Pentazocine prodrug capable of being used for long-acting injection as well as preparation method and application of pentazocine prodrug

Abstract

The invention relates to a dipentazocine ester compound as shown in a formula (I) or pharmaceutically acceptable salt thereof and a preparation method thereof. Meanwhile, the invention also relates to a long-acting injection and a preparation method thereof, and application of the long-acting injection in preparation of various medicines for treating acute and chronic pains.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a bis-pentazocine diacid ester compound or a pharmaceutically acceptable salt thereof and a preparation method thereof. At the same time, it also relates to a composition of the compound, a preparation method thereof and its medical use. Background Art

[0002] Pain is a highly complex, heterogeneous and dynamic process that involves multiple interconnected neurotransmitter and neuromodulatory systems in the spinal cord, ascending and descending spinal pathways, and supraspinal sites (Eur J Pain 2021, 25(8): 1668). These sensory processes interact with ascending and descending information (e.g., emotional processes) to trigger an unpleasant acute sensation associated with potential or actual tissue damage (Handb Exp Pharmacol 2022, 271: 315). As an important physiological function, acute pain is one of the body's self-protective mechanisms. It serves as a warning of harm or imminent danger to body tissues, as well as the need to avoid injury and / or take care of oneself (Curr Opin Anaesthesiol 2023, 36(2): 222). However, under certain pathological conditions, such as inflammation, cancer, viral infection, diabetes, or central sensitization, the same sensation has the potential to evolve into a chronic, debilitating disease. Chronic pain can also develop even in the absence of identifiable tissue damage (Cleve Clin J Med 2023, 90(4): 245). Chronic pain is a major public health problem. In the United States, approximately 50.2 million adults report experiencing pain on most or all days. Despite its prevalence, the condition remains incompletely understood and treatment is unsatisfactory.

[0003] Pentazocine, chemically named (2R,6R,11R)-cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine-8-ol, has the following structural formula:

[0004]

[0005] Pentazocine is a cationic drug with high lipid solubility. Different from other mixed opioid receptor agonist-antagonists such as butorphanol and nalbuphine, pentazocine is the only opioid receptor agonist-antagonist among the above three that can increase systolic blood pressure. Pentazocine has a wide range of clinical applications. A large number of studies have confirmed its exact analgesic effect and few adverse reactions.

[0006] The pharmacological effects and clinical applications of pentazocine: Calculated by equivalent dose, the analgesic potency of this drug is 1 / 3 of that of morphine. Generally, the analgesic effect of subcutaneous or intramuscular injection of 30 mg is equivalent to that of 10 mg of morphine. Its respiratory depression effect is about 1 / 2 of that of morphine; when the dose is increased to more than 30 mg, the respiratory depression effect does not increase proportionally; when the dose reaches 60 - 90 mg, mental symptoms may occur, and large doses of naloxone can counteract it. This drug can slow down gastric emptying and delay the time for the intestinal tract to transport intestinal contents, but its excitatory effect on the sphincter of the bile duct is weak, and the pressure in the bile duct does not rise significantly. Its effect on the cardiovascular system is different from that of morphine. Instead, large doses increase the heart rate and blood pressure. In patients with coronary heart disease, intravenous injection can increase the mean aortic pressure and left ventricular end-diastolic pressure, thus increasing the cardiac work. This drug can increase the level of norepinephrine in the plasma, which is related to its excitatory effect on the cardiovascular system. Since this drug still has a certain antagonistic effect on μ receptors, its addiction potential is very small, and it has been classified as a non-narcotic drug in the drug administration of many countries. This drug can weaken the analgesic effect of morphine; in patients who have developed tolerance to morphine, it can promote the occurrence of withdrawal symptoms. Its antagonistic effect on the respiratory depression of morphine-like drugs is not obvious. It is suitable for various chronic severe pains. After oral administration and injection, the absorption is good. After intramuscular injection, the peak plasma concentration is reached in 0.25 - 1 hour. After oral administration, the first-pass elimination in the liver is significant, and less than 20% of the pentazocine enters the systemic circulation. Therefore, it takes 1 - 3 hours to reach the peak plasma concentration after oral administration, and the effect lasts for more than 5 hours after oral administration.

[0007] Clinical experience with pentazocine has been available abroad for decades, but it has only been applied in China in recent years, and its clinical experience is still scarce. Especially in the application of postoperative analgesia, it is still in the exploratory stage, and there is still a lack of large-sample, multi-center clinical studies.

[0008] One of the challenges in providing an active pharmaceutical ingredient (API) in a long-acting injection composition is to incorporate a sufficient amount of the drug to maintain an effective plasma level of the API over a long period (e.g., weeks or months), while maintaining a total composition volume that is readily injectable in a single injection and convertible to an active therapy. This challenge becomes even more difficult when the API is in prodrug form, as its molecular weight is higher than that of the parent API. In addition, the physicochemical properties of such prodrugs (including but not limited to chemical stability, physical stability, physical form, and solubility) are very important for their suitability for long-acting injection compositions.

[0009] Such long-acting injectable compositions can be suspensions of solids in aqueous (liquid) compositions or suspensions in oily injection solutions. For example, suspensions of API prodrugs in aqueous compositions can be prepared for long-acting compositions. Lipophilic prodrugs can also be dissolved in specific oily matrices. In such systems, the physicochemical properties of the prodrug, including the crystallinity and solubility of the solid material, are very important for its ability to deliver the drug at therapeutic plasma concentrations over a longer period. In particular, prodrugs with low water solubility are important for long-acting injectable suspensions.

[0010] There is still a need for pharmaceutical formulations that can be administered in multiple ways, such as intramuscular injection. In addition, there is a need for long-acting pharmaceutical formulations, such as those that can provide extended effective plasma levels after infrequent dosing (e.g., once a month).

