Morphinan-type compound, preparation method therefor, composition thereof and use thereof

Abstract

The present invention relates to a morphinan-type compound, a preparation method therefor, a composition thereof and the use thereof. Specifically disclosed is a compound I or a pharmaceutically acceptable salt thereof. The morphinan-type compound of the present invention has one or more of the following effect advantages: (1) a relatively high binding affinity for an opioid receptor; (2) a significant agonistic effect on KOR and MOR; (3) good selectivity for a κ receptor; and (4) a good therapeutic effect on inflammatory pain (for example, rapid onset of action or significant analgesic effect).

Description

A morphinan compound, its preparation method, its composition and application

[0001] This application claims priority to Chinese Patent Application No. 2024105420915, filed on April 30, 2024, and Chinese Patent Application No. 2025104579030, filed on April 11, 2025. This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to a morphinan compound, its preparation method, its composition and application. BACKGROUND

[0003] Opioid receptors are widely distributed in the nervous system and are involved in various pathophysiological processes such as pain, inflammation, and itching through G protein coupling mechanisms. There are mainly three types of opioid receptors: mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR). The special distribution of kappa opioid receptor and endorphin in the nervous system, especially in the spinal cord, suggests that kappa receptor is involved in the regulation of pain sensation (see Anatomy of CNS opioid redeptors, 2004: 9(1): 24-9). Kappa opioid agonists have analgesic effects, lower addiction, and do not cause constipation and respiratory depression.

[0004] Eptazocine is also a selective KOR agonist with strong analgesic effect and lower dependence, drowsiness, and respiratory depression. Difelikefalin is a selective KOR agonist that acts on the peripheral nervous system and certain immune cells in the human body. The FDA has approved the drug for the treatment of moderate to severe itching associated with chronic kidney disease in adults receiving hemodialysis in the United States. It also shows certain long-acting analgesic activity in clinical trials.

[0005] A class of morphinan compounds and their use as kappa receptor agonists are disclosed in patent application PCT / US2020 / 025717. However, there is still a need to continue to develop compounds with high binding affinity to kappa receptors, good agonistic activity, and good analgesic activity to achieve better therapeutic effects to meet market demand. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the defect of single kind of kappa receptor agonist in the prior art. Therefore, a morphinan compound, a preparation method thereof, a composition thereof and application thereof are provided. The morphinan compound of the present application has one or more of the following effect advantages: (1) high binding affinity to opioid receptors; (2) obvious agonistic effect on KOR and MOR; (3) good selectivity for kappa receptors; (4) good treatment effect on inflammatory pain (for example, fast onset time or obvious pain relief effect).

[0007] The present application solves the above technical problem by the following technical scheme.

[0008] The present application provides a compound I or a pharmaceutically acceptable salt thereof:

[0009] wherein,

[0010] n is 1, 2 or 3;

[0011] R 1 is halogen or C1-C6 alkyl substituted with one or more halogens;

[0012] R 2 is hydroxyl, C1-C6 alkyl or -O-C1-C6 alkyl;

[0013] m is 0, 1 or 2;

[0014] each R 3 is independently hydroxyl, C1-C6 alkyl or -O-C1-C6 alkyl;

[0015] R 4 is hydrogen, halogen, hydroxyl, C1-C6 alkyl or -O-C1-C6 alkyl;

[0016] R 5 is hydroxyl, C1-C6 alkyl, -O-C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 5-1 ;

[0017] R 5-1 is C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with one or more hydroxyl groups;

[0018] p is 0, 1, 2 or 3;

[0019] each R 6 is independently hydroxyl, cyano, -C(=O)NH2, halogen, amino, nitro, thiol, C1-C6 alkyl, -O-C1-C6 alkyl or -O-C6-C 10 aryl.

[0020] In some embodiments, R1 In some embodiments, the halogen is fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0021] In some embodiments, R 1 In some embodiments, the C1-C6alkyl of the C1-C6alkyl substituted with one or more halogens is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl.

[0022] In some embodiments, the halogen of the C1-C6alkyl substituted with one or more halogens is fluorine, chlorine, bromine, or iodine; preferably fluorine.

[0023] In some embodiments, the C1-C6alkyl substituted with one or more halogens is trifluoromethyl.

[0024] In some embodiments, R 2 In some embodiments, the C1-C6alkyl of the C1-C6alkyl and -O-C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl.

[0025] In some embodiments, R 3 In some embodiments, the C1-C6alkyl of the C1-C6alkyl and -O-C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl.

[0026] In some embodiments, R 4 In some embodiments, the C1-C6alkyl of the C1-C6alkyl and -O-C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl.

[0027] In some embodiments, R 4 In some embodiments, the halogen is fluorine, chlorine, bromine, or iodine.

[0028] In some embodiments, R 5 In some embodiments, the C1-C6alkyl of the C1-C6alkyl, -O-C1-C6alkyl, and C1-C6alkyl substituted with one or more R 5-1 In some embodiments, the C1-C6alkyl of the C1-C6alkyl, -O-C1-C6alkyl, and C1-C6alkyl substituted with one or more R

[0029] In some embodiments, R 5-1 In some embodiments, the C3-C6cycloalkyl of the C3-C6cycloalkyl and C3-C6cycloalkyl substituted with one or more hydroxyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0030] In some embodiments, R 6 each of said C1-C6alkyl and C6-C10aryl is independently phenyl or naphthyl.

