A phenylpiperazine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and use thereof in the preparation of a medicament for treating pain

Abstract

The present application relates to the field of medicinal chemistry and pharmacotherapy, in particular to a phenylpiperazine compound or a pharmaceutically acceptable salt thereof, a preparation method and use thereof in the preparation of analgesic drugs or drugs for treating pain, wherein the phenylpiperazine compound or the pharmaceutically acceptable salt thereof has the following structure: the phenylpiperazine compound has obvious inhibitory activity on TRPV1, can obviously inhibit the pain response, and has no side effect of body temperature rise.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmacotherapeutic technology, specifically relating to a phenylpiperazine derivative or its pharmaceutical salt, its preparation method, and its application in the preparation of pain-relieving drugs. Background Technology

[0002] Pain is a common clinical symptom, affecting approximately 500 million people annually with various forms of pain. Currently, the most commonly used analgesics in clinical practice fall into two main categories: narcotic analgesics that directly activate opioid receptors and antipyretic analgesics, primarily nonsteroidal anti-inflammatory drugs (NSAIDs). While these drugs have good clinical efficacy, they also have significant side effects, such as the addictive potential of opioids and the gastrointestinal side effects of NSAIDs. Furthermore, chronic and neuropathic pain cannot be effectively controlled with existing medications.

[0003] In recent years, with the development of related disciplines and the application of new technologies, some progress has been made in the research of various receptors and their selective ligands related to pain transmission. TRPV1, highly expressed in primary sensory neurons, is a non-specific cation channel that can be activated by hydrogen ions (pH < 5.5), high temperature (> 42°C), and other endogenous and exogenous ligands, playing an important role in the body's perception of temperature and pain. TRPV1 activation causes calcium ion influx, leading to the release of substance P and calcitonin gene-related peptide from nerve endings, thereby triggering pain. Downregulating TRPV1 expression or using TRPV1 antagonists can effectively prevent TRPV1 activation, inhibit the transmission of pain signals from peripheral nerves to the central nervous system, and alleviate pain caused by various nerve injuries. Research on TRPV1 antagonists has become one of the most promising directions in analgesic drug research. Some TRPV1 antagonists have the side effect of elevated body temperature, limiting the clinical progress of this class of drugs. Developing novel TRPV1 antagonists without the side effect of elevated body temperature is a research hotspot in this field. Based on this, this application was developed. Summary of the Invention

[0004] The purpose of this invention is to overcome the defects and deficiencies of the existing technology and provide a phenylpiperazine derivative or its pharmaceutical salt. This phenylpiperazine compound or its pharmaceutical salt can inhibit hTRPV1 receptors, thereby producing a pain-relieving effect.

[0005] The present invention also provides a method for preparing the above-mentioned phenylpiperazine derivative or its pharmaceutically applicable salt and its application in the preparation of pain-relieving drugs.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A phenylpiperazine derivative or a pharmaceutically acceptable salt thereof, wherein the phenylpiperazine derivative is defined as compound I, and the structure of compound I is shown below:

[0008]

[0009] Among them, ring A is cyclohexyl, aryl, or heteroaryl;

[0010] R1 is hydrogen, halogen, alkyl, nitrile, alkynyl, alkoxy, or cycloalkoxy;

[0011] R2 is hydrogen, halogen, alkyl, nitrile, nitro, alkoxy, or cycloalkoxy;

[0012] R3 is hydrogen, halogen, alkyl, nitrile, nitro, alkoxy, or cycloalkoxy;

[0013] X is CONH or CONHSO2.

[0014] Specifically, in R1, at least one hydrogen atom of the alkyl group is substituted with a halogen, at least one hydrogen atom of the alkoxy group is substituted with a halogen, and at least one hydrogen atom of the cycloalkoxy group is substituted with a halogen.

[0015] In R2, at least one hydrogen atom of the alkyl group is substituted with a halogen, at least one hydrogen atom of the alkoxy group is substituted with a halogen, and at least one hydrogen atom of the cycloalkoxy group is substituted with a halogen.

[0016] In R3, at least one hydrogen atom of the alkyl group is substituted with a halogen, at least one hydrogen atom of the alkoxy group is substituted with a halogen, and at least one hydrogen atom of the cycloalkoxy group is substituted with a halogen.

[0017] Furthermore, ring A is cyclohexyl, a benzene ring, or a pyridine ring;

[0018] R1 is hydrogen, methyl, trifluoromethyl, ethynyl, tert-butyl, nitrile, methoxy, fluorine, or chlorine;

[0019] R2 is hydrogen, methyl, trifluoromethyl, nitro, fluorine, or chlorine;

[0020] R3 is hydrogen, methyl, trifluoromethyl, nitro, fluorine, or chlorine.

