A low molecular weight polyethylene glycol compound of hydromorphone and dihydromorphine drugs, its preparation method and application

Abstract

This invention provides a method for preparing hydromorphone and dihydromorphine-like drugs via polyethylene glycol modification and their applications, which have the compound structure shown in general formula (I). The compounds provided by this invention reduce lipid solubility through polyethylene glycol modification, thereby slowing the rate of crossing the blood-brain barrier, slowing the release rate, prolonging the duration of action, and reducing the possibility of abuse. At high doses, they exhibit analgesic effects comparable to opioids, without producing side effects such as respiratory depression or addiction, demonstrating good safety.

Description

Technical Field

[0001] This application relates to, but is not limited to, the pharmaceutical field, specifically to a low molecular weight polyethylene glycol compound of hydromorphone and dihydromorphine drugs, its preparation method, and its application. Background Technology

[0002] Opioids have excellent analgesic effects and are widely used in clinical practice. However, while providing pain relief, opioids also pose problems such as respiratory depression, drug addiction, and potential abuse. Currently, there are no abuse prevention agents containing hydromorphone available globally. Summary of the Invention

[0003] This application provides low molecular weight polyethylene glycol-modified hydromorphone and dihydromorphine-like drugs, which reduce lipid solubility to slow down the rate of crossing the blood-brain barrier. The release rate is slower than that of hydromorphone, and there are no obvious opioid side effects at high doses. It has a capping effect, prolonging the duration of action while exerting analgesic efficacy, and avoiding a series of side effects to a certain extent.

[0004] This application provides, in one aspect, a low-molecular-weight polyethylene glycol-modified hydromorphone and dihydromorphine-like drugs, such as compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0005]

[0006] in:

[0007] R1 is -OH or -[OCH2CH2] m OMe or -[OCH2CH2] m OBn, and It is a single bond; or R1 is 0, and It is a double bond;

[0008] R2 is -OH, -Cl, -OMe, or -OBn;

[0009] m is selected from integers from 1 to 10;

[0010] n can be 1, 3, 4, 5, 6, 7, 8, 9, or 10.

[0011] In the embodiments of this application, Me is methyl; Bn is benzyl.

[0012] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein m is 3.

[0013] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein n is 3, 4 or 6.

[0014] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein m is 3; n is 3, 4 or 6.

[0015] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein R1 is -OH, -[OCH2CH2]3OMe or -[OCH2CH2]3OBn, and It is a single bond; and it has an α configuration.

[0016] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein R1 is -OH, -[OCH2CH2]3OMe or -[OCH2CH2]3OBn, and It is a single bond; and it has a β configuration.

[0017] In some embodiments of this application, the compound represented by formula (Ⅰ) provided in this application or a pharmaceutically acceptable salt thereof is provided, wherein R1 is -OH, -[OCH2CH2]3OMe or -[OCH2CH2]3OBn, and It is a single bond; and it is a mixture of α and β configurations.

[0018] In some embodiments of this application, the compound represented by formula (Ⅰ) or a pharmaceutically acceptable salt thereof is provided in this application, wherein R1 is O, and It is a double bond.

[0019] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OH, n is 3, and has the following structure:

[0020]

[0021] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OH, n is 3, and has the following structure:

[0022]

[0023] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OH, n is 4, and has the following structure:

[0024]

[0025] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OH, n is 4, and has the following structure:

[0026]

[0027] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -Cl, n is 4, and has the following structure:

[0028]

[0029] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -Cl, n is 4, and has the following structure:

[0030]

[0031] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OMe, n is 3, and has the following structure:

[0032]

[0033] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OMe, n is 3, and has the following structure:

[0034]

[0035] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is O and It is a double bond, R2 is -OH, n is 3, and has the following structure:

[0036]

[0037] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -[OCH2CH2]mOMe and It is a single bond, R2 is -OMe, m is 3, n is 3, and has the following structure:

[0038]

[0039] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -[OCH2CH2]mOMe and It is a single bond, R2 is -OMe, m is 3, n is 3, and has the following structure:

[0040]

[0041] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is O and It is a double bond, R2 is -OH, n is 4, and has the following structure:

[0042]

[0043] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is O and It is a double bond, R2 is -Cl, n is 4, and has the following structure:

[0044]

[0045] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is O and It is a double bond, R2 is -OMe, n is 3, and has the following structure:

[0046]

[0047] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OBn, n is 3, and has the following structure:

[0048]

[0049] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -OH and It is a single bond, R2 is -OBn, n is 3, and has the following structure:

[0050]

[0051] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -[OCH2CH2]mOBn and It is a single bond, R2 is -OBn, m is 3, n is 3, and has the following structure:

[0052]

[0053] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is -[OCH2CH2]mOBn and It is a single bond, R2 is -OBn, m is 3, n is 3, and has the following structure:

[0054]

[0055] Preferably, in one specific embodiment of this application, R1 in the compound of formula (I) is O and It is a double bond, R2 is -OH, n is 6, and has the following structure:

[0056]

[0057] In embodiments of this application, a "pharmaceutically acceptable salt" of the compound refers to those salts that retain the bioavailability and properties of the free base of the compound and are obtained by reaction with a non-toxic inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid; and such organic acid as formic acid, acetic acid, butyric acid, succinic acid, citric acid, fumaric acid, maleic acid, etc.

[0058] Secondly, this application also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the preparation method comprising the following steps:

[0059] The substitution reaction between compound (Π) and compound (III) yields the compound shown in formula (I):

[0060]

[0061] In this compound, R1 in formula (Π) is defined the same as R1 in formula (I); R2 in formula (III) is defined the same as R2 in formula (I), and X is a leaving group such as chlorine, bromine, or sulfonate group (methanesulfonate or p-toluenesulfonate).