[0011] A long-acting analgesic effect is particularly desirable for patients suffering from pain, such as postoperative pain, post-traumatic pain, and burn pain, which may last for about 3 days. Pentazocine has strong but short-acting analgesic activity. Prolonging the duration of action would make pentazocine more valuable in the clinical treatment of pain.

[0012] Therefore, there is a need for an alternative dosage form that can provide a long-acting effect of pentazocine, thereby reducing the frequency of administration. In addition, there is a need for alternative dosage forms to overcome the problems associated with oral administration and reduce the opportunity for abuse, so that the release of the analgesic cannot be manipulated by the patient or other external sources.

[0013] The above two pentazocine prodrugs invented by the present inventors have been synthesized and reported for oral administration to improve bioavailability and intestinal absorption. However, to the applicant's knowledge, no known pentazocine ester has been used for long-acting injection purposes by parenteral administration.

[0014] Patent documents of the present inventors:

[0015] CN111349111, a pentazocine prodrug, its preparation method and its uses.

[0016] Application No. 202510157222.2, a pentazocine benzoate gluconate and its preparation method and uses.

[0017] Therefore, there is still a need in the art to develop a suitable pharmaceutical composition to make pentazocine exhibit a long-acting analgesic effect. Summary of the Invention

[0018] Pentazocine ordinary tablets (TALWIN )After oral administration, the drug has slow dissolution or incomplete dissolution. At the same time, due to the influence of first-pass metabolism, the bioavailability is relatively low, only about 18% - 22%. Meanwhile, the metabolism is extensive, and large-scale post-marketing surveillance surveys show that the gastrointestinal side effects are extremely large. Pentazocine injection Although intravenous injection of drugs has high bioavailability, the elimination half-life in the body is short after intravenous injection, and the average residence time is relatively short. This will lead to an increase in the number of drug administrations, resulting in a decrease in patient compliance, low bioavailability, and limiting its clinical application. Moreover, the pharmacodynamic time of immediate-release injection is relatively short, mostly only lasting for 3 - 4 hours, and the postoperative pain relief time is relatively short. Therefore, designing and preparing a suitable pentazocine preparation to extend the duration of drug effect meets the clinical needs.

[0019] Based on the above, the applicant tries its best to extend the action time of pentazocine. In the present invention, several pharmaceutical compositions containing pentazocine ester derivatives and a selected oil carrier are prepared. These compositions are proven to exhibit long-acting analgesia lasting for several days (for example, 3 to 5 days).

[0020] The present invention modifies the structure of pentazocine to prepare a prodrug with long-acting properties. This type of drug is prepared into a preparation that can be intramuscularly, subcutaneously or intravenously injected through formulation means. After intramuscular, subcutaneous or intravenous injection, a drug depot is formed in the body, and the drug is slowly, continuously and stably released from the depot and converted into pentazocine, thereby exerting a long-acting effect. The present invention adopts the following technical solutions to achieve:

[0021] The purpose of the present invention is to make up for the deficiencies existing in the prior art and provide a bis-pentazocine ester compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Wherein: n is 1, 2, 3 or 4, preferably n is 2 or 3.

[0024] Another object of the present invention is to provide a preparation method of bis-pentazocine sebacate, and its preparation method is: pentazocine is esterified with sebacyl chloride in an organic solvent and an alkali acid-binding agent, and the reaction formula is as follows:

[0025]

[0026] Wherein n is the same as that in claim 1.

[0027] Preferably, the post-treatment steps include quenching, washing, column chromatography, crystallization, etc.

[0028] As a well-known technology, drugs that have been successfully clinically marketed using this technology, such as haloperidol decanoate (FDA, ) Injectable solution. Gelders reported in International Clinical Psychopharmacology, (1986) Vol.1, 1-11, and C.N. Hinko et al. reported in Neuropharmacology, (1988) Vol.27, 475-483, the formulation of a controlled-release dosage form containing fluphenazine decanoate in an injectable oil (such as sesame oil or soybean oil), the sedative effect of which is prolonged so that the dosing interval can be extended from 2 to 4 times a day to 1 to 2 times a month; another example is fluphenazine decanoate injection (FDA, ), T.R. Norman reported in

[0029] International Clinical Psychopharmacology, (1987) Vol.2, 299-305, the preparation of fluphenazine decanoate from fluphenazine. C.N. Hinko reported in Neuropharmacology, (1988), Vol.27, 475-483, the preparation of an ester of 3-piperidinecarboxylic acid (nipectic acid). C.L. Broekkamp reported in

[0030] Journal of Pharmacy and Pharmacology, (1988) Vol.40, 434-437, the preparation of nicotinylmorphine ester from morphine. J.V. Joshi et al. reported in Steroids, (1989) Vol.53, 751-761, a precursor preparation of norethisterone enanthate, which can be formulated to have a longer dosing interval of up to 2 months.

[0031] However, due to unknown factors existing in nature, rapid release of the target drug from the oil carrier may sometimes occur. For example, it has been found that the release of testosterone from intramuscularly administered testosterone suspension is rapid (T. Tanaka (1974), Chemical & Pharmaceutical Bulletin, Vol. 22, pp. 1275 - 1284). H. A. C. Titulaer reported adding artemisinin to parenteral oils to form various dosage forms for intramuscular, intravenous, oral, or rectal administration. However, the drug was rapidly released from these dosage forms (Journal of Pharmacy and Pharmacology (1990), Vol. 42, pp. 810 - 813). Z. Zuidema et al. reported in International Journal of Pharmaceutics (1994), Vol. 105, pp. 189 - 207 that the release rate and extent of dosage forms for parenteral administration are very irregular and variable.

[0032] Based on the foregoing studies, dosage forms containing a pharmaceutical composition with the drug suspended or dissolved in an oil carrier do not necessarily exhibit a longer therapeutic effect time. Generally, any attempt to add a target drug to an oil carrier to obtain a long - acting dosage form needs to consider the physical solubility, stability, and release rate of the target drug from the carrier.

