antipyretic drugs represented by non-steroidal anti-inflammatory drugs (NSAIDs). analgesics. Although these drugs have good clinical effects, their side effects are also obvious, such as the addiction of opioids and the gastrointestinal side effects of non-steroidal anti-inflammatory drugs. In addition, a considerable number ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/4725A61K31/4439A61K31/4427A61P29/00
Inventor 严琳李金玉聂存斌胡静乔玥
Owner HENAN UNIVERSITY
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