CN113233996B - Novel TRPV1 antagonistic/FAAH inhibition double-target drug, and preparation method and application thereof - Google Patents

Novel TRPV1 antagonistic/FAAH inhibition double-target drug, and preparation method and application thereof Download PDF

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CN113233996B
CN113233996B CN202110549403.1A CN202110549403A CN113233996B CN 113233996 B CN113233996 B CN 113233996B CN 202110549403 A CN202110549403 A CN 202110549403A CN 113233996 B CN113233996 B CN 113233996B
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cyclohexane
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indol
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CN113233996A (en
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严琳
乔振蕊
王玉睢
高梦康
陈英达
王国豪
宋德朴
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Henan University
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    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/56—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07D209/04—Indoles; Hydrogenated indoles
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Abstract

The invention discloses a novel TRPV1 antagonistic/FAAH inhibition double-target drug and a preparation method and application thereof, wherein the structural general formula of the TRPV1 antagonistic/FAAH inhibition double-target drug or pharmaceutically acceptable salt thereof is as follows:
Figure DDA0003074824040000011
Ar1is substituted phenyl or aromatic heterocyclic radical; ar (Ar)2Is composed of
Figure DDA0003074824040000012

Description

Novel TRPV1 antagonistic/FAAH inhibition double-target medicine and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel TRPV1 antagonist/FAAH inhibition double-target medicament, and also discloses a preparation method thereof, a medicinal preparation using the compound as an active ingredient, and application of the compound as a TRPV1 antagonist/FAAH inhibitor or in preparation of an analgesic medicament for treating pain.
Background
The chronic pain seriously affects the life quality of people, and is a great problem to be solved urgently in clinic. At present, the clinical treatment of chronic pain mainly adopts antipyretic analgesics represented by non-steroidal anti-inflammatory drugs, and although the antipyretic analgesics can temporarily relieve pain, the antipyretic analgesics are often accompanied with obvious side effects after long-term administration. Recent studies on chronic pain have been mainly developed around peripheral nociceptors and spinal cord levels, however practice has shown that only peripheral and/or spinal cord levels are targeted and there are few well-received analgesic drugs. Therefore, aiming at the newly discovered analgesic target, the research on the medicine for treating the chronic pain is of great significance.
TRPV1 is a highly expressed receptor in primary nociceptive neurons, and TRPV1 antagonists were once considered to be one of the most promising analgesic research directions, since nociceptor activation is the first step in nociceptor production. However, it has been found that TRPV1 antagonists with different chemical structure types cause different degrees of body temperature elevation. TRPV1 is also expressed centrally in addition to peripheral sensory neurons. TRPV1 is co-localized with CB1 in peripheral and central nervous tissues and interacts with the endocannabinoid system through the common agonist AEA, affecting pain transmission. Centrally, TRPV1 activation is dependent on elevated AEA (N-arachidonic acid ethanolamine) levels, exhibits greater sensitivity to this mediator in neuropathological conditions, and in the case of tissue inflammation or nerve injury, can also be functionally sensitized by stimulation of local inflammatory mediators, resulting in a decrease in pain threshold.
Fatty Acid Amide Hydrolase (FAAH) is an integral membrane serine hydrolase that degrades signal lipids of the fatty acid amide family, including endogenous cannabinamide. Endocannabinoids are present in different pain-regulating areas of the center and their level in the local area of pain regulation has been shown to be a prerequisite for their analgesic action. AEA is by far the most studied endocannabinoid and is also a high affinity cannabinoid receptor agonist. AEA shows centrally inhibitory mechanical and thermal hyperalgesia, which is mainly catabolized by FAAH, so that inhibition of FAAH increases local levels of AEA, and thus analgesia is a particularly promising target for neuropathic and inflammatory pain.
AEA has a dual role in the center, where AEA levels are low, acting preferentially on its high affinity CB1 receptor, inhibiting expression of anxiety and the like, without altering pain perception, but with FAAH inhibitors, producing analgesia; when the AEA level is further increased, it may cause activation of TRPV 1. Inhibition of FAAH reduces the production of inflammatory mediators prostaglandins, reduces sensitization and upregulation of TRPV1, and antagonizes TRPV1, which also exerts a strong inhibitory effect on peripheral sensitization. Therefore, a dual-target single drug that both inhibits FAAH and blocks TRPV1 may be a new strategy to develop treatments for chronic pain.
Disclosure of Invention
The invention aims to provide a novel TRPV1 antagonistic/FAAH inhibition double-target drug, which has carbamate and carbamido structures and can be used for preparing novel analgesic drugs.
The invention also provides a preparation method of the novel TRPV1 antagonistic/FAAH inhibition double-target drug, and application of the novel TRPV1 antagonistic/FAAH inhibition double-target drug as a TRPV1 antagonistic/FAAH inhibition double-target drug or in preparation of an analgesic drug.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a novel TRPV1 antagonistic/FAAH inhibition double-target drug or a pharmaceutically acceptable salt thereof, which has the following structural general formula:
Figure BDA0003074824030000021
in the formula, Ar2Is composed of
Figure BDA0003074824030000022
Etc.; ar (Ar)1Is substituted phenyl or aromatic heterocyclic radical, the substituted phenyl is meta-substituted phenyl or para-substituted phenyl, such as substituted phenyl of F, Cl, Br, 3, 4-dimethoxy, etc., and the substituted phenyl can also beChanging the position of a substituent on the aromatic heterocycle; preferably, Ar is1Is 4-bromophenyl, 3, 4-dimethoxy-phenyl, 3, 4-dichloro-phenyl, 4-chlorophenyl, 3-isopropylphenyl, 4-tert-butylphenyl, etc.; x is N or O.