[0033] Based on the above, to achieve the goal of prolonging the action time of pentazocine, the applicant provides in this case a long - acting pharmaceutical composition, which contains a pentazocine ester derivative having the chemical formula (I) and a pharmaceutically acceptable adjuvant. Preferably, the long - acting pharmaceutical composition is for injection.

[0034] Another object of the present invention is to provide a pharmaceutical composition containing:

[0035]

[0036] Wherein, the injection oil is selected from olive oil, corn oil, sesame oil, peanut oil, almond oil, coconut oil, poppy seed oil, cottonseed oil, and castor oil, and the injection oil is preferably sesame oil.

[0037] The present invention also provides that the suspending agent for the long - acting injection is selected from one or more of sodium carboxymethylcellulose and aluminum stearate; the dispersing agent is selected from one or more of Tween 80, lecithin, and glycerol monostearate; the antioxidant is selected from one or more of benzyl alcohol and vitamin E.

[0038] Another object of the present invention is to provide a method for preparing the long - acting injection, which comprises the following steps:

[0039] 1) Weigh the prescribed amount of suspending agent and add it to the injection oil. Heat and stir to dissolve it. Stop heating when the oil solution becomes clear, transparent, and golden yellow, and let it cool to room temperature.

[0040] 2) Add the prescribed amount of dispersant and antioxidant to the oil in step 1, and stir evenly.

[0041] 3) Gradually add the raw material drug of the compound of formula (I) to the mixture in step 2, stirring while adding. After mixing evenly, add injection oil to reach the required volume.

[0042] 4) Put the initially mixed suspension obtained in step 3 into a ball mill for grinding. The preferred rotation speed is 700 - 900 rpm.

[0043] More preferably, grind for 3 minutes in each cycle and stop for 5 minutes.

[0044] More preferably, grind for a total of 5 cycles.

[0045] 5) Fill the solution obtained in step 4 into vials, ampoules, or pre-filled syringes, fill the headspace with nitrogen, and seal.

[0046] 6) Sterilize at high temperature to obtain the product. The preferred temperature is 100 - 130 °C, and more preferably 121 °C.

[0047] Another object of the present invention is the use of the compound of the present invention or its pharmaceutical composition in the preparation of drugs for various acute and chronic pains.

[0048] The key points of the present invention are as follows:

[0049] The compound has good solubility and is suitable for preparation into injection solutions. The compound has good stability, has basically no toxicity to normal human liver cells, and shows good efficacy in animal pharmacodynamic experiments and safety experiments, with a lasting analgesic effect, no obvious irritation to local tissues, and good safety and tolerance. Animal pharmacokinetic experiments show that the compound has a long half-life time and can achieve the effect of long-acting release. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0051] Figure 1 It is the structural formula of pentazocine bisdecanedioate.

[0052] Figure 2It is the hydrogen spectrum of pentazocine bis(decane-1,10-dioate).

[0053] Figure 3 It is the carbon spectrum of pentazocine bis(decane-1,10-dioate).

[0054] Figure 4 It is the IR of pentazocine bis(decane-1,10-dioate). Detailed implementation manners

[0055] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0056] Next, the present invention will be further explained and described in conjunction with specific implementation manners.

[0057] Example 1:

[0058]

[0059] 100 mg of pentazocine, 35 mg of triethylamine and 20 ml of dichloromethane were added to a 50 ml reaction flask, cooled to 0 - 5 °C, and 42 mg of sebacoyl chloride was added dropwise, with the dropping temperature not exceeding 10 °C. After the dropping was completed, the reaction was carried out at 20 - 25 °C for 2 hours. TLC (developing agent: MeOH:DCM = 1:20) showed that the reaction was completed. It was washed once with 20 ml of purified water, dried, concentrated, and passed through a silica gel column (developing agent: MeOH:DCM = 1:50) to obtain 0.19 g of a pale yellow oily substance, HPLC 97.84%, yield: 75.6%.

[0060] MS: m / z [M+H]+ 737.7;

[0061] 1 H-NMR (400 MHz, DMSO / TMS, ppm):

[0062] δ 7.15 - 7.12 (2H, d, benzene ring); δ 6.92 - 6.84 (4H, m, benzene ring); δ 5.19 - 5.16 (2H, t, CH2CH=C);

[0063] δ 3.07 - 2.90 (8H, m, CHCH2N, CHCH2C); δ 2.61 - 2.52 (4H, m, CH2CH2N); δ 1.92 - 1.64 (22H, m, CHNCH, CH2CH2, CH3C=CH); δ 1.35 - 1.20 (20H, m,, CH3C=CH, CH2CH2, CCH3); δ 0.77 - 0.75 (6H, m, CH3CH);

[0064] 13 C NMR (101 MHz, DMSO) δ 175.02, 172.23, 149.28, 143.45, 134.37, 133.93, 128.34, 122.99, 119.30, 118.63, 67.79, 56.77, 52.27, 45.16, 42.12, 41.44, 36.66, 34.28, 33.99, 28.99, 28.83, 26.11, 25.55, 25.02, 24.80, 23.73, 23.26, 18.28, 14.28.

