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Indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof

An indoline piperidinyl urea, dual-target technology, applied in the directions of drug combinations, pharmaceutical formulations, antipyretics, etc., can solve the problems of reducing analgesic effect, drug tolerance and increasing drug dosage, and reduce side effects. , the effect of broad analgesic application prospects and practical value

Active Publication Date: 2022-06-07
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, long-term use of such drugs can lead to the expression and release of chemokines, pro-inflammatory cytokines, and nociceptive neurotransmitters in the spinal cord area and dorsal root ganglia, thereby antagonizing the analgesic effect of opioid receptors, leading to drug toxicity. Tolerance increases with dose, reduces analgesic effect

Method used

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  • Indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof
  • Indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof
  • Indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: N-(2,4-dimethylphenyl)-1-propionylspirocycle [indoline-3,4'-piperidine]-1'-carboxamide represented by formula (1) preparation

[0051]

[0052] The preparation method includes the following steps:

[0053] (a) Preparation of spiro[indole-3,4'-piperidine]-1'-carboxylate tert-butyl ester

[0054] Dissolve 10 g (0.0469 mol) of 1-Boc-4-piperidinal in 468 mL of dichloromethane to prepare a 0.1 mol / L solution, add 4.615 mL (0.0469 mol) of phenylhydrazine under ice bath, and stir for 10 min, and slowly add trifluorocarbon 6.964 mL (0.0938 mol) of acetic acid was reacted at room temperature overnight, 100 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane 3 times, each using 100 mL, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain spiro[indole] -3,4'-Piperidine]-1'-carboxylic acid tert-butyl ester is a brown oily liquid.

[0055] (b) Preparation of spiro[indo...

Embodiment 2

[0064] Example 2: N-(2,5-dimethylphenyl)-1-propionylspirocycle [indoline-3,4'-piperidine]-1'-carboxamide represented by formula (2) preparation

[0065]

[0066] Substitute 2,4-dimethylaniline in step (g) of Example 1 with 137 μL (1.101 mmol) of 2,5-dimethyl-aniline, and refer to the preparation method in Example 1 for other steps to obtain compound ( 2) to obtain a white solid, yield: 63%. The experimental data is as follows:

[0067] C 24 H 29 N 3 O 2 , White solid (47.6% yield), mp=182.5-184.5℃; 1 H NMR (300MHz, DMSO-d 6 )δppm 8.11(d,J=8.0Hz,1H,NH),8.07(s,1H,Ar-H),7.31-7.14(m,2H,Ar-H),7.04(q,J=7.3Hz,3H , Ar-H), 6.87(d, J=7.5Hz, 1H, Ar-H), 4.12(d, J=13.8Hz, 2H, Piperidine), 4.07(s, 2H, pyrrolidine), 3.00(t, J =12.4Hz, 2H, Piperidine), 2.64-2.52(m, 2H, CH 2 ),2.25(s,3H,Ar-CH 3 ),2.15(s,3H,Ar-CH 3 ),1.87-1.71(m,2H,Piperidine),1.63(d,J=12.8Hz,2H,Piperidine),1.09(t,J=7.2Hz,3H,CH 3 ).

Embodiment 3

[0068] Example 3: Preparation of N-(2,5-dichlorophenyl)-1-propionylspiro[indoline-3,4'-piperidine]-1'-carboxamide represented by formula (3)

[0069]

[0070] Substitute 2,4-dimethylaniline in step (g) of Example 1 with 83 μL (1.167 mmol) of 2,5-dichloro-aniline, and refer to the preparation method in Example 1 for other steps to obtain compound ( 3) to obtain a white solid, yield: 61%. The experimental data is as follows:

[0071] C 22 H 23 Cl 2 N 3 O 2 , White solid (47.6% yield), mp=174.5-176.5℃; 1 H NMR (300MHz, DMSO-d 6 )δppm 8.39(s,1H,NH),8.11(d,J=7.9Hz,1H,Ar-H),7.68(t,J=2.8Hz,1H,Ar-H),7.50(d,J=8.6 Hz,1H,Ar-H),7.22-7.19(m,J=15.3,13.1,8.3Hz,3H,Ar-H),7.02(t,J=7.4Hz,1H,Ar-H),4.14(d ,2H,Piperidine),4.07(s,2H,pyrrolidine),3.06(t,J=12.5Hz,2H,Piperidine),2.64-2.51(m,2H,CH 2 ),1.90-1.73(m,2H,Piperidine),1.65(d,J=12.9Hz,2H,Piperidine),1.08(t,J=7.2Hz,3H,CH 3 ).

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Abstract

The invention belongs to the technical field of pharmacy, and particularly discloses an indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target medicine as well as a preparation method and application of the indoline piperidine urea TRPV1 antagonistic and MOR agonistic double-target medicine. In particular to a compound in general formula (I) and pharmaceutically acceptable salts thereof, which can be used for preventing and / or treating diseases related to TRPV1 and / or MOR activity, such as pain, inflammation, immune dysfunction, neurological and psychiatric disorders, respiratory diseases, urinary and reproductive disorders; the invention also relates to a preparation method of the compounds and a pharmaceutical preparation containing the compounds.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to an indoline piperidinamide TRPV1 antagonism and MOR agonist dual target drug and a preparation method and application thereof. The dual target drug is an indoline piperidinamide compound as Active ingredient. Background technique [0002] Pain is a painful experience associated with actual or potential tissue damage and includes sensory, emotional, cognitive and social components. According to its different time course, pain can be divided into acute pain and chronic pain: the former occurs in tissue damage and has a warning and protective effect on the body; while the latter is mediated by long-term pathological changes caused by nerve damage or abnormal nerve activity , is a major clinical problem that needs to be solved urgently. However, due to insufficient understanding of the mechanism of chronic pain, existing analgesic drugs have poor efficacy or significan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10A61K31/438A61P29/00A61P37/02A61P25/00A61P11/00A61P13/00A61P15/00
CPCC07D471/10A61P29/00A61P37/02A61P25/00A61P11/00A61P13/00A61P15/00
Inventor 严琳宋德朴王国豪陈英达王冰新郭宁邵芦莲
Owner HENAN UNIVERSITY
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