[0031] In some embodiments, R 6 each of said C1-C6alkyl and C6-C10aryl is independently phenyl or naphthyl. 10 each of said C1-C6alkyl and C6-C10aryl is independently phenyl or naphthyl. 10 each of said C1-C6alkyl and C6-C10aryl is independently phenyl or naphthyl.

[0032] In some embodiments, n is 1 or 2.

[0033] In some embodiments, R 1 is halogen.

[0034] In some embodiments, R 1 is located ortho to O in the furan ring.

[0035] In some embodiments, R 2 is C1-C6alkyl.

[0036] In some embodiments, m is 0.

[0037] In some embodiments, R 4 is hydroxyl.

[0038] In some embodiments, R 5 is C1-C6alkyl substituted with one or more R 5-1 .

[0039] In some embodiments, R 5-1 is C3-C6cycloalkyl.

[0040] In some embodiments, p is 1.

[0041] In some embodiments, R 6 is hydroxyl.

[0042] In some embodiments, R 1 is chloro.

[0043] In some embodiments, R 2 is methyl.

[0044] In some embodiments, R 5 is

[0045] In some embodiments, the compound I is compound I-1 or compound I-2:

[0046] wherein n, R1 , R 2 , R 4 , R 5 and R 6 are as defined above;

[0047] Preferably,

[0048] n is 1 or 2;

[0049] R 1 is halogen;

[0050] R 1 is located at ortho position of O in furan ring.

[0051] In some embodiments, the compound I is any one of the following compounds:

[0052] The present application provides a preparation method of the above compound I, comprising the following steps: performing an amide condensation reaction as shown below on compound II and compound III in the presence of a base and a condensing agent in a solvent to obtain compound I;

[0053] wherein n, R 1 , R 2 , m, R 3 , R 4 , R 5 , p and R 6 are as defined in any one of the preceding embodiments.

[0054] In some embodiments, the solvent is a conventional solvent for performing such an amide condensation reaction in the art, preferably an amide solvent, and more preferably N,N-dimethylformamide (DMF).

[0055] In some embodiments, the molar volume ratio of the compound II to the solvent can be 0.1-0.2 mol / L; preferably 0.14 mol / L.

[0056] In some embodiments, the base is a conventional base for performing such an amide condensation reaction in the art, preferably an organic base, and more preferably triethylamine.

[0057] In some embodiments, the molar ratio of the compound II to the triethylamine can be 1:(2-5); preferably 1:3.

[0058] In some embodiments, the condensing agent is a conventional condensing agent for performing such an amide condensation reaction in the art, preferably N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU).

[0059] In some embodiments, the molar ratio of the compound II to the condensing agent can be 1 : (0.9-1.3); preferably 1 : 1.1.

[0060] In some embodiments, the molar ratio of the compound II to the compound III can be 1 : (0.9-1.3); preferably 1 : 1.1.

[0061] In some embodiments, the reaction temperature of the amide condensation reaction can be conventional in the art, preferably room temperature, for example 15-35 °C; preferably 20-25 °C.

[0062] In some embodiments, the reaction time of the amide condensation reaction is related to the reaction scale. Generally, the disappearance of raw materials or no longer increase of the product is used as the reaction endpoint.

[0063] In some embodiments, the amide condensation reaction further comprises the following post-treatment steps: after the reaction is completed, washing, drying, column chromatography to obtain the compound I.

[0064] The present application provides a compound III':

[0065] wherein n and R 1 are as defined above;

[0066] R 7 is OH or C1-C6 alkyl.

[0067] The present application provides a compound III':

[0068] wherein n and R 1 are as defined above;

[0069] R 7 is OH, C1-C6 alkyl or -O-C1-C6 alkyl.

[0070] In some embodiments, the compound III' is any one of the following compounds:

[0071] The present application provides a pharmaceutical composition comprising:

[0072] (1) the compound I or a pharmaceutically acceptable salt thereof as described above, and

[0073] (2) a pharmaceutically acceptable excipient.

[0074] The present application provides the use of the compound I or a pharmaceutically acceptable salt thereof as described above, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a disease or a disorder.

[0075] In some embodiments, the disease or condition is pain or itch; preferably the pain is postoperative pain, cancer-induced pain, neuropathic pain, inflammatory pain (e.g. osteoarthritis pain) or traumatic pain; preferably the itch is inflammatory itch, uremic itch, cholestatic itch, diabetic itch, chronic kidney disease-associated itch.

[0076] The present application provides use of Compound I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a medicament for treating a disease or condition associated with kappa receptors.

[0077] In some embodiments, the disease or condition is pain or itch; preferably the pain and itch are as described above.

[0078] The present application provides use of Compound I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a kappa receptor agonist.