[0065] <![CDATA[Absorption peak wave number (cm -1 )]]> Vibration type Group Absorption peak intensity 2966 =C-H stretching vibration =C-H s 2924,2854 -C-H stretching vibration -C-H s, s 1757 C=C stretching vibration Alkene bond s 1643,1608,1583 Benzene ring skeleton C=C stretching vibration Benzene ring w, s, s 1492 C-H bending vibration Methylene s 1375,1325 C-H bending vibration Methyl m, s 1139 C-O stretching vibration Ar-O-C (phenolic hydroxyl group) s 1072,1012 Ring breathing vibration Cyclohexyl s, s 902,844 =C-H out-of-plane bending vibration 1, 2, 4-trisubstituted benzene s, s

[0066] IR:

[0067] Example 2:

[0068] 2 g of pentazocine, 0.71 g of triethylamine and 30 ml of dichloromethane were added to a 50 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 0.84 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 2.5 hours. TLC (developing solvent: MeOH:DCM = 1:20) showed that the reaction was completed. It was washed once with 30 ml of purified water, dried, concentrated, and passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 4.18 g of a pale yellow oily substance, yield: 81%.

[0069] Example 3:

[0070] 10 g of pentazocine, 3.55 g of triethylamine and 200 ml of dichloromethane were added to a 500 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 4.19 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 4 hours. TLC (developing solvent: MeOH:DCM = 1:20) showed that the reaction was completed. It was washed once with 200 ml of purified water, dried, concentrated, the residue was added to 200 ml of isopropyl ether, stirred at 0 - 5 °C for 1 h, filtered, and the filtrate was concentrated to obtain 19.3 g of a pale yellow oily substance, yield: 75.0%.

[0071] Example 4:

[0072] 1 g pentazocine, 0.45 g DIPEA and 20 ml of dichloromethane were added to a 50 ml reaction flask, cooled to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 2 hours. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. It was washed once with 20 ml of purified water, dried, concentrated, and passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.53 g of a pale yellow oil, with a yield of 79.1%.

[0073] Example 5:

[0074] 1 g pentazocine, 0.28 g pyridine and 20 ml of dichloromethane were added to a 50 ml reaction flask, cooled to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 1 hour. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. It was washed once with 20 ml of purified water and once with 20 ml of 2N hydrochloric acid, dried, concentrated, and passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.53 g of a pale yellow oil, with a yield of 79.1%.

[0075] Example 6:

[0076] 2 g pentazocine, 0.71 g triethylamine and 30 ml of toluene were added to a 50 ml reaction flask, cooled to 0 - 5 °C, and 0.84 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 2.5 hours. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. It was filtered, the filtrate was concentrated, and passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 4.02 g of a pale yellow oil, with a yield of 78.3%.

[0077] Example 7:

[0078] 1 g pentazocine, 0.28 g pyridine and 20 ml of toluene were added to a 50 ml reaction flask, cooled to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 1 hour. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. It was filtered, the filtrate was concentrated, and passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.39 g of a pale yellow oil, with a yield of 72.2%.

[0079] Example 8:

[0080] 1 g of pentazocine, 0.45 g of DIPEA and 20 ml of dichloromethane were added to a 50 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 2 hours. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. The mixture was filtered, and the filtrate was concentrated. It was passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.65 g of a pale yellow oily substance with a yield of 85.5%.

[0081] Example 9:

[0082] 1 g of pentazocine, 0.45 g of DIPEA and 20 ml of isopropyl ether were added to a 50 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 2 hours. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. The temperature was lowered to 0 - 5 °C and stirred for 1 h. The mixture was filtered, and the filtrate was concentrated. It was passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.35 g of a pale yellow oily substance with a yield of 69.9%.

[0083] Example 10:

[0084] 1 g of pentazocine, 0.45 g of DIPEA and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 0.42 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 1 hour. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. It was concentrated to dryness, 20 ml of ethyl acetate was added, and it was washed once with 20 ml of water. After concentration, it was passed through a silica gel column (developing solvent: MeOH:DCM = 1:50) to obtain 1.29 g of a pale yellow oily substance with a yield of 66.83%.

[0085] Example 11:

[0086] 10 g of pentazocine, 3.55 g of triethylamine and 200 ml of isopropyl ether were added to a 500 ml reaction flask. The temperature was lowered to 0 - 5 °C, and 4.19 g of sebacoyl chloride was added dropwise with the dropping temperature not exceeding 10 °C. After the addition was complete, the reaction was carried out at 20 - 25 °C for 4 hours. TLC (developing solvent: MeOH:DCM = 1:20) indicated the completion of the reaction. The temperature was lowered to 0 - 5 °C, 20 ml of n - hexane was added and stirred for 1 h. The mixture was filtered, and the filtrate was concentrated to obtain 19.41 g of a pale yellow oily substance with a yield of 75.19%.

[0087] Example 12:

[0088] 1 g pentazocine, 0.28 g pyridine and 20 ml of acetonitrile were added to a 50 ml reaction flask, and the temperature was lowered to 0 - 5 °C. 0.42 g of sebacoyl chloride was added dropwise, and the dropping temperature was not higher than 10 °C. After the addition was completed, the reaction was carried out at 20 - 25 °C for 1 hour. TLC (developing agent: MeOH:DCM = 1:20) showed that the reaction was completed. The mixture was filtered, and the filtrate was concentrated to dryness to obtain 1.31 g of a pale yellow oily substance, with a yield of 67.87%.

[0089] Comparative Example 1:

[0090] Decanoyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.09 g of pentazocine decanoate, with a yield of 59.0%.

[0091] Comparative Example 2:

[0092] Undecanedicarbonyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.22 g of pentazocine undecanecarbonate, with a yield of 83.3%.

[0093] Comparative Example 3:

[0094] Nonanedicarbonyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.16 g of pentazocine nonanedioate, with a yield of 66.3%.

[0095] Comparative Example 4:

[0096] Octanedicarbonyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.13 g of pentazocine octanedioate, with a yield of 55.0%.

[0097] Comparative Example 5:

[0098] Adipoyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.14 g of pentazocine adipate, with a yield of 62.0%.

[0099] Comparative Example 6:

[0100] Dodecanedicarbonyl chloride was used instead of sebacoyl chloride, and the preparation method was the same as in Example 1 to obtain 0.18 g of pentazocine dodecanedioate, with a yield of 67.2%.