[0062] Thirdly, this application provides a pharmaceutical composition comprising: an effective dose of a compound of formula (I) of this application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0063] Such pharmaceutically acceptable excipients may be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), excipients, diluents (e.g., solid diluents such as fillers or fillers; and liquid diluents such as solvents and cosolvents), granulators, binders, flow aids, coating agents, controlled-release agents (e.g., delayed-release polymers or waxes), adhesives, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tension modifiers, thickeners, flavor enhancers, sweeteners, pigments, plasticizers, taste maskers, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0064] Pharmaceutical compositions containing compounds having chemical formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, (18th Edition, 1990), Mack Publishing Company, Easton, PA, USA.

[0065] The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otopathic, rectal, vaginal, or transdermal administration.

[0066] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, or patches such as buccal patches.

[0067] Fourthly, this application provides the use of the compound described in (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of analgesic drugs.

[0068] Fifthly, this application provides the compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicine or for analgesic purposes.

[0069] In a sixth aspect, this application provides a method of analgesia, comprising administering to a subject in need a therapeutically effective amount of the compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0070] The beneficial effects of this invention are: polyethylene glycol-modified hydromorphone and dihydromorphine-like drugs, while exerting analgesic effects, prolong the duration of action, thereby avoiding a series of side effects to a certain extent and increasing safety.

[0071] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the solutions described in the description and the accompanying drawings. Attached Figure Description

[0072] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0073] Figure 1 The maximum probable analgesic effect of compound 1 of this invention compared with the solvent group, blank group, and positive control group is given, and the data are expressed as mean ± standard error. One-way ANOVA with Dunnett's multiple comparison test was used, and *p<0.05, **p<0.01, ***p<0.001, compared with the solvent group. Detailed Implementation

[0074] To make the objectives, technical solutions, and advantages of this application clearer, the general method for increasing the safety of hydromorphone and dihydromorphine-like drugs provided by this invention will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other. The general formula compounds of this invention, their preparation methods, and applications will be further described in detail below with reference to specific embodiments. The following embodiments are merely illustrative and explanatory of this invention and should not be construed as limiting the scope of protection of this invention. All technologies implemented based on the above content of this invention are covered within the scope of protection intended by this invention. The raw materials and reagents provided by this invention are commercially available.

[0075] Example 1:

[0076] (4R,4aR,7S,7aR,12bS)-9-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7-ol

[0077]

[0078] Compound a (200 mg, 0.70 mmol) and NaOH (180 mg, 4.50 mmol) were dissolved in 20 mL of purified water and stirred for 10 min. Compound 1p (360 mg, 2.13 mmol) was weighed and added to the solution, and the mixture was heated to 110 °C and refluxed for 24 h. LC-MS showed no residue of the starting material and the presence of the target molecular weight. Heating was stopped, and the mixture was allowed to cool to room temperature. The mixture was extracted twice with purified water and dichloromethane. The organic phases were combined, washed twice with water, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 300 mg of an oily substance. Compound 1 (30 mg, yield 10.27%, UPLC > 95%) was prepared, purified, and lyophilized. MS m / z (ESI): 420.39 [M+H] + .

[0079] 1 H NMR (500MHz, CDCl3) δ12.64(s,1H),6.63(d,J=8.1Hz,1H),6.54(d,J=8.2Hz, 1H),4.54(s,1H),4.29(s,1H),4.17(s,1H),4.06(s,1H),3.69(d,J=17.3Hz,2 H),3.52(d,J=16.3Hz,8H),3.40(s,4H),3.02-2.82(m,2H),2.74(s,3H),2.1 3(t,J=11.2Hz,1H),1.76-1.62(m,2H),1.48-1.39(m,2H),1.19-1.12(m,1H).

[0080] Example 2:

[0081] (4R,4aR,7S,7aR,12bS)-9-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7-ol

[0082]

[0083] Take a (200 mg, 0.70 mmol) and NaOH (110 mg, 2.75 mmol), dissolve them in 50 mL of purified water, stir for 10 min, weigh 3p (500 mg, 2.16 mmol) and add it to the mixture, then heat to 110 °C and reflux for 24 h. LC-MS showed that there was no residue of the starting material and the target molecule was formed. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 280 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 2 (26 mg, yield 8.06%, UPLC > 95%). MS m / z (ESI): 464.31 [M+H]+.

[0084] 1 H NMR (500MHz, CDCl3) δ12.72(s,1H),6.79(d,J=8.1Hz,1H),6.66(d,J=8.2Hz, 1H),4.62(s,1H),4.29(s,1H),4.21(s,1H),4.13(s,1H),3.80(d,J=17.3Hz,2 H),3.66(d,J=16.3Hz,12H),3.57(s,4H),3.04-2.92(m,2H),2.82(s,3H),2.2 6(t,J=11.2Hz,1H),1.84-1.74(m,2H),1.52-1.43(m,2H),1.26-1.19(m,1H).

[0085] 13 C NMR (126MHz, CDCl3) δ147.16,141.24,128.72,122.44,119.24,116.45,89.66,72.47,70.30,70.21, 70.15,69.86,69.61,68.74,65.79,61.36,47.87,41.05,39.99,38.98,34.33,27.46,21.11,17.73.

[0086] Example 3:

[0087] (4R,4aR,7S,7aR,12bS)-9-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7-ol

[0088]

[0089] Take a (200 mg, 0.70 mmol) and NaOH (110 mg, 2.75 mmol), dissolve them in 50 mL of purified water, stir for 10 min, weigh 3p (500 mg, 2.16 mmol) and add it to the mixture, then heat to 110 °C and reflux for 24 h. LC-MS showed that the starting material was complete and reached the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 280 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 3 (56 mg, yield 16.69%, UPLC > 95%). MS m / z (ESI): 482.32 [M+H]+.