[0079] In some embodiments, the kappa receptor agonist can be used in vivo in a mammalian organism; it can also be used in vitro, mainly as a standard or control sample for comparison, or in a kit according to the methods of the art, for rapid detection of the effect of agonizing the kappa receptor.

[0080] Terminology

[0081] In the present application, the term "pharmaceutically acceptable salt" refers to a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compound with a sufficient amount of the desired pharmaceutically acceptable base in a suitable inert solvent. Where the compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compound with a sufficient amount of the desired pharmaceutically acceptable acid in a suitable inert solvent. See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0082] In the present application, the term "pharmaceutically acceptable excipient" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, which is generally divided into two categories of excipients and additional agents. For details, see the People's Republic of China Pharmacopoeia (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0083] In the present application, the structure fragment in refers to the structure fragment connected to the rest of the molecule through the bond. For example, refers to cyclopropyl.

[0084] In the present application, the "-" at the end of the group refers to the group connected to the rest of the molecule through the site. For example, -OH refers to hydroxyl.

[0085] In the present application, the term "one or more" refers to 1, 2, 3, 4 or 5, for example 1, 2 or 3.

[0086] In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0087] In the present application, the term "alkyl" refers to a straight-chain or branched-chain, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0088] In the present application, the term "alkoxy" refers to a group R Y -O-, R Y The definition of the term "alkyl" applies. Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0089] In the present application, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to: , and the like.

[0090] In the present application, the term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C6-C 10 ), which is monocyclic or polycyclic (e.g., 2 or 3), and when polycyclic, shares two atoms and one bond between the monocyclic rings, and each ring has aromaticity. The aryl group is connected to the rest of the molecule through the ring with aromaticity. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0091] The above-mentioned preferred conditions can be combined arbitrarily without departing from the common knowledge in the art, thereby obtaining preferred examples of the present application.

[0092] The reagents and raw materials used in the present application are commercially available.

[0093] The positive progress effect of the present application is that the morphinan compound has one or more of the following effect advantages: (1) high binding affinity to opioid receptors; (2) significant agonistic effect on KOR and MOR; (3) good selectivity for kappa receptors; (4) good therapeutic effect on inflammatory pain (e.g. fast onset of action or significant pain relief); (5) can be used for preparing a drug for relieving or treating pain, thereby providing a new strategy for the research and development of analgesic drugs. DETAILED DESCRIPTION

[0094] The experimental methods in the following examples are conventional methods unless otherwise specified. The reagents used in the experimental methods are commercially available unless otherwise specified.

[0095] 1 H NMR data were collected and recorded by Bruker ultrashield 600 NMR spectrometer at 600 MHz, using DMSO-d6 as solvent, and TMS (δ = 0) as internal standard to report the chemical shift δ value (ppm). Mass spectrometry was collected and recorded by Waters ACQUITY liquid chromatograph-mass spectrometer system. Column: ACQUITY UPLC BEH C8, 50 mm x 2.1 mm, 1.7 μm (20180306-C8-17); mobile phase A: 0.1% formic acid / water; mobile phase B: 0.1% formic acid / acetonitrile; detector wavelength: UV-210 nm + full wavelength (190 nm-400 nm); QDa: cone hole voltage: positive scan 15 volts, negative scan 15 volts; capillary voltage: positive 0.8 kilovolts, negative 0.8 kilovolts;

[0096] Elution program:

[0097] Synthesis of Example 1 T01-5

[0098] In a single-neck flask, 3-furfurylcarboxaldehyde (1.0 eq, 30.0 g), pyridine 15 mL and malonic acid (1.0 eq, 32.5 g) were added in turn, stirred and dissolved, equipped with a reflux condenser, heated at 95°C oil bath for 2 h. TLC monitoring showed that the reaction was complete. After concentration, column chromatography gave 43.5 g of yellow oil T01-1. MS m / z = 139.02 [M+H] + .

[0099] T01-1 (1.0 eq, 20.0 g) was weighed, 200 mL of analytical pure ethanol was added, and 47.2 g of trimethylsilyl chloride was added at room temperature while stirring. TLC was used to monitor the completion of the reaction, and the reaction solution was concentrated by evaporation. Column chromatography gave 19.6 g of yellowish oil T01-2. MS m / z = 167.01 [M+H] + .

[0100] T01-2 (1.0 eq, 0.80 g) was weighed, 8 mL of analytical pure DMF was added and stirred to dissolve, and a DMF solution of N-chlorosuccinimide (NCS, 1.1 eq, 0.65 g) was added to the reaction bottle, and the reaction was carried out at 25°C. TLC was used to monitor the completion of the reaction, and purified water was added, followed by extraction with ethyl acetate twice, and the organic phase was washed with saturated sodium bicarbonate solution twice, dried, and rotary evaporated. Column chromatography gave 0.29 g of oil T01-3. MS m / z = 201.07 [M+H] + .