[0101]

[0102] Among these typical long-acting prodrugs, pentazocine sebacate has a specifically significant and non-obvious long-acting effect.

[0103] Example 13: Investigation of the solubility in oil.

[0104] In the invention of the oil phase, typical representative compounds of the present invention were selected and screened as follows:

[0105]

[0106]

[0107] The results showed that sesame oil was superior to other injection oils.

[0108] The following compounds were all formulated into sesame oil solutions at 90 mg / ml, and their solubility was observed. Further, it was investigated whether an oil suspension could be prepared for medicinal use.

[0109]

[0110]

[0111] Conclusion: Pentazocine bisdecanoate of the present invention is most suitable for further drug development research.

[0112] Example 14: Preparation of pentazocine bisdecanoate injection.

[0113] Preparation process:

[0114] 1) Take the prescribed amount of suspending agent and add it to the injection oil. Heat and stir to dissolve it. Stop heating when the oil solution becomes clear, transparent, and golden yellow, and let it cool to room temperature.

[0115] 2) Add the prescribed amount of dispersant and antioxidant to the oil in step 1 and stir evenly.

[0116] 3) Add pentazocine bisdecanoate to step 2 in portions, stirring while adding. After mixing evenly, add injection oil to the volume.

[0117] 4) Put the initially mixed suspension in step 3 into a ball mill and grind it at a rotation speed of 700 - 900 rpm. Grind for 3 minutes in each cycle, stop for 5 minutes, and grind for a total of 5 cycles.

[0118] 5) Seal the solution in step 4 in vials, ampoules, or pre-filled syringes, fill the headspace with nitrogen, and seal.

[0119] 6) Sterilize at 121 °C to obtain the product.

[0120] Table 1: Injection prescription

[0121]

[0122]

[0123] Example 15: Study on physical and chemical properties.

[0124] HPLC detection method: Chromatographic conditions: Octadecylsilane chemically bonded silica gel was used as the filler (specification 4.6×100 mm; 2.6 μm); 15 mmol / L sodium borate (adjusted to pH 10.0 with 10 mol / L sodium hydroxide) was used as mobile phase A, and methanol was used as mobile phase B for gradient elution; the flow rate was 0.5 ml per minute; the column temperature was 40 °C; the detection wavelength was 225 nm; the injection volume was 20 μl.

[0125] 1. Apparent solubility in different organic solvents.

[0126] Take 1 ml of dichloromethane, ethanol, benzyl alcohol, NMP, ethyl acetate, acetone, acetonitrile, pyridine, and THF respectively and place them in 1.5 ml EP tubes. Add an excess of pentazocine bisdecyl sebacate, vortex for 30 min, sonicate for 5 min, keep warm in a constant temperature shaking water bath at 20 °C, with a shaking speed of 90 RPM, and sample once every 24 h until equilibrium is reached. Take an appropriate amount of the supernatant each time, centrifuge at 12,000 rpm for 3 min, take 0.1 ml of the supernatant, dilute it with methanol, and then inject it into a high-performance liquid chromatograph for analysis until the direct dissolution is completely balanced.

[0127] Table 2: Apparent solubility of pentazocine bisdecyl sebacate in different organic solvents

[0128]

[0129] The solubility in different organic solvents shows that pentazocine bisdecyl sebacate has extremely low polarity and at the same time retains the polarity containing N, which can significantly achieve long-acting effects and provide a basis for the selection of long-acting solvents.

[0130] 2. Detection of solubility in simulated human buffer solution.

[0131] The purpose of the present invention is long-acting injection, and its metabolically active ingredient is pentazocine. Referring to the solubility determination method in the General Provisions of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, the prodrug and its metabolite pentazocine were detected. The specific solubility differences are shown in the following table:

[0132] Table 3: Solubility of pentazocine bisdecyl sebacate in simulated human buffer solution

[0133]

[0134] The solubility of pentazocine bisdecyl sebacate in water is extremely low, and it belongs to a poorly soluble drug. Moreover, its solubility decreases with the increase of pH. The above results suggest that the solubility of pentazocine bisdecyl sebacate in aqueous solution is extremely low. According to the Noyes-Whitney equation, the dissolution rate of the drug is positively correlated with the solubility. Therefore, the dissolution rate of pentazocine bisdecyl sebacate in water may also be slow. The slow dissolution rate is conducive to the realization of slow release and conforms to the principle of long-acting metabolism.

[0135] 3. Apparent solubility in different dissolution media.

[0136] The dissolution media was prepared using sodium dihydrogen phosphate dihydrate and sodium hydroxide, with a certain amount of Tween 80 and sodium dodecyl sulfate added respectively. Purified water was added, and the pH was adjusted to 7.4 with phosphoric acid to prepare dissolution media containing different concentrations of surfactants.

[0137] Excess pentazocine bisdecanedioate was dispersed in different dissolution media to obtain corresponding supersaturated solutions, which were placed in 10-ml stoppered test tubes and shaken at 90 rpm in a 37°C constant temperature water bath for 72 h. Samples were taken every 24 h to measure the solubility. When measuring the solubility, the supernatant was taken, filtered through a 0.45-μm microporous membrane, 2 ml of the initial filtrate was discarded, 1 ml of the subsequent filtrate was taken, and analyzed by injection using a high performance liquid chromatograph. The solubility of pentazocine bisdecanedioate in different dissolution media was calculated by the external standard method. The whole process was carried out rapidly. After the sample was taken and before further dilution, it was kept warm in a 37°C water bath to prevent the influence of temperature change on solubility.

[0138] Table 4: Apparent solubility of pentazocine bisdecanedioate in different dissolution media

[0139]

[0140]

[0141] The solubilization of poorly soluble drugs by surfactants is achieved by forming micelles. When the concentration of the surfactant exceeds the critical micelle concentration, the solubility of the poorly soluble drug increases significantly. As its concentration increases, the solubilization amount of the poorly soluble drug increases linearly and conforms to concentration dependence.

