Transient receptor potential vanilloid 1/epoxidase 2(TRPV1/COX-2) dual inhibitor, and preparation method and application thereof in preparation of analgesic medicament

A technology of drugs and medicinal salts, applied in the field of medicinal chemistry, can solve problems such as elevated body temperature

Inactive Publication Date: 2014-03-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in follow-up studies, it was found that the side effect of TRPV1 antagonists that caused elevated body temperature

Method used

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  • Transient receptor potential vanilloid 1/epoxidase 2(TRPV1/COX-2) dual inhibitor, and preparation method and application thereof in preparation of analgesic medicament
  • Transient receptor potential vanilloid 1/epoxidase 2(TRPV1/COX-2) dual inhibitor, and preparation method and application thereof in preparation of analgesic medicament
  • Transient receptor potential vanilloid 1/epoxidase 2(TRPV1/COX-2) dual inhibitor, and preparation method and application thereof in preparation of analgesic medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] 2-[(4-isobutylphenyl)propionyl]proline (5)

[0075] In a 100ml round bottom flask, 9.62g (46.7mmol) of ibuprofen was dissolved in 20ml of anhydrous dichloromethane, and stirred under ice-water bath conditions. Dissolve 20 g (280.7 mmol) of thionyl chloride in 50 ml of dichloromethane, add 2 drops of DMF, and drop into the reaction flask under ice-salt bath conditions. After dripping and heating to reflux for 3 h, the excess thionyl chloride was evaporated under reduced pressure, and carried twice with toluene to obtain a yellow oil, i.e. acid chloride 3, which was directly used in the next reaction.

[0076] In a 100ml round-bottomed flask, 5.37g (46.7mmol) of proline was dissolved in 26ml of 2N aqueous sodium hydroxide solution, and stirred in an ice bath. Acid chloride 3 and 12ml of 4N aqueous sodium hydroxide solution were added dropwise into the reaction flask alternately. After dripping, the reaction was continued for 1 h under the condition of ice bath, and then...

Embodiment 2

[0078] 1-[(2-(4-isobutylphenyl)propionyl]-2-(N-o-methylphenylformamide)pyrrolidine (A 01 )

[0079] In a 25ml round bottom flask, 51g (3.28mmol) of the compound was dissolved in 5ml of dichloromethane, and stirred in an ice-salt bath. 1.26g (6.56mmol) of EDCI and DMAP (catalytic amount) were dissolved in 10ml of dichloromethane, added dropwise to the reaction solution, and the reaction was continued for 0.5h under ice-bath conditions after dropping. 0.35 g (3.29 mmol) of o-methoxyaniline was dissolved in 10 ml of dichloromethane, and added dropwise to the reaction solution. After the dropwise addition was completed for 0.5 h, the ice bath was removed and the reaction was carried out at room temperature for 12 h. The next day, the TLC reaction was complete, washed with 1N dilute hydrochloric acid (10ml×2), washed with saturated brine (10ml×2), washed with saturated sodium bicarbonate solution (10ml×2), washed with saturated brine (10ml×2), no water and sodium sulfate to dry....

Embodiment 3

[0084] 1-[(2-(4-isobutylphenyl)propionyl]-2-[N-(4-tert-butylphenyl)formamide]pyrrolidine (A 02 )

[0085] Refer to A 01 The preparation of compound 51.00g (3.28mmol), EDCI1.26g (6.56mmol), DMAP (catalytic amount), p-tert-butylaniline 0.60g (3.94mmol), all the other operations are the same as IA 01 Preparation of pure product 0.44g, yield: 29.53%, m.p.136-137°C.

[0086] 1 HNMR (DMSO-d 6 , 300MHz): δppm9.73 (s, 1H, NH), 7.49 (d, J=8.49Hz, 2H, Ar-H,), 7.12 (d, J=8.46Hz, 2H, Ar-H,), 7.21 (d, J=7.95Hz, 2H, Ar-H,), 7.12(d, J=7.47Hz, 2H, Ar-H,), 4.79(d, J=7.32Hz, 1H, C-2”pyrr) , 3.80(m, 1H, CH 3 CHC=O), 3.63(m, 1H, C-5"pyrr), 3.30(m, 1H, C-5"pyrr), 2.47(m, 3H, C-3"pyrr and CH 2 CH(CH 3 ) 2 ,), 2.16(m, 1H, C-3"pyrr), 1.85(m, 2H, C-4''pyrr), 1.72(m, 1H, CH(CH 3 ) 2 ), 1.49 (d, J=6.81Hz, 3H, CH 3 CHC=O), 1.31(s, 9H, (CH 3 ) 3 C), 0.92(d, J=6.60Hz, 6H, CH(CH 3 ) 2 ,);

[0087] IR (KBr, cm -1 ): 3301 (v N-H ), 1902, 1636 (v C=O ), 1596, 1534 (aromatic);

[0088] MS (...

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Abstract

The invention relates to a compound in a general formula (I) and a salt of the compound, wherein the compound is a TRPV1 / COX-2 dual inhibitor and has a good analgesic effect. The invention also relates to a preparation method of the compound, a medicinal preparation containing the compound, and application thereof in preparation of the analgesic medicament.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of TRPV1 / COX-2 dual inhibitors. The invention also discloses its preparation method and the use of the compound as an active ingredient to prepare analgesic drugs. 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 analgesics represented by non-steroidal anti-inflammatory drugs (NSAIDs). pain medicine. Although these drugs have good clinical effects, they all act on a single target and have obvious side effects. Such as the addiction of opioids, the gastrointestinal side effects of non-steroidal anti-inflammatory drugs, etc. In addition, a large number of pains such as chronic and neuropathic pain ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16A61K31/401A61P29/00
CPCC07D207/16
Inventor 黄文龙钱海王敬杰戴冬艳邱倩倩邓欣
Owner CHINA PHARM UNIV
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