[0101] A three-necked flask was evacuated and protected by nitrogen, 15 ml of anhydrous DMSO was added, sodium hydride (60%, 3.0 eq, 0.43 g) was weighed into the reaction bottle and stirred, and trimethylsulfoxonium iodide (3.0 eq, 3.9 g) was weighed into the reaction bottle and stirred until dissolved. Oil T01-2 (1.0 eq, 1.0 g) was weighed into 10 mL of anhydrous DMSO and stirred to dissolve. After the solids in the first reaction bottle were dissolved, the solution system was added dropwise to the second reaction bottle, and heated in an oil bath at 50°C. Sample LCMS was used to monitor the completion of the reaction, and 25 mL of purified water was added to quench, followed by extraction with ethyl acetate three times. The combined extract was washed with water three times. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to give 0.68 g of yellow transparent oil T01-4. MS m / z = 215.07 [M+H] + .

[0102] 1 H NMR (600 MHz, DMSO-d6) δ 7.60 (t, J = 2.1 Hz, 1H), 6.44 (s, 1H), 2.13 (d, J = 7.2 Hz, 1H), 2.04 - 1.95 (m, 2H), 1.92 (dd, J = 8.8, 5.1 Hz, 1H), 1.22 - 1.20 (m, 3H), 0.86 (dt, J = 8.0, 4.2 Hz, 2H).

[0103] Take T01-4 (1.0 eq, 0.1 g), add ethanol to dissolve and stir, add 1M sodium hydroxide solution to adjust the pH of the solution to 12-13, stir at room temperature in the dark, TLC monitor the reaction complete, with 1M HC1 to adjust to pH = 2-3, ethyl acetate extraction, to get 57 mg white solid T01-5. MS m / z = 185.01 [M-H]-.

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 2.11 - 2.05 (m, 1H), 1.81 - 1.75 (m, 1H), 1.41 - 1.32 (m, 1H), 1.23 (ddd, J = 8.4, 6.3, 4.3 Hz, 1H).

[0105] Example 2 Synthesis of T01-7

[0106] Take naltrexone (1.0 eq, 36.6 g), add 750 mL of toluene and stir to dissolve, add N-methylbenzylamine (1.5 eq, 19.5 g), p-toluenesulfonic acid (0.01 eq, 0.18 g), heat to reflux, react for 3 days, LCMS monitor the reaction complete, reduce pressure to dryness, add 500 mL of ethanol and stir evenly, add sodium cyanoborohydride (1.5 eq, 10.1 g) to the solution and stir at room temperature for 1 day. LCMS monitor the reaction complete, add water and stir at room temperature for 1 day. Filter, filter the filtrate with ethyl acetate three times, combine the organic phase, dry with anhydrous sodium sulfate and rotary evaporate, silica gel column chromatography to get 21.2 g of white solid T01-6. ESI-MS m / z: 447.35 [M+H] + .

[0107] Dissolve T01-6 (1 eq, 0.5 g) in 10 mL of acetic acid, add 12 mg of 10% palladium on carbon, stir under hydrogen atmosphere at 25°C, LCMS monitor the reaction complete. Filter with diatomite, reduce pressure to concentrate the filtrate, add 3.5 mL of water, adjust the pH to 9.5 with ammonia water, extract twice with dichloromethane, combine the organic phase, dry and concentrate to get 0.38 g of yellowish solid T01-7, ESI-MS m / z: 357.27 [M+H].

[0108] Example 3 Synthesis of compound T01

[0109] T01-5 (1.1 eq, 115 mg) was weighed into 4 mL of N,N-dimethylformamide and stirred to dissolve. HATU (1.1 eq, 235 mg), T01-7 (1.0 eq, 200 mg), and triethylamine (3.0 eq, 170 mg) were added in sequence, and the reaction was allowed to proceed at room temperature until completion. Ethyl acetate was added, and the mixture was washed with water. The organic phase was dried and concentrated, and column chromatography was performed to obtain 192 mg of light yellow solid T01, ESI-MS m / z = 525.22 [M+H] + .

[0110] 1 H NMR (600 MHz, DMSO-d6) δ 9.74-9.11 (m, 1H), 7.90-7.32 (m, 1H), 6.77-5.83 (m, 3H), 5.05-4.66 (m, 1H), 4.19-3.60 (m, 2H), 3.39-3.27 (m, 2H), 3.21-2.78 (m, 6H), 2.49-2.34 (m, 2H), 2.30-1.96 (m, 2H), 1.96-1.78 (m, 1H), 1.78-1.69 (m, 2H), 1.51-1.33 (m, 3H), 1.32-1.16 (m, 1H), 1.15-0.97 (m, 2H), 0.71-0.66 (m, 1H), 0.61-0.56 m, 1H), 0.53-0.48 (m, 1H), 0.43-0.39 (m, 1H).

[0111] Synthesis of compound T02 of Example 4

[0112] A three-neck flask was evacuated and purged with nitrogen. 15 mL of anhydrous DMSO was added, and sodium hydride (60%, 3.0 eq, 0.43 g) was added to the flask and stirred to dissolve. Trimethylsulfoxonium iodide (3.0 eq, 3.9 g) was added to the flask and stirred to dissolve. Oil T01-2 (1.0 eq, 1.0 g) was weighed into 10 mL of anhydrous DMSO and stirred to dissolve. After the solid in the first flask was dissolved, the solution was added dropwise to the second flask, and heating was performed at 50°C in an oil bath. The reaction was monitored by LCMS until completion, and 25 mL of purified water was added to quench the reaction. Ethyl acetate was added and extracted three times. The combined extract was washed with water three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 0.68 g of yellow transparent oil T02-1. MS m / z = 181.10 [M+H] + .