[0090] 1H NMR (500MHz, CDCl3) δ12.71(s,1H),6.78(d,J=8.2Hz,1H),6.66(d,J=8.2Hz,1H),4.60(d,J= 5.4Hz,1H),4.34-4.30(m,1H),4.20-4.16(m,1H),4.13(s,1H),3.71(d,J=5.9Hz,2H),3.67-3 .62(m,10H),3.60(t,J=5.8Hz,2H),3.46(s,2H),3.04-2.91(m,2H),2.81(s,3H),2.72(d,J=1 0.7Hz,2H),2.32-2.26(m,1H),1.81(t,J=16.1Hz,2H),1.52-1.42(m,2H),1.27-1.20(m,1H).

[0091] Example 4:

[0092] (4R,4aR,7S,7aR,12bS)-9-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7-ol

[0093]

[0094] Take 1.0 g (6.09 mmol) of 4p and pyridine (0.72 g, 9.10 mmol), dilute with 5 mL of dichloromethane, and stir at room temperature. Weigh 1.09 g (9.16 mmol) of thionyl chloride, dilute with 5 mL of dichloromethane, and slowly add dropwise at room temperature. After the addition is complete, heat to 40 °C and reflux for 24 h. LC-MS monitoring shows that there is almost no reactant remaining, and the target molecule has been formed. Stop heating, add a solution prepared with concentrated hydrochloric acid (0.9 g, 9.16 mmol) and 40 mL of purified water, and stir for 10 min. Extract twice with 20 mL of dichloromethane, combine the organic phases, wash twice with 20 mL of purified water, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 0.9 g of yellow oily substance 4.

[0095] Take a (200 mg, 0.70 mmol) and NaOH (110 mg, 2.75 mmol), dissolve them in 20 mL of purified water, stir for 10 min, weigh 4 (500 mg, 2.74 mmol) and add it to the mixture, heat to 110 °C, and reflux for 24 h. LC-MS showed that there was no residue of the starting material and the target molecule was formed. Stop heating, let cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 380 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 4 (100 mg, yield 33.14%, UPLC > 95%). MS m / z (ESI): 434.38 [M+H]+.

[0096] 1H NMR (500MHz, CDCl3) δ12.38(s,1H),6.78(d,J=8.0Hz,1H),6.64(d,J=8.2Hz,1H),4.60(d,J=4.8Hz,1H ),4.32(d,J=4.8Hz,1H),4.19–4.16(m,1H),4.12(s,1H),3.79(d,J=15.2Hz,2H),3.72–3.67(m,2H),3 .65(d,J=4.2Hz,2H),3.63–3.59(m,2H),3.54–3.50(m,4H),3.35(s,3H),2.98(m,2H),2.82(s,3H),2. 71(d,J=9.8Hz,2H),2.29(t,J=11.8Hz,1H),1.86–1.73(m,2H),1.52–1.42(m,2H),1.27-1.20(m,1H).

[0097] Example 5:

[0098] (4R,4aR,7aR,12bS)-9-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)one

[0099]

[0100] Take b (130 mg, 0.46 mmol) and NaOH (73 mg, 1.83 mmol), add 20 mL of purified water to dissolve, stir for 10 min, weigh 6p (300 mg, 1.78 mmol) and add it to the mixture, heat to 110 °C, and reflux for 24 h. LC-MS showed that there was no residue of the starting material and the target molecule was formed. Stop heating, let cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 220 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 5 (85 mg, yield 44.69%, UPLC > 95%). MS m / z (ESI): 418.34 [M+H]+.

[0101] 1H NMR (500MHz, CDCl3) δ13.05(s,1H),6.84(d,J=8.0Hz,1H),6.71(d,J=8.2Hz,1H),4.77(s,1H),4.37(s,2H),3.93(s,1H),3.86(t,J=8.2Hz,2H),3. 73-3.70(m,5H),3.47(s,5H),3.15-3.06(m,2H),2.88(s,3H),2.67(t,J= 10.6Hz,1H),2.52-2.41(m,3H),1.98(t,J=14.1Hz,2H),1.26-1.20(m,1H)

[0102] Example 6:

[0103] (4R,4aR,7S,7aR,12bS)-7,9-bis(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline

[0104]

[0105] Take 15p (1.0 g, 6.09 mmol) and pyridine (0.72 g, 9.10 mmol), dilute with 5 mL of dichloromethane, and stir at room temperature. Weigh 1.09 g (9.16 mmol) of thionyl chloride, dilute with 5 mL of dichloromethane, and slowly add it dropwise at room temperature. After the addition is complete, heat to 40 °C and reflux for 24 h. LC-MS monitoring shows that there is basically no starting material remaining, and heating is stopped. Add a solution prepared with concentrated hydrochloric acid (0.9 g, 9.16 mmol) and 40 mL of purified water, and stir for 10 min. Extract twice with 20 mL of dichloromethane, combine the organic phases, wash twice with 20 mL of purified water, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 0.9 g of yellow oily substance 15.

[0106] Dihydromorphine (200 mg, 0.70 mmol) and NaOH (110 mg, 2.75 mmol) were dissolved in 20 mL of purified water and stirred for 10 min. 15 (500 mg, 2.74 mmol) was weighed and added to the solution, and the mixture was heated to 110 °C and refluxed for 24 h. LC-MS showed no residue of the starting material and the presence of the target molecular weight. Heating was stopped, and the mixture was allowed to cool to room temperature. The mixture was extracted twice with purified water and dichloromethane. The organic phases were combined, washed twice with water, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 380 mg of an oily substance. The solution was prepared, purified, and lyophilized to give compound 6 (11 mg, yield 2.73%, UPLC > 95%). MS m / z (ESI): 580.36 [M+H]+.