Specifically, the pharmaceutically acceptable salts of the present invention include salts with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid, and the like, and salts with similar known acceptable acids.
The novel TRPV1 antagonist/FAAH inhibitor dual-target drug of the present invention or a pharmaceutically acceptable salt thereof is preferably, but not limited to, the following compounds:
phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate (1),
Phenyl (1- ((3, 4-dimethoxyphenyl) carbamoyl) cyclohexyl) carbamate (2),
Phenyl (1- ((3, 4-dichlorophenyl) carbamoyl) cyclohexyl) carbamate (3),
1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-chlorophenyl) cyclohexane-1-carboxamide (4),
1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-bromophenyl) cyclohexane-1-carboxamide (5)
1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (3-isopropylphenyl) cyclohexane-1-carboxamide (6)
1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-tert-butylphenyl) cyclohexane-1-carboxamide (7)
N- (4-chlorophenyl) -1- (3- (2- (5-methoxy-indol-3-yl) ethyl) ureidooxy) cyclohexane-1-carboxamide (8)
N- (3-isopropylphenyl) -1- (3- (2- (5-methoxy-1H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide (9)
N- (4- (tert-butyl) phenyl) -1- (3- (2- (5-methoxy-1H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide (10) and the like.
The preparation method of the phenyl (1- (arylcarbamoyl) cyclohexyl) carbamate compound (1-3) is shown as the following scheme A:
Figure BDA0003074824030000031
(a) preparation of intermediate (i)
Weighing 1-aminocyclohexyl formic acid (10.83mmol) into a 250mL eggplant-shaped bottle, dissolving with tetrahydrofuran (50mL), weighing NaOH (21.66mmol) into water (50mL), dropwise adding NaOH aqueous solution into the reaction bottle, then adding di-tert-butyl dicarbonate (13.00mmol) to continue reacting for 16h at room temperature, concentrating the reaction solution under reduced pressure after the reaction is finished to remove tetrahydrofuran, adding 1N HCl to adjust pH to 1-2 to precipitate white solid, and filtering to obtain an intermediate (i).
(b) Preparation of intermediate (ii)
To a 100mL single-neck flask, intermediate (i) (4.727mmol) was added and dissolved in methylene chloride (40mL), 1-hydroxybenzotriazole (4.727mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (4.727mmol) were added successively to a reaction flask, and after stirring at room temperature for 30min, aromatic amine (3.151mmol) and triethylamine (2mL) were added, and the reaction was continued at room temperature for 18h, and after completion of the reaction, the reaction solution was washed successively with a 10% citric acid solution (30 mL. times.3) and a saturated aqueous salt solution (30 mL. times.3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give intermediate (ii).
(c) Preparation of intermediate (iii)
Intermediate (ii) (1.55mmol) was added to a 100mL single-neck flask at room temperature, dissolved in dry dichloromethane (36mL), trifluoroacetic acid (4mL) was added dropwise over an ice bath, and the reaction was allowed to warm to room temperature for 1 h. After the reaction was completed, the pH was adjusted to 8 with a saturated sodium bicarbonate solution, extraction was performed, the aqueous phase was back-extracted with methylene chloride (30 mL. times.3), and the organic phases were combined and concentrated under reduced pressure to obtain an intermediate (iii).
(d) Preparation of object Compound (iv)
At room temperature, intermediate (iii) (1.150mmol) was added to a 100mL single-neck flask, and dissolved in methylene chloride (20mL), and triethylamine (1.380mmol) and an aromatic chloroformate (1.265mmol) were gradually added in this order under ice-bath conditions, and after completion of addition, the temperature was raised to room temperature to react for 2 hours. After the reaction, water (10mL) was added and the reaction solution was quenched, extracted, the aqueous phase was back-extracted with dichloromethane (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether: ethyl acetate 4:1) to obtain the objective compound (iv).
The process for the preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N-phenylcyclohexane-1-carboxamide compounds (4-10) according to the invention is illustrated in scheme B below:
Figure BDA0003074824030000041
(1) preparation of intermediates (i) - (iii) Steps (a) - (c) of scheme A;
(2) preparation of object Compound (iv)
Adding tryptamine or 5-methoxytryptamine (1.870mmol) into a two-neck flask under the protection of nitrogen in ice bath, stirring and dissolving with dry dichloromethane (30mL), dissolving triphosgene (0.6171mmol) with dichloromethane (2mL), slowly dropping, and adding Et3N (5.610mmol), after reaction for 30min, intermediate (iii) (1.870mmol) was dissolved in dichloromethane (10mL) and slowly added dropwise, and the reaction was allowed to proceed overnight. The reaction was quenched with water (10mL), extracted, the aqueous phase was back-extracted with dichloromethane (30mL × 2), the organic phases were combined, concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether: ethyl acetate 1.5:1) to obtain the objective compound (iv).
The invention provides a pharmaceutical preparation, which comprises a novel TRPV1 antagonistic/FAAH inhibiting dual-target drug with the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable drug carrier. Pharmaceutically acceptable carriers are those conventional in the pharmaceutical art, e.g., one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants, etc., which do not adversely affect the active compound or the patient.
Specifically, the dosage form of the pharmaceutical preparation provided by the invention is a common dosage form in pharmaceutics, such as tablets, capsules, pills, suppositories, soft capsules, oral liquid, suspension or injection. Tablets and capsules for oral use contain conventional excipients such as fillers, diluents, lubricants, dispersants and binders. The various dosage forms of the pharmaceutical formulations of the present invention may be prepared according to methods well known in the pharmaceutical art. The dosage of the active ingredient of the above general formula (I) will vary depending on the formulation.