[0113] Take oil T02-1 (1.0 eq, 1.0 g), add analytical 8 mL of DMF to dissolve and stir, place in a 0-5 °C constant temperature reaction bath, slowly drop N-chlorosuccinimide (NCS, 2.2 eq, 1.6 g) DMF solution into the reaction bottle, low temperature stirring for 24 h. TLC monitoring reaction complete, add purified water, then add ethyl acetate to extract twice, then wash the organic phase with saturated sodium bicarbonate solution twice, dry, rotary evaporation. Column chromatography to obtain 0.63 g of oil T02-2. MS m / z = 249.02 [M+H] + .

[0114] 1 H NMR (600 MHz, DMSO-d6) δ 6.56 (d, J = 2.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.11 (dddd, J = 8.8, 6.4, 4.2, 1.8 Hz, 1H), 2.00 - 1.94 (m, 1H), 1.20 (td, J = 7.1, 1.8 Hz, 3H), 0.83 (q, J = 8.8, 6.3 Hz, 2H).

[0115] Take T02-2 (1.0 eq, 0.1 g), add ethanol to dissolve and stir, add 1M sodium hydroxide solution to adjust the pH of the solution to 12-13, room temperature, avoid light stirring, TLC monitoring reaction complete, adjust to pH = 2-3 with 1M HCl, ethyl acetate extraction, to obtain 68 mg of white solid T02-3. MS m / z = 219.15 [M-H] - .

[0116] 1 H NMR (600 MHz, DMSO-d6) δ 6.56 (d, J = 2.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.11 (dddd, J = 8.8, 6.4, 4.2, 1.8 Hz, 1H), 2.00 - 1.94 (m, 1H), 1.20 (td, J = 7.1, 1.8 Hz, 3H), 0.83 (q, J = 8.8, 6.3 Hz, 2H).

[0117] Take T02-3 (1.1 eq, 136 mg), add 4 mL of N,N-dimethylformamide to dissolve and stir, add N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (HATU, 1.1 eq, 235 mg), T01-7 (1.0 eq, 200 mg), triethylamine (3.0 eq, 170 mg) in turn, and react at room temperature until complete. Add ethyl acetate, wash with water, dry, column chromatography to obtain 215 mg of light yellow solid T02. MS m / z = 559.45 [M+H]+ .

[0118] 1 H NMR (600 MHz, DMSO-d6) δ 9.59 - 9.09 (m, 1H), 6.74 - 5.90 (m, 4H), 5.03 - 4.74 (m, 1H), 4.17 - 3.59 (m, 2H), 3.35 - 3.26 (m, 2H), 3.22 - 2.81 (m, 6H), 2.67 - 2.51 (m, 1H), 2.47 - 2.36 (m, 1H), 2.33 - 2.00 (m, 2H), 1.97 - 1.65 (m, 2H), 1.54 - 1.30 (m, 3H), 1.29 - 1.16 (m, 1H), 1.17 - 0.99 (m, 2H), 0.70 - 0.65 (m, 1H), 0.62 - 0.55 (m, 1H), 0.53 - 0.50 (m, 1H), 0.42 - 0.38 (m, 1H).

[0119] Example 6 Opioid receptor binding assay

[0120] Reagents: DOR (PerkinElmer, RBHODM400UA); KOR (PerkinElmer, ES-541-M400UA); MOR (PerkinElmer, ES-542-M400UA); [ 3 H]DADLE (PerkinElmer, NET1130); [ 3 H]U-69,593 (PerkinElmer, NET952); [ 3 H]DAMGO (PerkinElmer, NET902250UC); Naloxone hydrochloride (Sigma, Bachem H-4044); DAMGO (MCE, 78123-71-4); ULTIMA GOLD (PerkinElmer, 77-16061); Polyethylenimine (Sigma, 408727); HEPES (Sigma, 7365-45-9); BSA (Sigma, 9048-46-8); Tris-base (Sigma, 77-86-1).

[0121] Membrane stock: 50mM Hepes (pH 7.4) and 10mM MgCl2plus 1mM EDTA for DOR; 50mM Tris (pH 7.4) and 5mM MgCl2for KOR; 50mM HEPES (pH 7.4) and 0.025% BSA for MOR.

[0122] 0.5% polyethylenimine solution: take 0.5 mL polyethylenimine in a flask, add water to constant volume to 100 mL, store at 4°C for standby.