[0107] 1 H NMR(500MHz, CDCl3) δ6.82(d,J=8.2Hz,1H),6.68(d,J=8.2Hz,1H),4.34(s, 2H),3.91(s,1H),3.83(t,J=4.8Hz,4H),3.72-3.68(m,4H),3.66-3.62(m,8H ),3.53(d,J=5.0Hz,4H),3.31(s,6H),3.14-3.00(m,4H),2.80(s,3H),2.63 -2.56(m,4H),2.50-2.36(m,4H),1.94(t,J=13.3Hz,2H),1.24-1.15(m,1H).

[0108] Example 7:

[0109] (4R,4aR,7aR,12bS)-9-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0110]

[0111] Take b (300 mg, 1.05 mmol) and NaOH (173 mg, 4.33 mmol), dissolve in 50 mL of purified water, stir for 10 min, weigh 3p (600 mg, 2.60 mmol) and add to it, heat to 110 °C, and reflux for 24 h. LC-MS showed no residue of the starting material and the formation of the target molecule. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 490 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 7 (42 mg, yield 8.65%, UPLC > 95%). MS m / z (ESI): 462.36 [M+H]+.

[0112] 1 H NMR (500MHz, CDCl3) δ13.14(s,1H),6.84(d,J=8.0Hz,1H),6.71(d,J=8.0Hz ,1H),4.77(s,1H),4.35(s,2H),3.84(s,2H),3.71(s,4H),3.66(s,6H),3.5 9(s,2H),3.37(d,J=8.9Hz,1H),3.22-3.14(m,3H),3.07(d,J=19.5Hz,1H), 2.86(s,3H),2.65-2.40(m,4H),1.97-1.95(m,2H),1.22(d,J=12.4Hz,1H).

[0113] 13 C NMR (126MHz, CDCl3) δ205.85,145.65,142.69,125.62,122.03,120.48,118.82,90.31,72.41,70.48,70 .42,70.37,70.08,69.79,69.60,61.45,60.54,47.56,44.92,41.05,39.19,38.86,32.68,24.69,20.89.

[0114] Example 8:

[0115] (4R,4aR,7aR,12bS)-9-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0116]

[0117] Take b (300 mg, 1.05 mmol) and NaOH (173 mg, 4.33 mmol), dissolve in 50 mL of purified water, stir for 10 min, weigh 3p (600 mg, 2.60 mmol) and add to it, heat to 110 °C, and reflux for 24 h. LC-MS showed no residue of the starting material and the presence of the target molecule. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 490 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 8 (17 mg, yield 3.37%, UPLC > 95%). MS m / z (ESI): 480.27 [M+H]+.

[0118] 1 H NMR (500MHz, CDCl3) δ13.22(s,1H),6.90(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.41(s,2H),3.90(s,2H),3.75(s,4H),3.70(s,6H),3.62(s,2 H),3.40(d,J=8.9Hz,1H),3.25-3.18(m,3H),3.12(d,J=19.5Hz,1H),2. 91(s,3H),2.70-2.35(m,4H),2.03-1.99(m,2H),1.30(d,J=12.4Hz,1H).

[0119] Example 9:

[0120] (4R,4aR,7aR,12bS)-9-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0121]

[0122] Take 15p (1.0 g, 6.09 mmol) and pyridine (0.72 g, 9.10 mmol), dilute with 5 mL of dichloromethane, and stir at room temperature. Weigh 1.09 g, 9.16 mmol of thionyl chloride, dilute with 5 mL of dichloromethane, and slowly add dropwise at room temperature. After the addition is complete, heat to 40 °C and reflux for 24 h. LC-MS monitoring shows that there is almost no reactant remaining, and the target molecule has been formed. Stop heating, add a solution prepared with concentrated hydrochloric acid (0.9 g, 9.16 mmol) and 40 mL of purified water, and stir for 10 min. Extract twice with 20 mL of dichloromethane, combine the organic phases, wash twice with 20 mL of purified water, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 0.9 g of yellow oily substance 15.

[0123] Take b (300 mg, 1.05 mmol) and NaOH (173 mg, 4.33 mmol), dissolve in 50 mL of purified water, stir for 10 min, weigh 15 (400 mg, 2.19 mmol) and add it to the mixture, then heat to 110 °C and reflux for 24 h. LC-MS showed no residue of the starting material and the formation of the target molecule. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 290 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 9 (110 mg, yield 24.25%, UPLC > 95%). MS m / z (ESI): 480.27 [M+H]+.

[0124] 1 H NMR(500MHz, CDCl3) δ6.83(d,J=8.2Hz,1H),6.69(d,J=8.2Hz,1H),4.74(s,1H) ,4.36(s,2H),3.91(s,1H),3.84(t,J=4.8Hz,2H),3.73-3.71(m,2H),3.67-3.6 3(m,4H),3.55(d,J=5.0Hz,2H),3.36(s,3H),3.16-3.05(m,2H),2.86(s,3H),2 .68-2.61(m,2H),2.53-2.41(m,4H),1.97(t,J=13.3Hz,2H),1.27-1.19(m,1H).

[0125] 13C NMR (126MHz, CDCl3) δ205.48,145.67,142.86,125.58,121.81,120.40,118.95,90.22,71.87 ,70.63,70.44,69.84,69.64,60.54,58.96,47.56,44.89,39.19,38.89,32.72,24.69,20.91.