The invention further provides a pharmaceutical preparation in the form of tablets, which comprises the following raw materials in parts by weight:
Figure BDA0003074824030000051
the invention also provides application of the novel TRPV1 antagonistic/FAAH inhibition double-target drug or pharmaceutically acceptable salt thereof as a TRPV1 antagonist/FAAH inhibitor or in preparation of analgesic drugs.
The invention also provides application of the medicinal preparation as a TRPV1 antagonistic/FAAH inhibition double-target medicament or in preparation of an analgesic medicament.
Compared with the prior art, the invention has the following beneficial effects:
the double-target analgesic designed and synthesized by the invention, which simultaneously has the functions of inhibiting FAAH and antagonizing TRPV1 receptors, is expected to balance the biological activities to different targets, achieve excitation-inhibition balance, and can produce better analgesic effect and fewer adverse reactions under lower dosage.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1: preparation of phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate (1)
Figure BDA0003074824030000052
(a) Preparation of 1- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid
Weighing 1-aminocyclohexyl formic acid (1.55g,10.83mmol) in a 250mL eggplant-shaped bottle, dissolving with tetrahydrofuran (50mL), weighing NaOH (0.8660g,21.66mmol) to dissolve in water (50mL), dropwise adding NaOH aqueous solution into a reaction bottle, then adding di-tert-butyl dicarbonate (2.8357g,13.00mmol), continuing to react for 16h at room temperature, after the reaction is finished, concentrating the reaction solution under reduced pressure to remove tetrahydrofuran, adding 1N HCl to adjust the pH value to 1-2 to precipitate white solid, and filtering to obtain 1- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid.
(b) Preparation of tert-butyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate
1- ((tert-Butoxycarbonyl) amino) cyclohexane-1-carboxylic acid (1.150g,4.727mmol) was dissolved in 40mL of dichloromethane, 1-hydroxybenzotriazole (0.7238g,4.727mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.9061g,4.727mmol) were added to a 100mL single-neck flask at room temperature, the mixture was stirred at room temperature for 30min, p-bromoaniline (0.5420g,3.151mmol) and triethylamine (2mL) were added, the reaction was continued at room temperature for 18 hours, and after the completion of the reaction, the reaction mixture was washed with a 10% citric acid solution (30 mL. times.3) and a saturated aqueous solution of sodium chloride (30 mL. times.3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate.
(c) Preparation of 1-amino-N- (4-bromophenyl) cyclohexane-1-carboxamide
In a 100mL single-neck flask under ice bath, tert-butyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate (1.220g,1.55mmol) was added, dissolved in dry dichloromethane (36mL), trifluoroacetic acid (4mL) was slowly added dropwise, and after the addition, the reaction system was warmed to room temperature and allowed to react for 1 h. After the reaction, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extraction was performed, the aqueous phase was back-extracted with dichloromethane (30 mL. times.3), and the organic phases were combined and concentrated under reduced pressure to give 1-amino-N- (4-bromophenyl) cyclohexane-1-carboxamide.
(d) Phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate
To a 100mL single-neck flask, phenyl chloroformate (0.5799g,3.704mmol) was added and dissolved in dry dichloromethane (40mL), triethylamine (0.3123g,4.040mmol) was slowly added, followed by 1-amino-N- (4-bromophenyl) cyclohexane-1-carboxamide (1.000g,3.367mmol) being slowly added, after reaction for 2 hours at room temperature, the reaction was quenched with water (10mL), extracted, the aqueous phase was back-extracted with dichloromethane (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate ═ 4:1) to give a white solid, phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate, yield 70%. The experimental data are as follows:
C20H21BrN2O3；yield:70％.white solid；1H NMR(400MHz,Chloroform-d)δppm 8.87(s,1H,NH),7.50-7.43(m,2H,Ar-H),7.31(s,2H,Ar-H),7.24(t,J＝7.8Hz,2H,Ar-H),7.16(t,J＝7.4Hz,1H,NH),7.05(dd,J＝12.8,7.6Hz,3H,Ar-H),2.15(d,J＝14.1Hz,2H,Cyclohexane),1.99(td,J＝14.0,12.8,3.6Hz,2H,Cyclohexane),1.73-1.60(m,3H,Cyclohexane),1.52-1.31(m,3H,Cyclohexane).
example 2: preparation of phenyl (1- ((3, 4-dimethoxyphenyl) carbamoyl) cyclohexyl) carbamate (2)
Figure BDA0003074824030000071
Compound 2 was obtained in 80% yield as a white solid by substituting 3, 4-dimethoxyaniline for p-bromoaniline in example 1 and otherwise referring to the preparation method in example 1. The experimental data are as follows:
C22H26N2O5；yield:80％,white solid；1H NMR(400MHz,DMSO-d6)δppm9.31(s,1H,NH),7.64(s,1H,Ar-H),7.37(t,J＝7.7Hz,2H,Ar-H),7.32(d,J＝2.4Hz,1H,Ar-H),7.22-7.14(m,2H,Ar-H),7.10(d,J＝8.0Hz,2H,Ar-H),6.87(d,J＝8.7Hz,1H,NH),3.72(d,J＝6.3Hz,6H,OCH3),2.05(d,J＝13.5Hz,2H,Cyclohexane),1.85(q,J＝12.1,8.6Hz,2H,Cyclohexane),1.67-1.50(m,6H,Cyclohexane).