[0123] According to the plate diagram, different concentrations of compounds were transferred to 96-well plates, 100 μL of membrane stock solution and 5 μL of cpds (1% DMSO) were added to each well, and incubated at room temperature with stirring at 500 rpm for 5 min. 300 μL of assay buffer containing opioid receptors was added to each well, and incubated at room temperature with stirring at 500 rpm for 5 min. Then 100 μL of [ 3 H]DADLE (final concentration 0.5 nM) / [ 3 H]U-69,593 (final concentration 1.5 nM) / [ 3 H]DAMGO (final concentration 1.0 nM) was added to each well, and incubated at room temperature with stirring at 500 rpm for 5 min and then at 27°C for 1 h. Then, the Unifilter-96 GF / C filter plate was soaked with 0.5% polyethylenimine solution per well at room temperature for 1 h, and the reaction mixture was filtered through the plate using a collector, and then each plate was washed four times with cold wash buffer (containing 50 mM Tris.HCl, pH 7.4). Then the filter plate was dried at 55°C for 10 min. After drying, 40 μL of ULTIMA GOLD was added to each well, and the radioactivity was counted in a Perkin Elmer MicroBeta2 counter.

[0124] Specific binding was determined by subtracting the binding CPM value in the presence of a 50-100-fold excess of cold ligand. The data were fitted using the nonlinear curve fitting program in Prism using the saturation analysis. The inhibition was calculated using the following equation:

[0125] % inhibition = (1-(assay well- average_LC) / (average_HC- average_LC))*100%

[0126] The binding data were analyzed using GraphPad Prism 5.0, and the IC 50 was generated by nonlinear regression from the dose-response curve. The data were fitted using the model "log(inhibitor) versus response-variable slope". The data are shown in Table 1.

[0127] Table 1 Binding affinity IC 50

[0128] "-" means not determined.

[0129] Conclusion: Compounds T01 and T02 have high binding affinity to opioid receptors and good selectivity.

[0130] Example 7 cAMP assay for agonistic activity of opioid receptors

[0131] When DOR, KOR or MOR binds to agonists, it can modulate the activity of adenylyl cyclase, thus changing the level of intracellular cAMP. Cells stably expressing MOR, KOR or DOR are first stimulated with compounds, and then induced to produce intracellular cAMP with forskolin. Compounds with agonistic activity of opioid receptors will inhibit the effect of forskolin on stimulating cAMP production. The change in intracellular cAMP content can be detected by a cAMP detection kit, which reflects the agonistic effect of the compound on opioid receptors.

[0132] Reagents: fetal bovine serum (AUS Gene X, FBS500-S); DMEM medium (Gibco, 11965-092); F12K medium (Hyclone, SH30526.01); double antibody (Gibco, 15140122); hygromycin B (Invivogen, ant-hg-5); forskolin (Selleck, S2449); 7.5% BSA (Perkin Elmer, CR84-100); cAMP detection kit (Perkin Elmer, TRF0263); IBMX (Sigma, I5879); HEPES buffer (Gibco, 15630080);

[0133] HEK293 cells overexpressing DOR and KOR were cultured in DMEM complete medium containing 10% FBS, 1% double antibody and 200 μg / mL hygromycin B. CHO cells overexpressing MOR were cultured in F12K complete medium containing 10% FBS, 1% double antibody and 200 μg / mL hygromycin B. Cells in the logarithmic growth phase were collected by centrifugation and counted, and 20,000 cells / well were added to a 384-well plate. Different concentrations of test compounds were added to the well plate, and incubated at 37°C for 10 min. Then 2.5 μL of forskolin (final concentration 8 μM) was added, and incubated at 37°C for 30 min. After the reaction was completed, 10 μL of Eu-cAMP tracer working solution and 10 μL of Ulight-anti-cAMP working solution were added to each well, and incubated at room temperature for 1 h in the dark. The 384-well plate was detected on the Envision 2015 multifunctional microplate reader.

[0134] DADLE, DynorphinA1-10 and Endomorphin 1 were used as positive drugs, respectively, and the activation rate (% Activity) under different concentrations was calculated by the following formula.

[0135] Activity = (Signalcmpd - SignalAve_VC) / (SignalAve_PC - SignalAve_VC) x 100.

[0136] The compound effect curve is drawn and the EC 50 value of the compound is calculated by the following formula

[0137] Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC 50 -X) * HillSlope))

[0138] X: compound concentration logarithm; Y: activation rate.

[0139] Table 2 agonist activity EC 50

[0140] "-" means not determined.

[0141] Conclusion: The compound of the present application has obvious agonistic effect on KOR and MOR relative to the positive drug, and the agonistic effect on KOR is equivalent to that of DynorphinA1-10.

[0142] Comparative Example Effect of Comparative Compound 5a on Formalin-induced Inflammatory Pain in Rats

[0143] The preparation method of comparative compound 5a refers to the preparation method described in patent PCT / US2020 / 025717.

[0144] A dilution multiple times of formalin solution is injected subcutaneously into the hind foot of a rat by using a micro-injection needle, so as to produce a sustained nociceptive stimulus, so that the animal has a spontaneous pain behavior response. The pain is divided into two stages: acute phase and chronic phase. In the experiment, the number of foot lifting and foot licking of the rat can be recorded by using an autonomous motion analyzer, so as to judge the degree of pain.

