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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  • Abstract
  • Description
  • Claims
  • Application Information

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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

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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