example 3: preparation of phenyl (1- ((3, 4-dichlorophenyl) carbamoyl) cyclohexyl) carbamate (3)
Figure BDA0003074824030000072
Compound 3 was obtained in 89% yield as a white solid by substituting 3, 4-dichloroaniline for p-bromoaniline in example 1 and otherwise referring to the preparation method in example 1. The experimental data are as follows:
C20H20Cl2N2O3；yield:89％,white solid；1H NMR(400MHz,DMSO-d6)δppm9.83(s,1H,NH),8.03(d,J＝2.4Hz,1H,NH),7.78(s,1H,Ar-H),7.65(dd,J＝8.8,2.5Hz,1H,Ar-H),7.55(d,J＝8.8Hz,1H,Ar-H),7.41-7.33(m,2H,Ar-H),7.22-7.16(m,1H,Ar-H),7.09(d,J＝7.9Hz,2H,Ar-H),2.00(d,J＝13.5Hz,2H,Cyclohexane),1.92-1.81(m,2H,Cyclohexane),1.58-1.29(m,J＝8.3Hz,6H,Cyclohexane).
example 4: preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-chlorophenyl) cyclohexane-1-carboxamide (4)
Figure BDA0003074824030000073
(a) Preparation of 1- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid
Weighing 1-aminocyclohexyl formic acid (1.55g,10.83mmol) in a 250mL eggplant-shaped bottle, dissolving with tetrahydrofuran (50mL), weighing NaOH (0.8660g,21.66mmol) to dissolve in water (50mL), dropwise adding NaOH aqueous solution into a reaction bottle, then adding di-tert-butyl dicarbonate (2.8357g,13.00mmol), continuing to react for 16h at room temperature, after the reaction is finished, concentrating the reaction solution under reduced pressure to remove tetrahydrofuran, adding 1N HCl to adjust the pH value to 1-2 to precipitate white solid, and filtering to obtain 1- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid.
(b) Preparation of tert-butyl (1- ((4-chlorophenyl) carbamoyl) cyclohexyl) carbamate
1- ((tert-Butoxycarbonyl) amino) cyclohexane-1-carboxylic acid (1.150g,4.727mmol) was dissolved in methylene chloride (40mL), 1-hydroxybenzotriazole (0.7238g,4.727mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.9061g,4.727mmol) was added to a 100mL single-neck flask at room temperature, the mixture was stirred at room temperature for 30min, p-chloroaniline (0.4020g,3.151mmol) and triethylamine (2mL) were added, the reaction was continued at room temperature for 18 hours, and after the completion of the reaction, the reaction mixture was washed with a 10% citric acid solution (30 mL. times.3) and a saturated aqueous salt solution (30 mL. times.3) in this order, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1- ((4-chlorophenyl) carbamoyl) cyclohexyl) carbamate.
(c) Preparation of 1-amino-N- (4-chlorophenyl) cyclohexane-1-carboxamide
To a 100mL single-neck flask, tert-butyl (1- (phenylcarbamoyl) cyclohexyl) carbamate (1.220g,1.55mmol) was added under ice-bath, dissolved in dry dichloromethane (36mL), and trifluoroacetic acid (4mL) was slowly added dropwise, after which the reaction was warmed to room temperature and allowed to react for 1 h. After the reaction, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extraction was performed, the aqueous phase was back-extracted with dichloromethane (30 mL. times.2), and the organic phases were combined and concentrated under reduced pressure to give 1-amino-N- (4-chlorophenyl) cyclohexane-1-carboxamide.
(d) Preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-chlorophenyl) cyclohexane-1-carboxamide
Tryptamine (300mg,1.872mmol) was added to a two-necked flask under nitrogen protection in ice bath, and after dissolving with dry dichloromethane (30mL) with stirring, triphosgene (183.4mg,0.6179mmol) was dissolved with dichloromethane (2mL) and slowly added dropwise, followed by Et3N (568.4mg,5.617mmol), reacted for 30min, and intermediate (iii) (473.2mg,1.872mmol) was dissolved in dichloromethane (10mL) and slowly added dropwise, and reacted overnight. The reaction was quenched with water (10mL), extracted, the aqueous phase was back-extracted with dichloromethane (30mL × 2), the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate ═ 1.5:1) to give 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-chlorophenyl) cyclohexane-1-carboxamide in 50% yield. The experimental data are as follows:
C24H27N4O2Cl；yield:50％,white solid；1H NMR(400MHz,DMSO-d6)δppm 10.81(s,1H,Indolyl,NH),9.73(s,1H,amide,NH),7.62(d,J＝8.9Hz,2H,Ar-H),7.51(d,J＝7.9Hz,1H,Ar-H),7.33(dd,J＝8.7,6.9Hz,3H,Ar-H),7.13(d,J＝2.3Hz,1H,Ar-H),7.06(ddd,J＝8.1,6.9,1.2Hz,1H,Ar-H),6.96(ddd,J＝8.0,7.0,1.0Hz,1H,Ar-H),6.28(t,J＝5.7Hz,1H,Ethylamine,NH),6.02(s,1H,NH),3.32-3.27(m,2H,Ethyl group,CH2),2.79(t,J＝7.1Hz,2H,Ethyl group,CH2),1.99(d,J＝12.9Hz,2H,Cyclohexane),1.67(td,J＝13.0,3.7Hz,2H,Cyclohexane),1.61-1.22(m,6H,Cyclohexane).
example 5: preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-bromophenyl) cyclohexane-1-carboxamide (5)
Figure BDA0003074824030000091
Compound 5 was obtained as a white solid with a yield of 57% by following the procedure of example 4 instead of p-chloroaniline in example 4 with p-bromoaniline. The experimental data are as follows:
C24H27N4O2Br；yield:57％,white solid；1H NMR(400MHz,DMSO-d6)δppm 10.84(s,1H,Indolyl,NH),9.76(s,1H,amide,NH),7.59(d,J＝8.8Hz,2H,Ar-H),7.53(d,J＝7.8Hz,1H,Ar-H),7.46(d,J＝8.8Hz,2H,Ar-H),7.35(d,J＝8.0Hz,1H,Ar-H),7.15(d,J＝2.2Hz,1H,Ar-H),7.10-7.05(m,1H,Ar-H),6.98(t,J＝7.4Hz,1H,Ar-H),6.30(t,J＝5.7Hz,1H,Ethylamine,NH),6.04(s,1H,NH),3.32(q,J＝6.7Hz,2H,Ethyl group,CH2),2.81(t,J＝7.1Hz,2H,Ethyl group,CH2),2.00(d,J＝13.2Hz,2H,Cyclohexane),1.69(td,J＝13.1,3.7Hz,2H,Cyclohexane),1.61-1.16(m,6H,Cyclohexane).