[0021] More preferably, the phenylpiperazine derivative or its pharmaceutically acceptable salt can be any of the following compounds:

[0022] N-Cyclohexyl-4-phenylpiperazine-1-carboxamide (I-1);

[0023] 4-Phenylon-N-(p-Tolyl)piperazin-1-carboxamide (I-2);

[0024] 4-Phenyl-N-(phenylsulfonyl)piperazine-1-carboxamide (I-3);

[0025] N-(4-(tert-butyl)phenyl)-4-phenylpiperazine-1-carboxamide (I-4);

[0026] N-(4-methoxypyridin-2-yl)-4-phenylpiperazine-1-carboxamide (I-5);

[0027] N-(3-ethynylphenyl)-4-phenylpiperazine-1-carboxamide (I-6);

[0028] 4-Phenylon-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-7);

[0029] N-(4-chlorophenyl)-4-phenylpiperazine-1-carboxamide (I-8);

[0030] 4-(4-Chlorophenyl)-N-(p-Tolyl)piperazin-1-carboxamide (I-9);

[0031] N-(phenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-10);

[0032] 4-(4-chlorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-11);

[0033] 4-(4-Chlorophenyl)-N-cyclohexylpiperazine-1-carboxamide (I-12);

[0034] N-Cyclohexyl-4-(4-nitrophenyl)piperazine-1-carboxamide (I-13);

[0035] 4-(4-nitrophenyl)-N-(p-tolyl)piperazin-1-carboxamide (I-14);

[0036] 4-(4-nitrophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-15);

[0037] 4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-16);

[0038] N-(3-ethynylphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-17);

[0039] 4-(2-Fluorophenyl)-N-(p-Tolyl)piperazin-1-carboxamide (I-18);

[0040] N-Cyclohexyl-4-(2-fluorophenyl)piperazine-1-carboxamide (I-19);

[0041] 4-(2-Fluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-20);

[0042] 4-(2,4-Difluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-21);

[0043] N-Cyclohexyl-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-22);

[0044] N-(p-Tolyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-23).

[0045] This invention discloses the use of the above-mentioned phenylpiperazine derivative or pharmaceutical salt in the preparation of analgesic drugs or pain-relieving drugs.

[0046] Specifically, the aforementioned applications produce therapeutic analgesia or pain relief effects by inhibiting hTRPV1 receptors. The pain referred to includes diabetic neuropathic pain, toothache, osteoarthritis pain, or postherpetic neuralgia, etc.

[0047] This invention also discloses a pharmaceutical composition comprising a therapeutically effective amount of the phenylpiperazine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The carrier, diluent, or excipient can be prepared using conventional techniques in the art.

[0048] The present invention also discloses the use of the above-mentioned pharmaceutical composition in the preparation of analgesic drugs or drugs for treating pain.

[0049] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0050] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Preferably, it is an alkyl group containing 1 to 10 carbon atoms; more preferably, it is an alkyl group containing 1 to 6 carbon atoms; more preferably, it is an alkyl group containing 1 to 3 carbon atoms; and most preferably, it is methyl. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and their various branched isomers. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable linking point, preferably by one or more of the following groups, independently selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0051] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.

[0052] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0053] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, being independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0054] "Pharmaceutical composition" refers to a mixture containing one or more of the compounds described in this invention or their pharmaceutically acceptable salts, or their prodrugs, along with other chemical components such as pharmaceutically acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to promote the absorption of the active ingredient by the organism, thereby facilitating the exertion of the active ingredient's biological activity within the body.

[0055] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0056] This invention discovers a novel class of phenylpiperazine derivatives and provides a method for their preparation. The synthesis process is simple and easy to operate, using inexpensive and readily available raw materials, making it suitable for large-scale production. This invention also provides pharmaceutical compositions using these compounds as active ingredients, and their applications in the preparation of analgesic or pain-relieving drugs. Experimental verification shows that the phenylpiperazine derivatives of this invention exhibit good inhibitory activity against TRPV1, good analgesic effects, and no side effect of increased body temperature, making them suitable for use as analgesics or pain-relieving drugs. Attached Figure Description

[0057] Figure 1 The effects of some compounds on mouse body temperature. Detailed Implementation

[0058] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0059] Unless otherwise specified, all raw materials used in the following embodiments are commercially available products that can be purchased directly or can be prepared using conventional methods in the art. Room temperature refers to 25±5℃.

[0060] Example 1: N-cyclohexyl-4-phenylpiperazine-1-carboxamide (I-1)

[0061]

[0062] Cyclohexyl isocyanate II-2 (0.367 g, 2.94 mmol) was dissolved in 20 mL of anhydrous dichloromethane. A solution of phenylpiperazine II-1 (0.5 g, 3.08 mmol) in 10 mL of anhydrous dichloromethane was slowly added dropwise under ice bath conditions. The reaction was carried out under ice bath conditions for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give 0.77 g of white solid I-1, in 90.8% yield. The chromatographic data are shown below.