[0126] Example 10:

[0127] (4R,4aR,7S,7aR,12bS)-9-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7-ol

[0128]

[0129] Weigh 7p (500 mg, 2.08 mmol) and thionyl chloride (0.60 mL, 8.32 mmol), heat to 80 °C, and reflux for 5 h. LC-MS monitoring showed that almost no starting material remained, indicating the formation of the target molecule. Heating was stopped, and after cooling to room temperature, anhydrous methanol was added, and the mixture was stirred for 1 h. The solution was concentrated under reduced pressure to obtain 530 mg of a yellow oily substance 7.

[0130] Take a (290 mg, 1.01 mmol) and NaOH (162 mg, 4.05 mmol), add 50 mL of purified water to dissolve, stir for 10 min, weigh out 7 (530 mg, 2.05 mmol) and add it to the mixture, heat to 110 °C, and reflux for 24 h. LC-MS showed that there was no residue of the starting material and the target molecule was formed. Stop heating, let cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 290 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 10 (44 mg, yield 8.55%, UPLC > 95%). MS m / z (ESI): 510.41 [M+H]+.

[0131] 1H NMR (500MHz, CDCl3) δ12.68(s,1H),7.32(d,J=4.3Hz,4H),7.28(d,J=4.1Hz,1H),6.78(d,J=8.2Hz,1H),6.65(d ,J=8.2Hz,1H),4.58-4.55(m,1H),4.54(s,2H),4.37-4.33(m,1H),4.20-4.16(m,1H),4.08(s,1H),3.85-3.80( m,2H),3.68(d,J=4.1Hz,1H),3.66-3.64(m,4H),3.62-3.60(m,2H),3.32(d,J=11.3Hz,1H),2.99(t,J=20.1Hz, 4H),2.81(s,3H),2.67(s,2H),2.26(t,J=10.6Hz,1H),1.82-1.75(m,2H),1.49-1.41(m,2H),1.24-1.19(m,1H).

[0132] 13 C NMR (126MHz, CDCl3) δ146.94,141.57,138.05,128.70,128.33,127.72,122.02,119.30,116.68,89.36,7 3.19,70.52,69.87,69.30,68.89,65.87,61.37,47.93,41.05,39.89,39.16,34.29,27.61,21.10,17.59.

[0133] Example 11:

[0134] (4R,4aR,7S,7aR,12bS)-7,9-bis(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline

[0135]

[0136] Take 7p (500 mg, 2.08 mmol), weigh thionyl chloride (0.60 mL, 8.32 mmol), heat to 80 °C, and reflux for 5 h. LC-MS monitoring showed that there was almost no reactant remaining. Stop heating, allow to cool naturally to room temperature, add anhydrous methanol, and stir for 1 h. Concentrate under reduced pressure to obtain 530 mg of yellow oily substance 7.

[0137] Take a (290 mg, 1.01 mmol) and NaOH (162 mg, 4.05 mmol), dissolve them in 50 mL of purified water, stir for 10 min, weigh out 7 (530 mg, 2.05 mmol) and add it to the mixture, then heat to 110 °C and reflux for 24 h. LC-MS showed that the starting material was complete and reached the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 290 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 11 (6 mg, yield 0.81%, UPLC > 95%). MS m / z (ESI): 732.56 [M+H]+.

[0138] 1 H NMR (500MHz, CDCl3) δ7.35(d,J=4.3Hz,8H),7.30(d,J=4.1Hz,2H),6.81(d,J=8.2Hz,1H),6.69(d,J=8.2Hz, 1H),4.60-4.58(m,1H),4.57(s,4H),4.40-4.36(m,1H),4.22-4.19(m,1H),4.12(s,1H),3.87-3.80(m,4H), 3.70(d,J=4.1Hz,1H),3.69-3.64(m,8H),3.63-3.61(m,4H),3.35(d,J=11.3Hz,1H),3.02(t,J=20.1Hz,8H) ,2.88(s,3H),2.69(s,2H),2.30(t,J=10.6Hz,1H),1.85-1.79(m,2H),1.51-1.44(m,2H),1.27-1.22(m,1H).

[0139] Example 12:

[0140] (4R,4aR,7aR,12bS)-9-((17-hydroxy-3,6,9,12,15-pentaheptadecyl)oxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanolbenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0141]

[0142] Take b (400 mg, 1.40 mmol) and NaOH (225 mg, 5.63 mmol), dissolve in 50 mL of purified water, stir for 10 min, weigh 6p (700 mg, 4.15 mmol) and add to it, heat to 110 °C, and reflux for 24 h. LC-MS showed no residue of the starting material and the presence of the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 220 mg of oil. Prepare, separate and purify, lyophilize to obtain compound 12 (12 mg, yield 1.56%, UPLC > 95%). MS m / z (ESI): 550.39 [M+H]+.

[0143] 1 H NMR (500MHz, CDCl3) δ13.10 (s, 1H), 6.82 (d, J = 8.0Hz, 1H), 6.68 (d, J = 8.0Hz, 1H),4.75(s,1H),4.32(s,2H),3.83(s,2H),3.70(s,4H),3.64-3.50(m,14H), 3.48(s,2H),3.37(d,J=8.9Hz,1H),3.21-3.13(m,3H),3.05(d,J=19.5Hz,1H ),2.82(s,3H),2.62-2.38(m,4H),1.94-1.92(m,2H),1.20(d,J=12.4Hz,1H).