example 6: preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (3-isopropylphenyl) cyclohexane-1-carboxamide (6)
Figure BDA0003074824030000092
Compound 6 was obtained in a white solid with a yield of 53% by following the preparation method in example 4 by replacing p-chloroaniline in example 4 with 3-isopropylaniline. The experimental data are as follows:
C27H34N4O2；yield:53％,white solid；1H NMR(400MHz,DMSO-d6)δppm 10.83(s,1H,Indolyl,NH),9.59(s,1H,amide,NH),7.53(d,J＝7.8Hz,1H,Ar-H),7.48(s,1H,Ar-H),7.43-7.38(m,1H,Ar-H),7.34(d,J＝8.1Hz,1H,Ar-H),7.22-7.13(m,2H,Ar-H),7.07(ddd,J＝8.1,7.0,1.2Hz,1H,Ar-H),6.97(ddd,J＝7.9,6.9,1.0Hz,1H,Ar-H),6.90(d,J＝7.7Hz,1H,Ar-H),6.30(t,J＝5.8Hz,1H,Ethylamine,NH),6.03(s,1H,NH),3.33-3.28(m,2H,Ethyl group,CH2),2.82(dt,J＝14.0,7.0Hz,3H),2.02(d,J＝13.3Hz,2H,Cyclohexane),1.69(td,J＝13.0,3.7Hz,2H,Cyclohexane),1.62-1.22(m,6H,Cyclohexane),1.18(d,J＝6.9Hz,6H,Isopropyl,CH3).
example 7: preparation of 1- (3- (2- (1H-indol-3-yl) ethyl) ureido) -N- (4-tert-butylphenyl) cyclohexane-1-carboxamide (7)
Figure BDA0003074824030000101
Compound 7 was obtained in 58% yield as a white solid by the preparation method of example 4 except that p-chloroaniline in example 4 was replaced with 4-tert-butylaniline. The experimental data are as follows:
C28H36N4O2；yield:58％,white solid；1H NMR(300MHz,DMSO-d6)δppm 10.83(s,1H,Indolyl,NH),9.58(s,1H,amide,NH),7.54(d,J＝7.8Hz,1H,Ar-H),7.48(d,J＝8.7Hz,2H,Ar-H),7.37-7.32(m,1H,Ar-H),7.28(d,J＝8.7Hz,2H,Ar-H),7.15(d,J＝2.3Hz,1H,Ar-H),7.11-7.03(m,1H,Ar-H),7.01-6.93(m,1H,Ar-H),6.29(t,J＝5.8Hz,1H,Ethylamine,NH),6.03(s,1H,NH),3.32(d,J＝6.2Hz,2H,Ethyl group,CH2),2.81(t,J＝7.1Hz,2H,Ethyl group,CH2),2.02(d,J＝13.3Hz,2H,Cyclohexane),1.69(dd,J＝13.4,10.1Hz,2H,Cyclohexane),1.50(d,J＝22.9Hz,6H,Cyclohexane),1.25(s,9H,Tert butyl).
example 8: preparation of N- (4-chlorophenyl) -1- (3- (2- (5-methoxy-indol-3-yl) ethyl) ureidooxy) cyclohexane-1-carboxamide (8)
Figure BDA0003074824030000102
Compound 8 was obtained in 62% yield as a white solid by substituting 5-methoxytryptamine for the tryptamine of example 4 and otherwise referring to the preparation of example 4. The experimental data are as follows:
C25H29N4O3Cl；yield:62％,white solid；1H NMR(400MHz,DMSO-d6)δppm 10.70(s,1H,Indolyl,NH),9.82(s,1H,amide,NH),7.66(d,J＝8.9Hz,2H,Ar-H),7.39-7.34(m,2H,Ar-H),7.27(d,J＝8.7Hz,1H,Ar-H),7.14(d,J＝2.3Hz,1H,Ar-H),7.04(d,J＝2.4Hz,1H,Ar-H),6.76(dd,J＝8.7,2.4Hz,1H,Ar-H),6.33(t,J＝5.7Hz,1H,Ethylamine,NH),6.08(s,1H,NH),3.78(s,3H,OCH3),3.34(q,J＝6.4Hz,2H,Ethyl group,CH2),2.81(t,J＝7.0Hz,2H,Ethyl group,CH2),2.03(t,J＝6.7Hz,2H,Cyclohexane),1.72(td,J＝13.1,3.7Hz,2H,Cyclohexane),1.64-1.24(m,6H,Cyclohexane).