[0145] Experimental materials:

[0146] SD rats, weighing 220-240 g, were purchased from Nanshile Jingda Experimental Animal Co., Ltd., with license number SCXK(Xiang)2019-0004; 0.9% sodium chloride injection was purchased from Shandong Kelun Pharmaceutical Co., Ltd., with batch number C23053303A; DMSO was purchased from Sigma-Aldrich, with batch number 1003544872; formaldehyde was purchased from Sigma, with batch number 252549; an electronic scale was purchased from Shanghai Ranhao Electronic Co., Ltd., with batch number JCS-51002C; an electronic balance was purchased from Ohaus Instruments (Changzhou), with batch number PX124ZH; a self-motion analyzer was purchased from Yichang Renfu Pharmaceutical Co., Ltd., with batch number NA; a vortex mixer was purchased from Shanghai Chitang Electronic Co., Ltd., with batch number XW-80A; T01 and T02 were selected from the compounds obtained in the examples of the present application.

[0147] Experimental preparation:

[0148] After the SD rats were adaptively fed for 2 days, the rats were transferred from the feeding room to the laboratory in the morning every day. A layer of training urine was placed on the training table, and a transparent white cylinder was placed on the training urine. Each rat was weighed and placed in the test transparent white cylinder to adapt to the test environment for about 1 hour. This was done for at least 3 consecutive days.

[0149] Experimental procedure:

[0150] After the rats were adaptively exposed to the experimental environment for 3 consecutive days, the rats weighing 220-240 g were numbered at the base of the tail. Rats that did not meet the weight requirement were continued to be fed until they met the weight requirement. Thirty minutes before the formal test, a metal sheet was attached to the left hind foot of the rat. The rats were placed in a transparent white cylinder to adapt. Fifteen minutes before the test, the test product or control product was administered. Fifteen minutes later, 50 μL of 2% formalin was injected subcutaneously into the dorsal foot of the rat to model the injection (the blank control group was not injected with formalin). Subsequently, the animals were placed in a self-motion analyzer instrument, and the number of times the rat withdrew, lifted, and licked its foot was automatically recorded. The data from 0-60 minutes after injection of formalin was statistically analyzed.

[0151] Detection index:

[0152] After the rat's dorsal foot was injected subcutaneously with 2% formalin, it was placed in a detection box, and the number of movements (the number of times the injected foot was lifted and licked) was recorded and analyzed from 0-60 minutes after injection of the formalin solution, including the early acute phase (phase I: 0-9 minutes) and the late tension phase (phase II: 10-60 minutes).

[0153] Calculate MPE% (Maximum Possible Effect, in percentage)

[0154] Note: ①MPE% of each group was calculated based on the standard of MPE of sham group = 100%, MPE of vehicle group = 0%. ②The number of movements of sham group was subtracted to exclude the influence of background noise on the experiment. ③Sham represents the average value of the sham group; Vehicle-Sham represents the average value of the vehicle group minus the sham group

[0155] Experimental data and processing:

[0156] The results and data of determination and observation were re-entered into the Excel table, and statistical analysis was performed.

[0157] Each index was represented by the mean standard error, and the data of each group was statistically analyzed and plotted by GraphPad prim 8 software. The statistical method was single factor analysis method (One-way ANOVA), and the statistical difference between each group was compared. The t-test was used for comparison between two groups, and p < 0.05 had statistical difference.

[0158] Table 3 Experimental phenomenon record

[0159] Experimental result analysis:

[0160] In the rat formalin model, under the condition of subcutaneous injection of drug (30 μg / kg) 15 min before modeling, the analgesic activity of compound T01 and comparative compound 5a was equivalent; at the same time, compound T02 had obvious analgesic activity tendency to 2% formalin-induced inflammatory pain in mice, and was significantly stronger than comparative compound 5a. The experimental results are shown in Table 4.

[0161] Table 4 Maximum possible analgesic effect graph 0-60 min after modeling

[0162] The above describes specific embodiments of the present application, but those skilled in the art should understand that modifications or improvements can be made on the basis of the present application, for example, the Cl atom on the furan ring in the two molecules of the present application can be replaced by Br, F or other atoms or groups, which is obvious to those skilled in the art. Without departing from the principles and essence of the present application, all belong to the protection scope of the present application.

Claims

1. A compound I or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2 or 3; R 1 halogen or Ci-C6alkyl substituted by one or more halogens; R 2 is hydroxyl, C1-C6alkyl or -O-C1-C6alkyl; m is 0, 1 or 2; each R 3 each independently is hydroxyl, C1-C6alkyl or -O-C1-C6alkyl; R 4 is hydrogen, halogen, hydroxyl, Ci-C6alkyl or -O-Ci-C6alkyl; R 5 is hydroxyl, C1-C6alkyl, -O-C1-C6alkyl, or C1-C6alkyl substituted by one or more R 5-1 substituted C1-C6alkyl; R 5-1 C3-C6-cycloalkyl or C3-C6-cycloalkyl substituted by one or more R-substituents; p is 0, 1, 2 or 3; each R 6 each independently is hydroxyl, cyano, -C(=0)NH2, halogen, amino, nitro, thiol, Ci-C6alkyl, -O-Ci-C6alkyl, or -O-C6-Ci2aryl; 10 aryl.