[0063] 1 H NMR(400MHz,Chloroform-d)δ7.40-7.19(m,2H),6.90(dd,J=17.9,7.8Hz,3H),4.41(t,J=7.5Hz,1H),3.67(m,1H),3.51 (dd,J=6.3,4.1Hz,4H),3.27-3.10(m,4H),2.08-1.86(m,2H),1.70(m,2H),1.62(m,1H),1.48-1.28(m,2H),1.13(m,3H). 13 C NMR(101MHz,Chloroform-d)δ157.02,151.07,129.21,120.24,116.44,49.51,49.15,43.75,34.00,25.70,25.11.ESI-MS m / z:288.4[M+H] + Elemental analysis calculations: For C 17 H 25 N3O: C, 71.04; H, 8.77; Measured values: C, 71.07; H, 8.74.

[0064] Example 2: 4-Phenyl-N-(p-Tolyl)piperazine-1-carboxamide (I-2)

[0065]

[0066] The synthesis method was the same as in Example 1, except that starting material II-2 was replaced with p-toluene isocyanate, yielding 0.38 g of a white solid with a yield of 92.5%. The spectral data are as follows.

[0067] 1 H NMR(400MHz,Chloroform-d)δ7.36-7.18(m,4H),7.09(d,J=8.1Hz,2H),7.00- 6.87(m,3H),6.49(s,1H),3.72-3.54(m,4H),3.24-3.09(m,4H),2.29(s,3H). 13 C NMR(101MHz,Chloroform-d)δ155.28,150.95,136.27,132.90,129.44,129.26,120.44,120.41,116.51,49.20,44.05,20.79.ESI-MS m / z:296.4[M+H] + Elemental analysis calculations: ForC 18 H 21 N3O: C, 73.19; H, 7.17; Measured values: C, 73.17; H, 7.14.

[0068] Example 3: 4-Phenyl-N-(phenylsulfonyl)piperazine-1-carboxamide (I-3)

[0069]

[0070] The synthesis method was the same as in Example 1, except that starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.38 g of a white solid with a yield of 92.5%. The spectral data are as follows.

[0071] 1 H NMR(400MHz,Chloroform-d)δ8.17-8.00(m,2H),7.58(t,J=8.7Hz,1H),7.50(t,J=8.5 Hz,2H),7.27-7.14(m,2H),6.84(m,3H),3.55(t,J=5.1Hz,4H),3.07(t,J=5.1Hz,4H). 13C NMR(101MHz,Chloroform-d)δ151.38,151.35,150.70,139.68,133.53,132.71,129.45, 129.26,129.19,128.99,128.12,126.32,120.54,117.04,116.60,49.02,46.78.ESI-MS m / z:346.4[M+H] + Elemental analysis calculations: For C 17 H 19 N3O3S: C, 59.11; H, 5.54; Measured values: C, 59.13; H, 5.54.

[0072] Example 4: N-(4-(tert-butyl)phenyl)-4-phenylpiperazine-1-carboxamide (I-4)

[0073]

[0074] The synthesis method was the same as in Example 1, except that starting material II-2 was replaced with p-tert-butylphenyl isocyanate, yielding 0.34 g of a white solid with a yield of 91.5%. The spectral data are as follows.

[0075] 1 H NMR(400MHz, DMSO-d6)δ8.52(d,J=10.3Hz,1H),7.42-7.32(m,2H),7.31-7.20(m,4H),6.99(d,J=7.1,1.1Hz,2H), 6.81(t,J=7.2Hz,1H), 4.09(q,J=5.3Hz,1H), 3.58(t,J=5.1Hz,3H), 3.16(t,J=4.9Hz,4H), 1.26(d,J=2.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ155.63,151.45,144.51,138.29,137.62,129.44,125.83,1 25.37,119.97,119.71,118.45,116.30,49.08,48.86,44.13,34.33,31.75.ESI-MS m / z:338.5[M+H] + Elemental analysis calculations: For C 21 H 27 N3O: C, 74.74; H, 8.06; Measured values: C, 74.73; H, 8.04.

[0076] Example 5: N-(4-methoxypyridin-2-yl)-4-phenylpiperazin-1-carboxamide (I-5)

[0077]

[0078] I-5 was synthesized using a one-pot reaction. Under nitrogen protection, a solution of 2-amino-4-methoxypyridine II-3 (0.2 g, 1.61 mmol) in anhydrous dichloromethane (20 mL) was slowly added dropwise to a solution of triphosgene II-4 (0.16 g, 0.54 mmol) in dichloromethane (20 mL). 4-Dimethylaminopyridine (DMAP) (0.59 g, 4.83 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, a solution of II-1 in dichloromethane (20 mL) was added, and the reaction was continued at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give 0.32 g of white solid I-5, with a yield of 63.6%. The chromatographic data are shown below.