[0144] Comparative Example 1:

[0145] (4R,4aR,7aR,12bS)-9-(2-(2-methoxyethoxy)ethoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one)

[0146]

[0147] Take a (200 mg, 0.70 mmol) and NaOH (180 mg, 4.50 mmol), add 20 mL of purified water to dissolve, stir for 10 min, weigh 13p (243 mg, 1.75 mmol) and add it to the mixture, heat to 110 °C, and reflux for 24 h. LC-MS showed that the starting material was complete and reached the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 300 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 13 (56 mg, yield 20.59%, UPLC > 95%). MS m / z (ESI): 388.45 [M+H]+.

[0148] Comparative Example 2:

[0149] (4R,4aR,7aR,12bS)-9-((35-hydroxy-3,6,9,12,15,18,21,24,27,30,33-undecoxapentadecanyl)oxy)-3-methyl-2,3,4,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0150]

[0151] Take 14p (1000 mg, 1.83 mmol), weigh thionyl chloride (0.80 mL, 10.97 mmol), heat to 80 °C, and reflux for 5 h. LC-MS monitoring showed that there was almost no reactant remaining. Stop heating, allow to cool naturally to room temperature, add anhydrous methanol, and stir for 1 h. Concentrate under reduced pressure to obtain 1022 mg of yellow oily substance 14.

[0152] Take 200 mg (0.70 mmol) of a and 180 mg (4.50 mmol) of NaOH, dissolve them in 20 mL of purified water, stir for 10 min, weigh 14 (1022 mg, 2.13 mmol) and add it to the mixture, then heat to 110 °C and reflux for 24 h. LC-MS showed that the starting material was complete and reached the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 1080 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 14 (88 mg, yield 15.43%, UPLC > 95%). MS m / z (ESI): 815.02 [M+H]+.

[0153] Comparative Example 3:

[0154] (4R,4aR,7aR,12bS)-9-((134-hydroxy-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,55,54,57,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99,102,105,108,111,114,117,120,123,126,129,132-tetratetraoxy-134-tetraoxy)oxy)-3-methyl-2,3,4,4,4a,5,6-hexahydro-1H-4,12-methylenebenzofuran[3,2-e]isoquinoline-7(7aH)-one

[0155]

[0156] Take 15 p (2000 mg, 1.00 mmol), weigh 0.44 mL (6.00 mmol) of thionyl chloride, heat to 80 °C, and reflux for 5 h. LC-MS monitoring showed that there was almost no reactant remaining. Stop heating, allow to cool naturally to room temperature, add anhydrous methanol, and stir for 1 h. Concentrate under reduced pressure to obtain 2030 mg of yellow oily substance 15.

[0157] Take a (114 mg, 0.40 mmol) and NaOH (64 mg, 1.60 mmol), add 20 mL of purified water to dissolve, stir for 10 min, weigh 15 (2030 mg, 1.00 mmol) and add it to the mixture, heat to 110 °C, and reflux for 24 h. LC-MS showed that the starting material was complete and reached the target molecular weight. Stop heating, allow to cool to room temperature, extract twice with purified water and dichloromethane, combine the organic phases, wash the organic phase twice with water, dry with anhydrous Na2SO4, filter, and concentrate the organic phase under reduced pressure to obtain 110 mg of oil. Prepare, separate and purify, freeze-dry to obtain compound 15 (110 mg, yield 12.14%, UPLC > 95%). MS m / z (ESI): 2268.94 [M+H]+.

[0158] Bioactivity testing:

[0159] The in vitro affinity tests were conducted on certain representative compounds of this invention as binding sites for opioid receptors (KOR, MOR, DOR). The main method employed was radioisotope binding. The affinity of the test compounds for opioid receptors was tested, and the affinities (IC50) of the test compounds, reference compound enkephalin, U-50488 (a selective KOR agonist), and naltrexindole hydrochloride on opioid receptors KOR, MOR, and DOR were measured respectively. 50(Value). Reference compounds U-50488, enkephalin, and naltriindole hydrochloride competitively bind to opioid receptors KOR, MOR, and DOR targets with their corresponding 3H-labeled dipronofine, enkephalin, and (D-propenol, D-leucine)-enkephalin, yielding stable IC50 values. 50 Value and Ki inhibition constant.

[0160] Preparation of test compounds: ① Test compound: start at 10 nM, with 8 serial dilutions of 4-fold. ② Reference compound dipronofine: start at 100 nM, with 8 serial dilutions of 4-fold. ③ Reference compounds enkephalin and U-50488: start at 1 nM, with 8 serial dilutions of 4-fold.

[0161] Experimental Procedure: 1) Transfer 1 μL of compound / high control / low control to the assay plate according to the plate diagram. 2) Following the plate diagram, add 100 μL of membrane stock solution to the plate. 3) Add 100 μL of radioactive ligand. 4) Seal the plate. Shake at 300 rpm for one hour at room temperature. 5) Soak each well of the unfilter-96 GF / C filter plate in 50 μL of 0.3% PEI for at least 0.5 hours at room temperature. 6) After the binding experiment, filter the reaction mixture through the GF / C plate using Perkin Elmer Filtermate Harvester, then wash each plate four times with cold wash buffer. 7) Dry the filter plate at 50°C for 1 hour. 8) After drying, seal the bottom of the wells of the filter plate with Perkin Elmer unfilter-96 back sealing tape. Add 50 μL of Perkin Elmer Microscint 20 mixture. Seal the top of the filter plate with Perkin Elmer TopSeal-A sealing membrane. 9) 3H captured using the Perkin Elmer MicroBeta2Reader count filter.

[0162] Calculate the inhibition rate using the following formula:

[0163] Inhibition rate (%) = (1 - (number of test wells - average low concentration) / (average high concentration - average low concentration)) × 100%

[0164] The test results for some compounds are shown in Table 1: NT indicates not tested.