2. The compound I according to claim 1, wherein, ###0002### or a pharmaceutically acceptable salt thereof. which satisfies one or more of the following conditions: (1) R 1 In particular, the halogen is fluorine, chlorine, bromine or iodine; preferably chlorine. (2) R 1 In the group of "C1-C6 alkyl substituted by one or more halogens", the C1-C6 alkyl group is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl group, preferably a methyl group. (3) R 1 In the C1-C6alkyl substituted with one or more halogens, the halogen is fluorine, chlorine, bromine, or iodine; preferably fluorine; more preferably, the C1-C6alkyl substituted with one or more halogens is trifluoromethyl; (4) R 2 each of the C1-C6 alkyl groups in the C1-C6 alkyl and -O-C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl; (5) R 3 C1-C6 alkyl and -O-C1-C6 alkyl, each independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl; (6) R 4 each of the C1-C6 alkyl groups in the C1-C6 alkyl and -O-C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl; (7) R 4 In some embodiments, the halogen is fluorine, chlorine, bromine, or iodine. (8)R 5 In the C1-C6 alkyl group, the C1-C6 alkyl group in the -O-C1-C6 alkyl group and the C1-C6 alkyl group with one or more R 5-1 The C1-C6 alkyl groups that are substituted are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl; (9) R 5-1 In particular, the C3-C6-cycloalkyl group and the C3-C6-cycloalkyl group substituted by one or more hydroxyl groups in the C3-C6-cycloalkyl group each independently are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl. (10) R 6 In particular, the C1-C6 alkyl and the C1-C6 alkyl of the -O-C1-C6 alkyl are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. (11) R 6 in particular -O-C6-C 10 in particular -O-C6-C 10 in particular -O-C6-C 3. The compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein which satisfies one or more of the following conditions: (1) n is 1 or 2; (2) R 1 is halogen; (3) R 1 ortho to the O in the furan ring; (4) R 2 Ci-C6-alkyl; (5) m is 0; (6) R 4 is hydroxyl; (7) R 5 C1-C6alkyl substituted by one or more R 5-1 C1-C6alkyl substituted by one or more R (8) R 5-1 is C3-C6cycloalkyl; (8) p is 1; and (9) R 6 is hydroxyl.

4. The compound I or a pharmaceutically acceptable salt thereof according to claim 3, wherein which satisfies one or more of the following conditions: (1)R 1 It is chlorine; (2) R 2 is methyl; (3) R 5 To 5. The compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound I is compound I-1 or compound I-2: wherein n, R 1 , R 2 , R 4 , R 5 and R 6 are as defined in claim 1 ; Preferably, n is 1 or 2; R 1 is halogen; R 1 The ortho position to the O in the furan ring.

6. The compound I or a pharmaceutically acceptable salt thereof according to claim 3, wherein The compound I is any one of the following compounds:

7. A process for the preparation of a compound I according to any one of claims 1 to 6, comprising the step of carrying out an amide condensation reaction of compound II and compound III as shown below in the presence of a base and a condensing agent in a solvent to give compound I; wherein, n, R 1 , R 2 , m, R 3 , R 4 , R 5 , p and R 6 are as defined in any one of claims 1-6.

8. The process for the preparation of Compound I according to claim 7, characterized in that, which satisfies one or more of the following conditions: (1) the solvent is an amide solvent, which is preferably N,N-dimethylformamide; (2) the molar volume ratio of the compound II to the solvent is 0.1-0.2 mol / L; preferably 0.14 mol / L; (3) the base is an organic base, which is preferably triethylamine; (4) the molar ratio of the compound II to the triethylamine is 1:(2-5); preferably 1:3; (5) the condensing agent is N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate; (6) the molar ratio of the compound II to the condensing agent is 1:(0.9-1.3); preferably 1:1.1; (7) the molar ratio of the compound II to the compound III is 1:(0.9-1.3); preferably 1:1.1; (8) the reaction temperature of the amide condensation reaction is 15-35°C; more preferably 20-25°C; and (9) the amide condensation reaction further comprises the following post-treatment step: after the reaction is completed, washing, drying, column chromatography to obtain the compound I.

9. A compound III’: wherein n and R 1 as defined in any one of claims 1-6; R 7 is OH, CrC6alkyl or -O-CrC6alkyl; Preferably, The compound III' is any one of the following compounds:

10. A pharmaceutical composition comprising: (1) the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, and (2) a pharmaceutically acceptable excipient.

11. Use of the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating a disease or disorder; the disease or disorder can be pain or itch; the pain is preferably postoperative pain, cancer-induced pain, neuropathic pain, inflammatory pain or traumatic pain; the inflammatory pain is more preferably osteoarthritis pain; the itch is preferably inflammatory itch, uremic itch, cholestatic itch, diabetic itch, chronic kidney disease-related itch.

12. Use of the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating a disease or disorder associated with kappa receptor; the disease or disorder is pain or itch; the pain and itch are as described in claim 11.

13. Use of the compound I or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or the pharmaceutical composition according to claim 10, in the preparation of a kappa receptor agonist.

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