[0142] Example 16: Stability test.

[0143] 1. Accelerated test:

[0144] Pentazocine bisdecanedioate will be used as the raw material drug for preparing suspension injections in the future, so the storage problem is very crucial. Other impurities may be introduced or generated during storage, affecting the use of the raw material drug. Therefore, the stability of the raw material drug of the present invention was investigated. Referring to the ICH guiding principle "Stability Testing of New Drug Substances and Products", the accelerated test was used to investigate the effects of temperature, humidity, and light on the raw material drug respectively. The conditions were set as follows: temperature 40 ± 2°C, humidity 75% ± 5%, light 4500 lx, and samples were taken after 10 days. The results are shown in the following table:

[0145] Table 5: Results of stability investigation of pentazocine bisdecanedioate

[0146]

[0147] Conclusion: As can be seen from the table, the active pharmaceutical ingredient of the present invention is relatively stable under the relevant settings and no obvious impurities are generated. Therefore, after the active pharmaceutical ingredient is prepared, it can be stored at room temperature.

[0148] 2. Heat stability study under nitrogen protection:

[0149] For the sample obtained by the melting method, accurately weigh 10 mg, dissolve it with pure acetonitrile and make up the volume to 50 ml, then dilute it 10 times with mobile phase B. Take 20 μl and inject it into the high performance liquid chromatograph, record the chromatogram, and calculate the percentage content by the external standard method.

[0150] Table 6: Results of heat stability study under nitrogen protection

[0151]

[0152] Conclusion: Under nitrogen protection, after the sample is heated to 230 °C and then cooled to room temperature, pentazocine bis(decanoate) is very stable, while pentazocine monodecanoate is unstable.

[0153] Example 17: Experimental study on the in vitro cytotoxicity of normal human hepatocytes.

[0154] 1. Experimental materials:

[0155] 1.1 Cells: LO2 cells, a human hepatocyte cell line;

[0156] 1.2 Drugs: Pentazocine bis(decanoate), HPLC purity 97.84%;

[0157] 1.3 Reagents and instruments: Modified RPMI-1640 medium, penicillin-streptomycin double antibody solution, 0.25% trypsin-EDTA, fetal bovine serum, MTT, dimethyl sulfoxide, CO-150 type carbon monoxide incubator, SW-CJ-2F type medical purification workbench, CKX-41-32 type inverted microscope, CU600 type electrothermal constant temperature water bath, RT-2100C type microplate reader.

[0158] 2. Experimental methods:

[0159] 2.1 Reagent preparation:

[0160] 2.1.1 Preparation of MTT: Weigh 0.5 g of MTT accurately with an analytical balance, place it in a 50 mL volumetric flask, add an appropriate amount of PBS, heat it in a water bath at 40-50 °C, shake well to dissolve it completely, add PBS to the scale, prepare a solution of 10 mg / kg, filter and sterilize it with a 0.22 μm microporous membrane, and store it in the dark at 4 °C in the refrigerator after aliquoting.

[0161] 2.1.2 Preparation of cell cryopreservation solution The cell cryopreservation solution is prepared by uniformly mixing 20% serum, 10% DMSO, and 70% 1640 medium, and stored at -20°C.

[0162] 2.1.3 Preparation of the compound of the present invention The mother liquor of the drug is prepared with DMSO, and then diluted to the concentration of the drug used with the culture medium. The final concentration of DMSO is controlled at ≤0.1%.

[0163] 2.2 LO2 cell culture Human normal LO2 cells are placed in a 25 cm 2 cell culture flask, and about 4 - 5 mL of RPMI-1640 culture medium containing 10% FBS is added. It is placed in a 37°C cell culture incubator and cultured in a 5% CO2 saturated humidity cell culture incubator. The culture medium is changed every 2 days, and the cell growth condition is observed every day. After 80% cell confluence, subculture or cryopreservation is carried out. Cells of passages 5 - 7 are used for the formal experiment.

[0164] 2.3 Grouping and administration The experiment is divided into a normal cell control group, and different concentration administration groups of the present invention are set according to the results of the preliminary experiment. The concentrations are 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320..0, 375.0 μmol / L respectively.

[0165] 2.4 MTT colorimetry of hepatocytes Take LO2 cells in the logarithmic growth phase, prepare a cell suspension of 5.0×103 cells / mL and inoculate it into a 96-well plate. Set a normal control group and different concentration administration groups of the present invention at 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0, 375.0 μmol / L. After culturing for 24 h, aspirate the culture medium, wash 2 - 3 times with PBS, and add the compounds of the present invention at the above different concentrations respectively. Each concentration has 8 replicate wells, and it is placed in a 37°C, 5% CO2 incubator for culture. After culturing for 24, 48, and 72 h, MTT solution is added at each time period and cultured in the dark for 4 h. After 4 h, aspirate the upper layer of the culture medium, and then add 150 μL of DMSO solvent to each well to dissolve the thiazole blue crystals, and gently shake the culture plate to make the dissolution uniform. The absorbance value of each well is measured at 490 nm with an enzyme-linked immunosorbent assay (ELISA) reader. The size of the absorbance value per well reflects the number of cells, and the two are directly proportional. The experiment is repeated 3 times. Calculate the cell viability rate: Cell viability rate (%) = absorbance of each group (OD490) × 100 / absorbance of the control group (OD490).

[0166] 2.5 Statistical analysis All data are expressed as mean ± standard deviation, and the data are processed using the SPSS 17.0 statistical software package. t-test statistical analysis is used. Paired t-test is used for self-comparison, and unpaired t-test is used for inter-group comparison. The test standard is P < 0.05.