[0079] 1 H NMR(400MHz,DMSO-d6)δ8.27-8.08(m,2H),7.22(m,2H),7.07-6.93(m,1H) ,6.93-6.76(m,3H),3.48-3.34(m,2H),3.16(d,J=5.9Hz,3H),3.09(s,6H). 13 C NMR(101MHz,DMSO-d6)δ156.55,150.51,141.90,129.53,120.28,116.40,107.33,49.00,45.77,42.86.ESI-MS m / z:313.5[M+H] + Elemental analysis calculations: For C 17 H 20 N4O2: C, 65.37; H, 6.45; Measured values: C, 65.36; H, 6.44.

[0080] Example 6: N-(3-ethynylphenyl)-4-phenylpiperazine-1-carboxamide (I-6)

[0081]

[0082] The synthesis method was the same as in Example 5, except that starting material II-3 was replaced with m-aminophenylacetylene, yielding 0.35 g of a white solid with a yield of 68.3%. The spectral data are as follows.

[0083] 1H NMR(300MHz,DMSO-d6)δ7.67(t,J=1.9Hz,1H),7.52(d,J=8.3Hz,1H),7.33-7.19(m,3H ),7.08-6.95(m,3H),6.90-6.73(m,1H),3.61(t,J=6.1Hz,4H),3.16(t,J=6.1Hz,4H). 13 C NMR(75MHz,DMSO-d6)δ155.23,151.37,141.21,129.44,129.25,125.44,12 2.78,122.08,120.54,119.74,116.31,84.16,80.55,48.82,44.10.ESI-MS m / z:306.4[M+H] + Elemental analysis calculations: For C 19 H 19 N3O: C, 74.73; H, 6.27; Measured values: C, 74.76; H, 6.24.

[0084] Example 7: 4-Phenylon-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-7)

[0085]

[0086] The synthesis method was the same as in Example 5, except that starting material II-3 was replaced with p-trifluoromethylaniline, yielding 0.27 g of a white solid with a yield of 65.2%. The spectral data are as follows.

[0087] 1 H NMR(300MHz,DMSO-d6)δ9.03(s,1H),7.81-7.49(m,5H),7.32-7.13(m,2H),7.09-6.9 3(m,2H),6.82(td,J=7.2,1.1Hz,1H),3.73-3.51(m,4H),3.18(dd,J=6.2,3.9Hz,4H). 13 CNMR(75MHz,DMSO-d6)δ154.98,151.35,144.85,129.43,126.89,126.10,126.05,12 3.30,122.27,121.84,119.76,119.35,118.57,116.31,107.15,48.82,44.14.ESI-MS m / z:350.4[M+H] + Elemental analysis calculations: For C 18 H 13F3N3O: C, 61.88; H, 5.19; Measured values: C, 61.86; H, 5.22.

[0088] Example 8: N-(4-chlorophenyl)-4-phenylpiperazine-1-carboxamide (I-8)

[0089]

[0090] The synthesis method was the same as in Example 5, except that starting material II-3 was replaced with p-chloroaniline, yielding 0.31 g of a white solid with a yield of 61.2%. The spectral data are as follows.

[0091] 1 H NMR(300MHz,DMSO-d6)δ8.76(s,1H),7.63-7.50(m,2H),7.38-7.19(m,4H),7.08-6 .93(m,2H),6.91-6.69(m,1H),3.60(t,J=5.1Hz,4H),3.16(dd,J=6.3,3.9Hz,4H). 13 C NMR(75MHz,DMSO-d6)δ155.23,151.37,139.98,129.44,129.10,128.64,125.77,121.44,119.75,116.31,48.82,44.08.ESI-MS m / z:316.8[M+H] + Elemental analysis calculations: ForC 17 H 18 ClN3O: C, 64.66; H, 5.75; Measured values: C, 64.68; H, 5.77.

[0092] Example 9: 4-(4-chlorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-9)

[0093]

[0094] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-chlorophenyl)piperazine and starting material II-2 was replaced with p-toluene isocyanate, yielding 0.18 g of a white solid with a yield of 91.8%. The spectral data are as follows.

[0095] 1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.42-7.29(m,2H),7.29-7.16(m,2H),7.14-6.99 (m,3H),6.99-6.88(m,1H),3.58(t,J=6.5Hz,4H),3.15(t,J=6.2Hz,4H),2.23(s,3H). 13 C NMR (101MHz, DMSO-d6) δ155.54,150.94,150.20,138.30,131.02,129.18,129.11,129. 00,123.15,122.49,120.27,117.67,117.12,49.63,48.58,45.97,43.95,20.82.ESI-MS m / z:330.8[M+H] + Elemental analysis calculations: For C 18 H 20 ClN3O: C, 65.55; H, 6.11; Measured values: C, 65.58; H, 6.13.