example 9: preparation of N- (3-isopropylphenyl) -1- (3- (2- (5-methoxy-1H-indol-3-yl) ethyl) ureido) hexane-1-carboxamide (9)
Figure BDA0003074824030000111
Compound 9 was obtained in 48% yield as a white solid by substituting 3-isopropylaniline for p-chloroaniline and 5-methoxytryptamine for tryptamine in example 4 and otherwise referring to the preparation method in example 4. The experimental data are as follows:
C28H36N4O3；yield:48％,white solid；1H NMR(400MHz,DMSO-d6)δppm 10.68(s,1H,Indolyl,NH),9.63(s,1H,amide,NH),7.48(s,1H,Ar-H),7.43-7.38(m,1H,Ar-H),7.27–7.14(m,2H,Ar-H),7.11(d,J＝2.3Hz,1H,Ar-H),7.02(d,J＝2.4Hz,1H,Ar-H),6.92-6.87(m,1H,Ar-H),6.72(dd,J＝8.7,2.4Hz,1H,Ar-H),6.30(t,J＝5.8Hz,1H,Ethylamine,NH),6.05(s,1H,NH),3.74(s,3H,OCH3),3.32(q,J＝6.7Hz,2H,Ethyl group,CH2),2.80(dt,J＝17.0,7.0Hz,2H,Ethyl group,CH2),2.08-1.97(m,2H,Cyclohexane),1.69(td,J＝13.1,3.7Hz,2H,Cyclohexane),1.61-1.22(m,6H,Cyclohexane),1.18(d,J＝6.9Hz,6H,Isopropyl).
example 10: preparation of N- (4- (tert-butyl) phenyl) -1- (3- (2- (5-methoxy-1H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide (10)
Figure BDA0003074824030000112
Compound 10 was obtained in 59% yield as a white solid by substituting 4-tert-butylaniline for p-chloroaniline and 5-methoxytryptamine for tryptamine in example 4 and otherwise referring to the preparation method in example 4. The experimental data are as follows:
C29H38N4O3；yield:59％,white solid；1H NMR(300MHz,DMSO-d6)δppm 10.67(s,1H,Indolyl,NH),9.62(s,1H,amide,NH),7.47(d,J＝8.7Hz,2H,Ar-H),7.26(dd,J＝13.9,8.7Hz,3H,Ar-H),7.11(d,J＝2.4Hz,1H,Ar-H),7.01(d,J＝2.4Hz,1H,Ar-H),6.72(dd,J＝8.7,2.4Hz,1H,Ar-H),6.28(t,J＝5.7Hz,1H,Ethylamine,NH),6.05(s,1H,NH),3.74(s,3H,OCH3),3.31(d,J＝6.1Hz,2H,Ethyl group,CH2),2.77(t,J＝7.0Hz,2H,Ethyl group,CH2),2.02(d,J＝13.2Hz,2H,Cyclohexane),1.69(t,J＝11.5Hz,2H,Cyclohexane),1.61-1.29(m,6H,Cyclohexane),1.25(s,9H,Tert butyl).
1. in vitro Activity screening of Compounds 1-10 of the present invention for the TRPV1 receptor
By adopting an aequorin reporter gene detection technology, the cell strain stably co-expresses aequorin and a TRPV1 receptor. Intracellular Ca when the receptor is excited2+Increase in Ca2+Coelenterazine reconstructs the photoprotein, producing a bioluminescent effect at 469 nm. By measuring the rapid chemiluminescent signal produced by the release of stimulated intracellular calcium, test samples can be screened for effects on the TRPV1 receptor.
The TRPV1 antagonistic activity screening experiment of the compound comprises the following steps: test compounds and capsaicin were brought to an initial concentration of 10mM in DMSO and diluted to a test concentration of 0.1mM in Try's solution, where the capsaicin was diluted to 250 nM. The initial concentration of calcium ion fluorescent probe was 5mM and was diluted to a concentration of 0.05mM with HBSS containing 33mg Pluronic F-127 per ml. Approximately 10000 HEK-293-TRPV1 cells per well were incubated at 37 ℃ with 10. mu.l of 0.05mM calcium ion fluorescent probe. After 20 minutes, 30. mu.l of HBSS containing 1% FBS was added and incubation was continued for 40 minutes. After 40 minutes, the HBSS and other fluids are aspirated from the wells and the wells are washed with Taiwan's solution, followed by 40 microliters of test compound at a concentration of 0.1mM per well. 3 duplicate wells were set for each compound, 3 of which were incubated at 37 ℃ for 30 minutes with only Tschmann's solution as a blank, and fluorescence intensity was measured at 488nm for excitation and 526nm for emission. Cells were then incubated at 37 ℃ for 30 minutes with 10. mu.l of capsaicin at a concentration of 250nM per well and fluorescence intensity was measured at an excitation wavelength of 488nM and an emission wavelength of 526 nM. And (3) representing the relative concentration of intracellular calcium ions by calculating the fluorescence intensity difference of each group before and after capsaicin addition so as to detect the antagonism degree of the compound to the capsaicin, thereby detecting the antagonism activity degree of the compound to the TRPV1 receptor. Part of the compound is 10-5Antagonistic activity against TRPV1 receptor at mol dose results are shown in table 1.
2. Assay for FAAH inhibitory Activity
And detecting the inhibitory activity of the target compound on FAAH in vitro by adopting a liquid chromatography-mass spectrometry method.
FAAH enzyme reaction: preparing 50mmol & L-1Tris acetate buffer (pH 7.4); 0.05% bovine serum albumin; 1 mmol. L-1The AEA substrate of (4); 100 mu mol. L-1DMSO solutions of the target compounds; 1 μ g μ L-1FAAH enzyme solution. Sequentially adding the above reagents into buffer solution, placing into a constant temperature shaking table at 37 ℃ for shaking reaction for 30min, adding 200 mu L of 1 nmol. L-1The reaction was terminated with a methanol solution of fatty acid (17: 0) as an internal standard.