[0167] 3. Experimental results:

[0168] Table 7 Experimental results of in vitro cytotoxicity of pentazocine bisdecyl sebacate on normal human hepatocytes

[0169]

[0170] Conclusion: After 72 h of administration of the present invention at different concentrations, the OD values of cells in each group showed an increasing trend, but the growth rate decreased, indicating that the cells were still in the growth stage and the growth rate was somewhat inhibited. The administration groups of the present invention at different concentrations had no inhibitory effect on cells. Compared with the normal group, the survival rate of cells was greater than 90%. In the range of 1.25 - 375.0 μmol / L, there was almost no inhibition on cell growth and no toxicity to cells.

[0171] Example 18: In vivo pharmacodynamic evaluation.

[0172] 1. Experimental animals:

[0173] Male healthy SD rats, weighing (200 ± 20) g.

[0174] 2. Experimental methods:

[0175] 2.1 Model preparation:

[0176] For the rats in the model group, an inflammatory pain model of foot swelling induced by plantar injection was established. 100 μL of complete Freund's adjuvant was subcutaneously injected into the left plantar surface of the rats for modeling. After injection, the injection site was massaged to promote absorption. The day of modeling was set as day 0.

[0177] 2.2 Grouping:

[0178] The experimental animals were evenly divided into 4 groups according to the basic nociceptive threshold, with 5 rats in each group, namely the experimental group, the positive control group, the blank control group and the negative control group. This experiment was strictly operated in accordance with the ethical guidelines for animal pain research.

[0179] 2.3 Determination of nociceptive threshold:

[0180] According to the principle of measuring the mechanical response threshold of rats using von Frey fibers, a von Frey nociception tester was used to measure the nociception value of the injected foot of the experimental animals. The measurement site was between the second and third toe metatarsals on the plantar surface, and the pain threshold (PWT) of the noxious pain that caused the positive paw withdrawal response in rats was used to represent it. In this experiment, the positive paw withdrawal response of rats was judged as rapid twitching or jittering. The test site of the blank control group was the same as that of the model group. Each measurement was carried out using the parallel experimental method for each group. In a quiet environment, the rats to be tested were placed in an iron cage. After each rat adapted to the iron cage environment for 10 min, the pain threshold of noxious pain was measured. Each rat was measured five times, with an interval of 5 min each time. The minimum pressure value that caused a positive response was taken as the nociception threshold (PWT) of the animal.

[0181] 2.4 Administration regimen:

[0182] The plantar subcutaneous tissue of the rat foot received 100 μL of complete Freund's adjuvant (CFA). The pain threshold of noxious pain was measured before the CFA injection and used as the baseline PWT. The pain threshold of the injection site of the rat was measured every day after the CFA injection until the pain threshold of the rat decreased to the lowest level and drug administration could be carried out. Rat drug administration could be carried out on the 5th day after the CFA administration. According to the experimental grouping, the experimental group used the long-acting injection (dissolved in sesame oil) with the injection number 1 in Example 14 (the low, medium, and high doses were 3 mg / kg, 4.5 mg / kg, and 6 mg / kg respectively), the positive control group was pentazocine immediate-release injection (dissolved in sesame oil, with 1.2% benzyl alcohol added) (1.5 mg / kg), the blank control group was a drug-free long-acting injection (sesame oil + 1.2% benzyl alcohol), and the negative control group used normal saline (0.2 mL / rat). The injections of each group were respectively injected into the plantar subcutaneous tissue of the rat foot. After drug administration, the pain threshold of noxious pain was measured according to the conditions under 2.3. The measurement times were before drug administration, 1 h, 2 h, 3 h, 6 h, 24 h, 30 h, 48 h, 54 h, and 72 h after drug administration, so as to compare the changes in the pain threshold of noxious pain in each group.

[0183] 3. Experimental results:

[0184] Table 8: Experimental results

[0185]

[0186]

[0187] Conclusion: Compared with the positive control pentazocine injection, *P < 0.05. The results show that the long-acting injection of the present invention has a significantly prolonged drug efficacy duration compared with the pentazocine immediate-release injection, indicating that the long-acting injection has a long-acting analgesic effect.

[0188] Example 19: Evaluation of drug administration irritation experiment.

[0189] Thirty Sprague-Dawley rats (200±10 g) were randomly divided into five groups: blank control group, pentazocine bis(decyl sebacate) group, pentazocine decanoate group, pentazocine bis(nonanedioate) group, and pentazocine bis(undecanedioate) group. 0.1 mL of normal saline and solutions of pentazocine bis(decyl sebacate), pentazocine decanoate, pentazocine bis(nonanedioate), and pentazocine bis(undecanedioate) were injected into the right hind paws of the rats in the five groups respectively (the preparation methods of the above compound solutions all refer to No. 1 in Example 14, that is, 90 mg of the compound, 1.2% (w / v) of benzyl alcohol, and sesame oil to make up the volume to full, and a solution with a concentration of 90 mg / ml was prepared). The first foot licking time and the total foot licking time within 30 min of the five groups of rats were observed and recorded.

[0190] Table 9: Initial foot licking time

[0191]

[0192] Table 10: Total foot licking time

[0193]

[0194] Conclusion: The average initial foot licking times of the blank control group and the pentazocine bis(decyl sebacate) group were 16.7 min and 17.5 min respectively, and there was little difference between the two. Within half an hour after administration, the average foot licking time of the pentazocine bis(decyl sebacate) group was longer than that of the control group. It shows that the pentazocine bis(decyl sebacate) group has little irritation and high safety. On the contrary, the average foot licking times of the pentazocine decanoate group, the pentazocine bis(nonanedioate) group, and the pentazocine bis(undecanedioate) group were all shorter than that of the control group, and they had partial irritation.

[0195] Example 20: Pharmacokinetic study in rats.