[0096] Example 10: N-(phenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-10)

[0097]

[0098] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-trifluoromethylphenyl)piperazine and starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.35 g of a white solid with a yield of 90.6%. The spectral data are as follows.

[0099] 1 H NMR (400MHz, DMSO-d6) δ7.97-7.91(m,2H),7.86(d,J=1.6Hz,1H),7.63(d,J=6.4Hz,1H),7.59(m,3H),7 .51(d,J=8.6Hz,2H),7.38(s,1H),7.06(d,J=8.6Hz,1H),3.48(d,J=5.4Hz,4H),3.26(d,J=5.4Hz,4H). 13C NMR(101MHz,DMSO-d6)δ153.44,152.82,144.59,142.41,132.63,132.24,129.38,129.27,129.01,127.74,127.66,126.80,12 6.76,126.67,126.64,126.61,126.57,126.04,124.07,118.70,118.39,115.39,115.30,114.83,47.25,44.79,43.00.ESI-MS m / z:414.4[M+H] + Elemental analysis calculations: For C 18 H 18 F3N3O3S: C, 52.31; H, 4.39; Measured values: C, 52.28; H, 4.36.

[0100] Example 11: 4-(4-chlorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-11)

[0101]

[0102] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-chlorophenyl)piperazine and starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.30 g of a white solid with a yield of 89.3%. The spectral data are as follows.

[0103] 1 H NMR (400MHz, DMSO-d6) δ7.95-7.89(m,2H),7.87-7.79(m,1H),7.57(d,J=3.8Hz,1H),7.38( s,1H),7.29-7.19(m,2H),6.99-6.82(m,2H),3.46(d,J=5.2Hz,4H),3.07(t,J=5.2Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ154.11,150.08,149.30,144.59,142.44,141.49,133.04,132.61,132.25,129.39,129.28,129.24,129.10, 129.01,127.71,127.64,126.03,124.06,123.20,118.01,117.72,55.38,52.78,49.08,48.50,45.83,43.15.ESI-MSm / z:380.9[M+H] + Elemental analysis calculations: For C17 H 18 ClN3O3S: C, 53.75; H, 4.78; Measured values: C, 53.78; H, 4.76.

[0104] Example 12: 4-(4-chlorophenyl)-N-cyclohexylpiperazine-1-carboxamide (I-12)

[0105]

[0106] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-chlorophenyl)piperazine, yielding 0.23 g of a white solid with a yield of 92.3%. The spectral data are as follows.

[0107] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.14(m,2H),7.04-6.92(m,2H),6.30(d,J=7.7Hz,1H),3. 46-3.40(m,4H),3.07(m,4H),1.84-1.62(m,4H),1.57(m,1H),1.21(m,4H),1.07(m,2H). 13 C NMR(101MHz,DMSO-d6)δ157.24,150.27,129.06,123.07,117.61,49.63,48.51,43.71,33.59,25.86,25.59.ESI-MS m / z:322.9[M+H] + Elemental analysis calculations: ForC 17 H 24 ClN3O: C, 63.44; H, 7.52; Measured values: C, 63.46; H, 7.53.

[0108] Example 13: N-cyclohexyl-4-(4-nitrophenyl)piperazine-1-carboxamide (I-13)

[0109]

[0110] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-nitrophenyl)piperazine, yielding 0.26 g of a yellow solid with a yield of 91.1%. The spectral data are as follows.

[0111] 1H NMR (400MHz, DMSO-d6) δ8.17-7.99(m,2H),7.10-6.88(m,2H),6.30(d,J=7.7 Hz, 1H), 3.45 (s, 8H), 1.72 (m, 4H), 1.57 (d, J = 12.8Hz, 1H), 1.30-0.96 (m, 6H). 13 C NMR(101MHz,DMSO-d6)δ157.13,155.06,137.30,126.16,113.00,49.66,46.42,43.22,33.82,33.58,25.84,25.57,24.93.ESI-MS m / z:322.9[M+H] + Elemental analysis calculations: For C 17 H 24 ClN3O: C, 63.44; H, 7.52; Measured values: C, 63.46; H, 7.53.

[0112] Example 14: 4-(4-nitrophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-14)

[0113]

[0114] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-nitrophenyl)piperazine and starting material II-2 was replaced with p-toluene isocyanate, yielding 0.21 g of a yellow solid with a yield of 92.5%. The spectral data are as follows.

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.15-8.01(m,1H),7.35(dd,J=8.4,6.5Hz,2H),7.05(dd,J=8.7,4.8Hz,3H),3.84-3.35(m,7H),2.23(s,3H). 13 C NMR(101MHz,DMSO-d6)δ155.48,155.00,153.31,138.23,138.02,137.36,131.10,13 0.62,129.53,129.19,126.18,120.32,118.49,113.03,46.46,43.47,20.81.ESI-MS m / z:341.4[M+H] + Elemental analysis calculations: For C 18 H 20N4O3: C, 63.52; H, 5.92; Measured values: C, 63.54; H, 5.93.