Hydrolysis product detection conditions of FAAH: the liquid chromatography column is ZORBAX Eclipse XDB-C18Columns (4.6 mm. times.50 mm, 1.8 mm); the column temperature was kept at 40 ℃; the sample injection amount is 5 mu L; mobile phase A: water (containing 0.25% acetic acid and 5 mmol. L-1Ammonium acetate), mobile phase B: methanol (containing 0.25% acetic acid and 5 mmol. L-1Ammonium acetate) at a flow rate of 0.6 mL/min-195% B for 4 min; mass spectrum is ESI negative ion source; the drying gas is N2(ii) a The temperature is 350 ℃; curtain gas 137.9 kPa; the scanning quality range is 50-400. For arachidonic acid [ M-H ] as FAAH hydrolysate]Quantitative analysis was performed at-m/z 303.
The inhibition rate detection method comprises the following steps: FAAH catalyzes the hydrolysis of AEA to arachidonic acid, and this reaction is inhibited by the addition of inhibitors. In the experiment, firstly, when no inhibitor is added, the abundance of the arachidonic acid peak generated by hydrolysis is measured by mass spectrometry; after the inhibitor is added, the abundance of the peak of arachidonic acid generated by hydrolysis is detected again, and the inhibition rate of the synthesized inhibitor on the FAAH catalyzed AEA reaction is detected by utilizing the abundance ratio of the arachidonic acid before and after the inhibitor is added. The initial rate is expressed as percent inhibition relative to the concentration of inhibitor relative to an uninhibited control reaction. The results are shown in Table 1
TABLE 1
Compound (I) TRPV1 inhibition ratio (%) FAAH inhibition (%)
Blank control NE NE
Example 1 70.64 72.09
Example 2 69.53 73.87
Example 3 75.38 80.51
Example 4 77.26 68.16
Example 5 62.53 68.28
Example 6 66.04 72.31
Example 7 73.52 78.63
Example 8 75.89 77.55
Example 9 60.79 69.98
Example 10 58.96 63.69
Note: inhibition ═ (blank difference-experimental difference)/blank difference 100%
Inhibition rate-abundance of arachidonic acid peak/abundance of post-inhibition arachidonic acid peak 100%
Fluorescence intensity after adding capsaicin in blank group-fluorescence intensity before adding capsaicin in blank group
The difference between the experimental group and the fluorescence intensity after adding capsaicin-the fluorescence intensity before adding capsaicin
NE: the blank control group had an inhibition ratio of 0.
The test result shows that the tested compound has the TRPV1 inhibition rate and the FAAH inhibition rate of more than 50 percent, which indicates that the tested compound has the TRPV1/FAAH inhibition activity.
3. Effect of Compounds 1-10 of the invention on a model of pain in mice
Formalin-induced foot licking behavior
Mice were randomly grouped by weight, 8 per group. Half an hour before the test, the oral gavage is carried out, the dosage is 30mg/kg, and the blank group is provided with 0.5 percent CMC-Na with equal volume. The volume of administration was 0.2mL/20 g. For testing, formalin solutions at 5% concentration in saline were injected into the hind paw, and the mice were then evaluated for response to licking by the injected paw within 30 minutes. The assessment was divided into two phases, the first (0-5min) being acute pain and the second (20-30min) being chronic pain. The results are shown in table 2 below.
TABLE 2
Figure BDA0003074824030000141
Note: t-test, p <0.05, p <0.01, p <0.001 compared to blank group.
Test results show that in a formalin-induced pain model, the tested compound has a significant difference compared with a blank group, and has a strong analgesic effect in both first-stage acute pain and second-stage chronic pain.
The above pharmacological data show that: the compounds with the general formula (I) respectively show stronger antagonistic/inhibitory action on TRPV1 and FAAH.

Claims (8)

  1. A TRPV1 antagonist/FAAH inhibiting dual target drug or a pharmaceutically acceptable salt thereof, characterized in that it is specifically the following compound:
    phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate,
    Phenyl (1- ((3, 4-dimethoxyphenyl) carbamoyl) cyclohexyl) carbamate,
    Phenyl (1- ((3, 4-dichlorophenyl) carbamoyl) cyclohexyl) carbamate,
    1-(3-(2-(1H-indol-3-yl) ethyl) ureido) -N- (4-chlorophenyl) cyclohexane-1-carboxamide,
    1-(3-(2-(1H-indol-3-yl) ethyl) ureido) -substituted compoundsN- (4-bromophenyl) cyclohexane-1-carboxamide,
    1-(3-(2-(1H-indol-3-yl) ethyl) ureido) -N- (3-isopropylphenyl) cyclohexane-1-carboxamide,
    1-(3-(2-(1H-indol-3-yl) ethyl) ureido) -N- (4-tert-butylphenyl) cyclohexane-1-carboxamide,
    N- (4-chlorophenyl) -1- (3- (2- (5-methoxy-indol-3-yl) ethyl) ureidooxy) cyclohexane-1-carboxamide,
    N- (3-isopropylphenyl) -1- (3- (2- (5-methoxy-1)H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide,
    N- (4- (tert-butyl) phenyl) -1- (3- (2- (5-methoxy-1)H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide.
  2. 2. The TRPV1 antagonist/FAAH inhibitory dual target drug or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt comprises a salt with: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid.