[0165] Table 1. Affinity Test Results

[0166]

[0167]

[0168] Formalin Test 1:

[0169] After purchasing SD rats, they were housed at a rate of 6 rats per cage, provided with ample water and feed, and allowed to acclimatize for 2 days. Each morning, the rats were transferred from the rearing area to the laboratory. A training urine pad was placed on the laboratory table, and a white cylinder was placed on top of the urine pad. The rats were then placed in the transparent white cylinders used for testing to acclimatize to the environment. Once the rats were calm, they were returned to their cages and back to the rearing area for at least 3 consecutive days. After 3 days of acclimatization, the rats were weighed, and those weighing 220-240g were numbered at the base of their tails. Rats that did not reach the target weight continued to acclimatize until they did. A training urine pad was placed on the laboratory table, and 30 minutes before the formal test, a metal plate was attached to the left hind paw of each rat. The rats were then placed in the transparent white cylinders to acclimatize. One hour before the test, each test sample was subcutaneously injected; then, 50 μL of 2% formalin was injected subcutaneously into the back of the left hind paw of the rat to establish the model (no formalin was injected into the control group). The formation of a skin wheal was considered a successful model establishment; if bleeding occurred at the injection site, the animal was discarded. Immediately after successful injection, the animal was placed in a self-movement analyzer, which automatically recorded the number of times the rat withdrew its paw, raised its paw, and licked its paw. The data from 0 to 60 minutes after formalin injection were statistically analyzed.

[0170] Calculate MPE% (Maximum Possible Effect, expressed as a percentage).

[0171] MPE% = [(solvent group - blank group) - (drug-treated group - blank group)] / (solvent group - blank group) x 100%

[0172] Remark:

[0173] ①Calculate the MPE of each group based on the standard that the blank group MPE% = 100% and the solvent group MPE% = 0.

[0174] ② The number of exercise cycles of the blank group was subtracted to eliminate the influence of background noise on the experiment.

[0175] Data Analysis:

[0176] Each indicator is expressed as mean ± standard error. Data for each group were statistically analyzed using GraphPad prim 8.0.1 software. The statistical method used was univariate analysis with additional Dunnett's multiple comparison test to compare whether there was a statistical difference between the groups. A p < 0.05 was considered statistically significant.

[0177] Test results

[0178] Table 2 Results of the formalin experiment

[0179]

[0180] Formalin test 2

[0181] The specific steps are as follows:

[0182] After purchasing SD rats, they were housed at a rate of 6 rats per cage, provided with ample water and feed, and allowed to acclimatize for 2 days. Each morning, the rats were transferred from the rearing area to the laboratory. A training urine pad was placed on the laboratory table, and a white cylinder was placed on top of the urine pad. The rats were then placed in the transparent white cylinder to acclimatize to the testing environment. Once the rats were calm, they were returned to their cages and back to the rearing area, for at least 3 consecutive days. After 3 days of acclimatization, the rats were weighed, and those weighing 220-240g were numbered at the base of their tails. Rats that did not reach the target weight continued to acclimatize until they did. A training urine pad was placed on the laboratory table, and 30 minutes before the formal test, a metal plate was attached to the left hind paw of each rat. The rats were then placed in the transparent white cylinder to acclimatize. 0.5 hours prior to injection, rats were administered 100 mg / kg pregabalin via gavage (the positive control for this model, used to verify its feasibility). The test drug was then injected subcutaneously at 0.5, 2, 4, 6, 12, and 24 hours prior to injection. Following this, 50 μL of 2% formalin was injected subcutaneously into the left hind paw of the rats to establish the model (the control group did not receive formalin). The formation of a skin wheal was considered a successful model establishment criterion; animals that bled at the injection site were discarded. Immediately after successful injection, the animals were placed in a spontaneous movement analyzer, which automatically recorded the number of times the rats withdrew, raised, or licked their paws. Data from 0-60 minutes after formalin injection were statistically analyzed.

[0183] Calculate MPE% (Maximum Possible Effect, expressed as a percentage).

[0184] MPE% = [(solvent group - blank group) - (drug-treated group - blank group)] / (solvent group - blank group x 100%)

[0185] Remark:

[0186] ①Calculate the MPE of each group based on the standard that the blank group MPE% = 100% and the solvent group MPE% = 0%.

[0187] ② The number of exercise cycles of the blank group was subtracted to eliminate the influence of background noise on the experiment.

[0188] Data Analysis:

[0189] Each indicator is expressed as mean ± standard error. Data for each group were statistically analyzed using GraphPad prim 8.0.1 software. The statistical method used was univariate analysis with additional Dunnett's multiple comparison test to compare whether there was a statistical difference between the groups. A p < 0.05 was considered statistically significant.

[0190] Test results Figure 1 :

[0191] Extending the administration time of compound 1 revealed a tendency for it to retain analgesic activity even after 12 hours, and PEGylated hydromorphone prolonged the duration of action.

[0192] Acetic acid writhing test:

[0193] The specific steps are as follows:

[0194] Purchased KM mice were housed separately in individual cages. Before the experiment, all animals were acclimatized in the animal housing for at least one day to allow them to adapt to the environment. The ambient temperature was maintained at 22±1℃, humidity at 40-60%, and sufficient water and feed were provided, with a 12-hour day-night cycle. Rats were weighed three days after acclimatization, and mice weighing 28-32g were numbered at the base of their tails, excluding those below the weight limit. One hour after subcutaneous injection of the positive control drug aspirin and the corresponding drug, a 0.6% acetic acid solution was administered intraperitoneally to establish the mouse model. After modeling, the mice were quickly placed in observation boxes, and the number of writhing movements and other behavioral changes were recorded over 30 minutes.