[0116] Example 15: 4-(4-nitrophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-15)

[0117]

[0118] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-nitrophenyl)piperazine and starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.24 g of a yellow solid with a yield of 88.5%. The chromatographic data are as follows.

[0119] 1 H NMR(400MHz,DMSO-d6)δ8.15-8.01(m,1H),7.93-7.87(m,1H),7.86-7.80(m,1H),7.7 0-7.49(m,4H),7.37(s,1H),7.14-6.91(m,1H),3.71-3.47(m,4H),3.47-3.30(m,4H). 13 C NMR(101MHz,DMSO-d6)δ154.93,154.47,144.58,138.41,137.31,132.26,132.00,129.39,12 9.11,128.80,127.57,126.17,126.10,126.03,113.88,112.99,46.47,44.10,42.90.ESI-MS m / z:391.4[M+H] + Elemental analysis calculations: For C 17 H 18 N4O5S: C, 52.30; H, 4.65; Measured values: C, 52.31; H, 4.63.

[0120] Example 16: 4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-16)

[0121]

[0122] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(4-nitrophenyl)piperazine and starting material II-2 was replaced with 4-trifluoromethylphenyl isocyanate, yielding 0.22 g of a yellow solid with a yield of 83.5%. The chromatographic data are as follows.

[0123] 1H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.20-8.02 (m, 2H), 7.71 (d, J = 8.6Hz, 2H), 7.6 0(d,J=8.6Hz,2H),7.14-6.95(m,2H),3.66(t,J=6.8Hz,4H),3.57(t,J=6.8Hz,4H). 13 CNMR(101MHz,DMSO-d6)δ154.94,144.72,137.41,126.42,126.20,126.12,12 6.08,123.72,122.31,122.00,119.43,118.58,113.04,46.38,43.50.ESI-MS m / z:391.4[M+H] + Elemental analysis calculations: For C 18 H 17 F3N4O3:C,54.85;H,4.35;Measured values:C,54.83;H,4.33.

[0124] Example 17: N-(3-ethynylphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-17)

[0125]

[0126] The synthesis method was the same as in Example 5, except that starting material II-1 was replaced with 1-(4-trifluoromethylphenyl)piperazine, and starting material II-3 was replaced with m-aminophenylacetylene, yielding 0.26 g of a white solid with a yield of 85.5%. The spectral data are as follows.

[0127] 1 H NMR(400MHz,DMSO-d6)δ7.67(dt,J=4.4,2.0Hz,1H),7.53(m,2H),7.41(m,1H),7.32- 7.24(m,1H),7.08(m,3H),4.17(s,1H),3.61(t,J=6.6Hz,4H),3.35(t,J=5.1Hz,4H). 13CNMR(101MHz,DMSO-d6)δ155.21,153.54,152.89,141.14,140.25,129.69,129.25,126.78,126.67,126.63,126.59,125.72,125.49,124.09,12 2.82,122.52,122.08,121.55,120.57,119.49,118.69,118.37,114.83, 114.69,84.14,84.01,80.87,80.54,79.81,47.31,47.01,43.74.ESI-MS m / z: 374.4 [M+H] + Elemental analysis calculations: For C 20 H 18 F3N3O: C, 64.34; H, 4.86; Measured values: C, 64.33; H, 4.89.

[0128] Example 18: 4-(2-fluorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-18)

[0129]

[0130] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(2-fluorophenyl)piperazine and starting material II-2 was replaced with p-phenylmethyl isocyanate, yielding 0.15 g of a white solid with a yield of 84.6%. The spectral data are as follows.

[0131] 1 H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 7.43-7.30 (m, 2H), 7.24-6.92 (m, 6H), 3.60 (t, J = 5.0Hz, 4H), 3.02 (t, J = 5.0Hz, 4H), 2.23 (s, 3H). 13 C NMR(101MHz,DMSO-d6)δ156.69,155.53,154.26,140.20,140.12,138.28,131.05,129.19,125.35,1 25.32,123.22,123.14,120.28,120.03,120.00,116.54,116.34,50.68,50.65,44.27,20.81.ESI-MS m / z:314.4[M+H] + Elemental analysis calculations: For C 18 H 20FN3O: C, 68.99; H, 6.43; Measured values: C, 68.97; H, 6.44.

[0132] Example 19: N-cyclohexyl-4-(2-fluorophenyl)piperazine-1-carboxamide (I-19)

[0133]

[0134] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(2-fluorophenyl)piperazine, yielding 0.18 g of a white solid with a yield of 88.6%. The spectral data are as follows.