  3. 3. The method for preparing a TRPV1 antagonistic/FAAH inhibiting dual target drug or a pharmaceutically acceptable salt thereof according to claim 1,
    the preparation method of the (I) phenyl (1- (aryl carbamoyl) cyclohexyl) carbamate compound is shown as a scheme A:
    Figure DEST_PATH_IMAGE002
    the method specifically comprises the following steps:
    (a) preparation of intermediate (i)
    Weighing 1-aminocyclohexyl formic acid in an eggplant-shaped bottle, dissolving the 1-aminocyclohexyl formic acid in tetrahydrofuran, weighing NaOH and dissolving the NaOH in water, dropwise adding NaOH aqueous solution into the eggplant-shaped bottle, then adding di-tert-butyl dicarbonate, continuing to react for 16 hours at room temperature, removing tetrahydrofuran from reaction liquid after the reaction is finished by decompression and concentration, adding HCl to adjust the pH =1-2, precipitating white solid, and performing suction filtration to obtain an intermediate (i);
    (b) preparation of intermediate (ii)
    Adding the intermediate (i) into a single-neck flask at room temperature, dissolving the intermediate (i) by using dichloromethane, sequentially adding 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into the single-neck flask, stirring at room temperature, adding aromatic amine and triethylamine, continuously reacting for 18 hours at room temperature, washing a reaction solution after the reaction is finished, drying, filtering, and concentrating under reduced pressure to obtain an intermediate (ii);
    (c) preparation of intermediate (iii)
    Adding the intermediate (ii) into a single-neck flask at room temperature, dissolving the intermediate (ii) by using dry dichloromethane, dropwise adding trifluoroacetic acid in an ice bath, heating the reaction system to room temperature after the addition is finished, continuing to react for 1h, adjusting the pH to 8 by using a saturated sodium bicarbonate solution after the reaction is finished, extracting, back-extracting a water phase by using dichloromethane, combining organic phases, and concentrating under reduced pressure to obtain an intermediate (iii);
    (d) preparation of object Compound (iv)
    At room temperature, adding the intermediate (iii) into a single-neck flask, dissolving the intermediate (iii) with dichloromethane, slowly adding triethylamine and chloroformic acid aromatic ester in sequence under an ice bath condition, heating to room temperature for reaction for 2 hours, adding water for quenching after the reaction is finished, extracting, performing back extraction on a water phase with dichloromethane, combining organic phases, performing reduced pressure concentration, and performing column chromatography separation and purification to obtain a target compound (iv);
    in the preparation method of the (mono) phenyl (1- (aryl carbamoyl) cyclohexyl) carbamate compound, the target compound (iv) is phenyl (1- ((4-bromophenyl) carbamoyl) cyclohexyl) carbamate, phenyl (1- ((3, 4-dimethoxyphenyl) carbamoyl) cyclohexyl) carbamate, phenyl (1- ((3, 4-dichlorophenyl) carbamoyl) cyclohexyl) carbamate;
    (di) 1- (3- (2- (1)H-indol-3-yl) ethyl) ureido) -N-phenylcyclohexane-1-carboxamides are prepared as shown in scheme B:
    Figure DEST_PATH_IMAGE004
    (1) intermediates (i) to (iii) were prepared as in steps (a) to (c);
    (2) preparation of object Compound (iv)
    Adding tryptamine or 5-methoxytryptamine into a two-neck flask under the protection of ice bath nitrogen, stirring and dissolving with dry dichloromethane, slowly dropwise adding triphosgene dissolved with dichloromethane, and then adding Et3N, after reacting for 30min, slowly dropwise adding the intermediate (iii) dissolved in dichloromethane, reacting overnight, adding water to quench the reaction, extracting, back-extracting the water phase with dichloromethane, combining organic phases, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the target compound (iv);
    the (di) 1- (3- (2- (1)H-indol-3-yl) ethyl) ureido) -NProcess for producing (iv) a target compound of 1- (3- (2- (1) or 2-carbonyl) amide compoundH-indol-3-yl) ethyl) ureido) -substituted compoundsN- (4-chlorophenyl) cyclohexane-1-carboxamide, 1- (3- (2- (1)H-indol-3-yl) ethyl) ureido) -N-(4-bromophenyl) cyclohexane-1-carboxamide, 1- (3- (2- (1)H-indol-3-yl) ethyl) ureido) -N- (3-isopropylphenyl) cyclohexane-1-carboxamide, 1- (3- (2- (1)H-indol-3-yl) ethyl) ureido) -N- (4-tert-butylphenyl) cyclohexane-1-carboxamide,N- (4-chlorophenyl) -1- (3- (2- (5-methoxy-indol-3-yl) ethyl) ureidooxy) cyclohexane-1-carboxamide,N- (3-isopropylphenyl) -1- (3- (2- (5-methoxy-1)H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide,N- (4- (tert-butyl) phenyl) -1- (3- (2- (5-methoxy-1)H-indol-3-yl) ethyl) ureido) cyclohexane-1-carboxamide.
  4. 4. A pharmaceutical formulation comprising the TRPV1 antagonist/FAAH inhibitory dual target drug of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable pharmaceutical carrier.
  5. 5. The pharmaceutical formulation of claim 4, in the form of a tablet, capsule, pill, suppository, soft capsule, oral liquid, suspension, or injection.
  6. 6. The pharmaceutical preparation according to claim 5, which is a tablet, and comprises the following raw materials:
    TRPV1 antagonistic/FAAH inhibiting or pharmaceutically acceptable salt thereof 40mg
    Lactose 100mg
    Corn starch 40mg
    Magnesium stearate 1.5mg
    10-15mL of ethanol.
  7. 7. The use of the TRPV1 antagonist/FAAH inhibitory dual target drug of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a TRPV1 antagonist/FAAH inhibitor or in the manufacture of an analgesic drug.
  8. 8. Use of a pharmaceutical formulation according to claim 5 for the preparation of a TRPV1 antagonist/FAAH inhibitor or for the preparation of an analgesic medicament.
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CN109761974B (en) * 2019-01-21 2021-05-14 河南大学 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof
CN111454233B (en) * 2020-05-08 2023-01-24 河南大学 4- (2- (pyrrolidine/piperidine-1-yl) benzyl) -piperazinylurea TRPV1 antagonist and preparation and application thereof
CN111423432B (en) * 2020-05-11 2023-01-24 河南大学 (S) -4/5-phenyl-2- (pyrrolidine-2-yl) thiazole TRPV1 antagonist and preparation and application thereof

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