[0195] The experiment was conducted in a blinded manner, meaning that one person administered the medication and did not participate in the counting; three people counted the medication and did not participate in the administration. The next group of medications was administered 20 minutes after the previous group of experiments ended, and the experimental procedure was the same as the previous one.

[0196] Testing indicators:

[0197] Record the number of writhing movements in mice over 30 minutes and calculate the percentage of writhing movement inhibition.

[0198]

[0199] Data collection and statistical analysis:

[0200] Each indicator is expressed as mean ± standard error. Data for each group were statistically analyzed using GraphPad prim 8.0.1 software. The statistical method used was univariate analysis with additional Dunnett's multiple comparison test to compare whether there was a statistical difference between the groups. A p < 0.05 was considered statistically significant.

[0201] The experimental results are shown in Table 3:

[0202] Table 3 Results of Acetic Acid Torsion Test

[0203]

[0204] The safety of the compounds described in this invention will be evaluated below using compounds 1 and 2 as examples.

[0205] Respiratory depression test

[0206] Objective: To evaluate the effects of a single subcutaneous injection of compounds 1 and 2 on respiratory function in SD rats.

[0207] The specific steps are as follows:

[0208] All animals participating in this experiment were placed in a recording box for environmental acclimatization training twice, each time for approximately 15 minutes, within two days prior to grouping. Animals exhibiting abnormal behavior, being overweight, or underweight were excluded, leaving a total of 40 animals (half male and half female). Forty SD rats (half male and half female) were used in the experiment and randomly divided into four groups: the solvent group, the hydromorphone group, the compound 1 group, and the compound 2 group, with 10 rats (half male and half female) in each group. Rats in the solvent group received a single subcutaneous injection of the solvent; rats in the hydromorphone group received a single subcutaneous injection of 10 mg / kg of hydromorphone; rats in the compound 1 and compound 2 groups received a single subcutaneous injection of 100 mg / kg of the corresponding test product. Animals were placed in a recording chamber one day before administration (D-1) and at 1, 3, 6, and 24 hours after administration to measure respiratory function parameters, including TV (tidal volume, mL), F (respiratory rate, bpm), MV (minute ventilation, mL), and enhanced pause (Penh). The obtained data were statistically analyzed.

[0209] Data collection and statistical analysis:

[0210] Each indicator is expressed as mean ± standard error. Data for each group were statistically analyzed using GraphPad prim 8.0.1 software. The statistical method used was univariate analysis with additional Dunnett's multiple comparison test to compare whether there was a statistical difference between the groups. A p < 0.05 was considered statistically significant.

[0211] Experimental results:

[0212] Hydromorphone group (10 mg / kg; sc): A single subcutaneous injection of hydromorphone at a dose of 10 mg / kg slowed the respiratory rate and increased the enhanced pause value in SD rats.

[0213] Compound 1 and Compound 2 (20-100 mg / kg; sc): Single subcutaneous injection of test compounds 1 and 2 at a dose of 100 mg / kg had no significant effect on the respiratory function of SD rats.

[0214] The details are shown in Table 4 below:

[0215]

[0216]

[0217] withdrawal test

[0218] Experimental objective: To establish a mouse model of induced withdrawal using hydromorphone, and to evaluate the effects of repeated administration of compound 1 and compound 2 followed by injection of naloxone antagonist on withdrawal symptoms such as jumping and weight changes in mice.

[0219] The specific steps are as follows:

[0220] Before the experiment, mice were weighed and initially numbered, then randomly divided into four groups of 10 mice each, and renumbered. The hydromorphone group received subcutaneous injections of 10, 20, 30, 40, 50, and 50 mg / kg; the solvent group received an equal volume of physiological saline subcutaneously; and the compound 1 and compound 2 groups received subcutaneous injections of 20, 40, 60, 80, 100, and 100 mg / kg. Doses were increased sequentially for 7 consecutive days, and mouse weight was recorded. One hour after the last dose on day 7, all mice in each group received an intraperitoneal injection of 10 mg / kg naloxone hydrochloride. Changes in jumping frequency and any abnormal behaviors were recorded from 0 to 40 minutes after naloxone injection. After the observation period, mouse weight was recorded again.

[0221] Experimental results:

[0222] Hydromorphone group (10-50 mg / kg; sc): Hydromorphone-dependent mice showed obvious withdrawal symptoms after naloxone-induced withdrawal, with a high number of skipping reactions, which were significantly different from the solvent group; after naloxone-induced withdrawal, the weight change was not obvious and there was no significant difference compared with the solvent group.

[0223] Compound 1 and Compound 2 (20-100 mg / kg; sc): After naloxone-induced withdrawal, drug-dependent mice showed no obvious withdrawal symptoms, and the number of skipping reactions was not significantly different from that in the solvent group. In terms of weight loss, there were no significant changes before and after withdrawal in the solvent group and all drug-treated groups.

[0224] The experimental results are shown in Tables 5 and 6 below:

[0225] Table 5. Changes in the body weight of experimental animals

[0226]

[0227] Table 6 Number of jumps by experimental animals

[0228] Group Number of jumps Jump occurrence rate solvent group 0±0 0％ Hydromorphone group 43.2±14.5 80％ Group 1 of compounds 0.5±0.2 20％ Group 2 of compounds 0.3±0.2 10％

[0229] in conclusion:

[0230] Based on the results of this experiment, neither compound 1 nor compound 2 produced obvious physical withdrawal reactions in mice.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from one of the following compounds: 。 2. A method for preparing compound 1, characterized in that, The preparation route of the method is as follows: 。 3. A method for preparing compound 2, characterized in that, The preparation route of the method is as follows: 。 4. A pharmaceutical composition, characterized in that, It comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of analgesic drugs.

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