[0135] 1 H NMR (400MHz, DMSO-d6) δ7.17-6.95 (m, 4H), 6.25 (d, J = 7.7Hz, 1H), 3.43 (t, J = 5.0Hz, 4H), 2.93 (dd,J=6.0,3.9Hz,4H),1.81-1.62(m,4H),1.62-1.44(m,1H),1.31-1.13(m,4H),1.08(m,2H). 13 C NMR(101MHz,Chloroform-d)δ157.05,156.94,154.49,139.86,139.77,124.54,124.51,122.95,1 22.87,119.11,119.09,116.28,116.08,50.40,50.36,49.51,43.93,33.96,25.68,25.12.ESI-MS m / z:306.4[M+H] + Elemental analysis calculations: ForC 17 H 24 FN3O: C, 66.86; H, 7.92; Measured values: C, 66.87; H, 7.94.

[0136] Example 20: 4-(2-fluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-20)

[0137]

[0138] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(2-fluorophenyl)piperazine and starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.21 g of white solid with a yield of 84.3%. The spectral data are as follows.

[0139] 1H NMR (400MHz, DMSO-d6) δ8.00-7.88(m,2H),7.70-7.49(m,3H),7.17-7.06(m,2H),7.06-6.91(m,2H),3.48(t,J=4.8Hz,4H),2.93(t,J=5.0Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ156.64,154.21,152.81,144.59,142.01,140.05,1 39.97,139.18,132.85,132.25,129.39,129.09,127.81,126.03,125.47,1 25.43,125.34,125.30,123.95,123.87,123.28,123.20,120.08,120.03,1 20.00,116.73,116.53,116.32,50.52,50.49,47.62,47.59,43.57.ESI-MS m / z: 364.4 [M+H] + Elemental analysis calculations: For C 17 H 18 FN3O3S: C, 56.19; H, 4.99; Measured values: C, 56.17; H, 4.97.

[0140] Example 21: 4-(2,4-difluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-21)

[0141]

[0142] The synthesis method was the same as in Example 1, except that starting material II-1 was replaced with 1-(2,4-difluorophenyl)piperazine, and starting material II-2 was replaced with benzenesulfonyl isocyanate, yielding 0.21 g of a white solid with a yield of 84.3%. The spectral data are as follows.

[0143] 1 H NMR (400MHz, DMSO-d6) δ8.01-7.87(m,2H),7.70-7.51(m,3H),7.28-7.12(m,1H),7.12-6.90(m,2H),3.48(t,J=4.8Hz,4H),2.88(t,J=5.0Hz,4H). 13C NMR(101MHz,Chloroform-d)δ159.55,157.13,154.51,151.71,139.83,136.04,133.38 ,132.79,129.18,128.01,126.35,120.00,110.97,105.09,50.57,47.85,44.13.ESI-MS m / z:382.4[M+H] + Elemental analysis calculations: For C 17 H 17 F2N3O3S: C, 53.54; H, 4.49; Measured values: C, 53.57; H, 4.47.

[0144] The TRPV1 inhibitory activity and in vivo analgesic activity of the compounds in this invention can be determined using the assay system described below. The following biological test examples illustrate this invention.

[0145] The experimental methods used in the test examples of this invention are generally performed under standard conditions or according to the conditions recommended by the product manufacturer. Reagents not specifically attributed are commercially available and commonly used.

[0146] Test Example 1: Arousal activity of the compound of the present invention on hTRPV1-HEK293 stable transgenic cells

[0147] The hTRPV1 inhibitory activity of the compounds of this invention was determined using the following method:

[0148] hTRPV1-HEK293 stable cells were converted at 2.5 × 10⁻⁶ 4Seeds were placed at a density of / wells into 96-well plates and cultured overnight in a cell culture incubator at 37°C and 5% CO2. Fluo-3AM calcium ion fluorescent probe was loaded at room temperature. First, a 2mM DMSO stock solution of Fluo-3AM was prepared. The Fluo-3AM solution was diluted with HBSS (Hank's balanced salt solution) to prepare a 5μM Fluo-3AM working solution. 10μL of the working solution was added to each well of the cell plate and incubated at 37°C for 30 minutes. Then, 50μL of HBSS containing 1% fetal bovine serum was added to each well, and the plate was incubated for another 40 minutes. Cells were washed four times with Tyrode's solution, and 40 μL of a 100 nM compound solution was added to each well. Three replicates were set up for each sample concentration. An equal volume of N-(4-(tert-butyl)phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) was added to the positive control group, while Tyrode's solution was added to the negative control group. After incubation at 37°C for 30 minutes, capsaicin (50 nM) was applied for stimulation. The absorbance at λex = 488 nm and λex = 540 nm before and after capsaicin stimulation was measured to characterize cytoplasmic calcium ion concentration. The results are shown in Table 1.

[0149] Inhibition rate = (Difference in blank group - Difference in experimental group) / Difference in blank group (Difference = Difference in fluorescence value before and after capsaicin administration)

[0150] Table 1: hTRPV1 receptor inhibitory activity

[0151]

[0152] The chemical structures corresponding to the compound codes in Table 1 are the same as those in the examples.

[0153] Test results show that all compounds of this invention have significant inhibitory activity against TRPV1 at different concentrations. Among them, compounds I-17, I-19, I-20 and I-21 have strong inhibitory activity, comparable to the positive control BCTC.

[0154] Test Example 2: The in vivo analgesic activity of the compounds of the present invention can be determined using two mouse pain model assay systems as described below:

[0155] (1) Acetic acid-induced writhing test

[0156] Ten-week-old male Kunming mice (clean-grade, 22-25g) were fasted for 12 hours prior to the experiment and randomly divided into groups of six based on body weight. The compound of this invention was administered by gavage 30 minutes before the test, at a dose of 30 mg / kg. The blank control group received an equal volume of 0.5% sodium carboxymethyl cellulose solution. During the test, mice were intraperitoneally injected with 0.6% acetic acid solution, and the number of writhing responses (abdominal retraction, hind limb extension, and hip elevation) observed within 15 minutes was recorded.

[0157] (2) Capsaicin-induced mouse foot-licking experiment

[0158] Ten-week-old male Kunming mice (clean-grade, 22-25g) were fasted for 12 hours prior to the experiment and randomly divided into groups of six based on body weight. The compound of this invention was administered by gavage 30 minutes before the test, at a dose of 30 mg / kg. The blank control group received an equal volume of 0.5% sodium carboxymethyl cellulose solution. During the test, 20 μl of capsaicin solvent (1.6 μg / 20 μl) was injected subcutaneously into the dorsal side of the right hind paw using a microsyringe. The cumulative time of paw licking within 5 minutes after capsaicin injection was observed and recorded.

[0159] (3) Hot water bath-induced tail retraction experiment in mice

[0160] Ten-week-old male Kunming mice (clean-grade, 22-25g) were fasted for 12 hours prior to the experiment and randomly divided into groups of six based on body weight. The compound of this invention was administered by gavage 30 minutes before the test, at a dose of 30 mg / kg. The blank control group received an equal volume of 0.5% sodium carboxymethyl cellulose solution. During the test, one-third of the mouse tail was immersed in a 52°C water bath. The tail retraction response time was observed and recorded before and 30 minutes after administration. The heat injury response was expressed as the maximal possible effect percentage (MPE%), calculated as: MPE% = (response time after administration - baseline response time) / (cutoff time - baseline response time) × 100% (where the cutoff time was 12 seconds to avoid tissue damage).

[0161] The experimental results are shown in Table 2. Table 2 shows that the preferred compound described in this invention exhibits high analgesic effects in all three pain models, comparable to the analgesic effect produced by the positive control BCTC.

[0162] Table 2 shows the analgesic activity of some compounds in three mouse pain models.

[0163]

[0164]

[0165] Test Example 3: The effects of some compounds of this invention on mouse body temperature can be determined using two mouse pain model assay systems as described below:

[0166] Ten-week-old male Kunming mice (clean-grade, 22–25 g) were fasted for 12 hours prior to the experiment and randomly divided into groups of six based on body weight. The test compound group and the positive control BCTC group were administered the compound by gavage at a dose of 30 mg / kg. The control group received an equal volume of 0.5% CMC-Na. Body temperature was measured in all mice before administration and at 30, 60, 90, and 120 minutes after administration. Results are as follows: Figure 1 As shown.

[0167] Depend on Figure 1 It can be seen that the body temperature of mice in the positive control BCTC group was significantly elevated, while the compound described in this invention did not have the side effect of elevated body temperature and has higher safety.

Claims

1. A phenylpiperazine derivative or its pharmaceutically acceptable salt, characterized in that, The phenylpiperazine derivative or its pharmaceutically acceptable salt is any one of the following compounds: N-(phenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide; 4-(4-chlorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide; 4-(4-nitrophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide; 4-(2,4-difluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide.

2. The use of the phenylpiperazine derivative or pharmaceutically acceptable salt of claim 1 in the preparation of analgesic or pain-relieving drugs.

3. The application according to claim 2, characterized in that, By inhibiting hTRPV1 receptors, a therapeutic analgesic or pain-relieving effect is produced.

4. The application according to claim 2, characterized in that, The pain referred to includes diabetic neuropathic pain, toothache, osteoarthritis pain, or postherpetic neuralgia.

5. A pharmaceutical composition, characterized in that, Contains a therapeutically effective amount of the phenylpiperazine derivative of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of the pharmaceutical composition of claim 5 in the preparation of analgesic or pain-relieving drugs.

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