[0196] 1. In vivo high performance liquid chromatography analysis method:

[0197] Chromatographic conditions: Octadecylsilane chemically bonded silica gel was used as the filler (specification 4.6×100 mm; 2.6 μm); 15 mmol / L sodium borate (adjusted to pH 10.0 with 10 mol / L sodium hydroxide) was used as mobile phase A, and methanol was used as mobile phase B for gradient elution; the flow rate was 0.5 ml per minute; the column temperature was 40 °C; the detection wavelength was 225 nm; the injection volume was 20 μl.

[0198] 2. Preparation of plasma samples:

[0199] Blank plasma sample: Take the blank plasma of rats. After thawing, accurately measure 100 μL and transfer it into a 1.0 mL centrifuge tube. Add 600 μL of 4% glacial acetic acid in methanol, vortex for 5 min, centrifuge at 9000 rpm for 10 min to precipitate proteins, aspirate the supernatant into a 1.0 mL centrifuge tube, and evaporate to dryness at 40 °C. Redissolve the residue in methanol, vortex for 6 min, sonicate for 15 min, centrifuge at 13000 rpm for 20 min, and the supernatant is the blank plasma sample solution.

[0200] Plasma sample after drug administration: Take the plasma of rats after drug administration. After thawing, accurately measure 100 μL and transfer it into a 1.0 mL centrifuge tube. Add 10 μL of internal standard metazocine (1 μg / mL, dissolved in methanol), vortex for 1 min to mix evenly. Add 600 μL of 4% glacial acetic acid in methanol, vortex for 5 min, centrifuge at 9000 rpm for 1 min to precipitate proteins, aspirate the supernatant into a 1.0 mL centrifuge tube, and evaporate to dryness at 40 °C. Redissolve the residue in methanol, vortex for 6 min, sonicate for 15 min to fully dissolve the drug, and then centrifuge at 13000 rpm for 20 min. The supernatant is the plasma sample solution after drug administration.

[0201] 3. Drug administration regimen and sample collection:

[0202] Randomly divide 12 rats into two groups of 6 each, and intramuscularly inject the oil suspension numbered 1 of the injection solution of Example 14 of the present invention at a dose of 7 mg / kg. Collect blood from the orbital vein of rats at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48 h, 96 h, 144 h, 192 h, and 240 h after drug administration. Each time, collect about 0.25 mL of blood and add it to an anticoagulant tube treated with sodium heparin. Centrifuge at 4000 rpm for 10 min, separate the upper plasma, and store it at -20 °C for analysis and detection.

[0203] 4. Plasma sample detection and data processing:

[0204] Take the plasma sample after drug administration and process it according to the method under 2 Preparation of plasma samples. Inject the sample under the chromatographic conditions in 1 In vivo high performance liquid chromatography analysis method. Substitute the ratio of the peak areas of the main drug and the internal standard peak into the standard curve to calculate the blood drug concentration, and use Phoenix software to process the results and calculate the relevant pharmacokinetic parameters.

[0205] 5. Results:

[0206] Table 11: Results of pharmacokinetic study of pentazocine bisdecanoate in rats

[0207] Parameter Unit Pentazocine bis-decanedioate AUC(0-t) h*mg / L 136.7 AUC(0-∞) h*mg / L 214.9 MRT(0-t) h 302.4 MRT(0-∞) h 451.3 Cmax mg / L 0.51 Tmax h 98.6 t1 / 2 h 203.5 Vz / F L / kg 2.8 CLz / F L / h / kg 0.8

[0208] The results show that the compounds of the present invention can be slowly, continuously and stably released and converted into pentazocine in vivo, so as to exert a long-acting effect. At the same time, it is released smoothly to achieve the long-acting release effect.

[0209] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A bispentazocetate compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in: n is 1, 2, 3 or 4.

2. The bispentazocetate compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: n is 2 or 3.

3. The method for preparing the bispentazocetate compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The following steps are involved: Pentazocine is prepared by esterification of diacyl chloride in an organic solvent and an alkaline acid-binding agent. The reaction formula is as follows: wherein the definition of n is the same as that in claim 1.

4. A pharmaceutical composition, characterized in that Contains the compound according to claim 1 or 2, and other pharmaceutical adjuvants.

5. The pharmaceutical composition according to claim 4, characterized in that contain:

6. The pharmaceutical composition according to claim 5, characterized in that: The oil for injection is selected from olive oil, corn oil, sesame oil, peanut oil, almond oil, coconut oil, poppy seed oil, cottonseed oil and castor oil, and is more preferably sesame oil.

7. The pharmaceutical composition according to claim 5, characterized in that: The suspending agent is selected from one or more of sodium carboxymethyl cellulose and aluminum stearate; the dispersing agent is selected from one or more of Tween 80, lecithin, and glyceryl monostearate; and the antioxidant is selected from one or more of benzyl alcohol, benzyl benzoate, and vitamin E.

8. The method for preparing the pharmaceutical composition according to claim 5, characterized in that: The following steps are involved: 1) Take the prescribed amount of suspending agent and add it to the injection oil, heat it while stirring to dissolve it, stop heating when the oil solution becomes clear and transparent golden yellow, and let it cool to room temperature; 2) Add the prescribed amount of dispersant and antioxidant to the oil in step 1 and stir evenly; 3) Add the raw material of the compound of formula (I) to step 2 in portions, stirring while adding, and after mixing, add injection oil to volume; 4) grinding the uniformly mixed initial suspension in step 3 in a ball mill; 5) Fill the solution in step 4 into a vial, ampoule or pre-filled syringe, fill the headspace with nitrogen, and seal; 6) High temperature sterilization is available.

9. The pharmaceutical composition according to claim 5, characterized in that: It is administered by intramuscular injection.

10. Use of the compound according to claim 1 or 2 or the pharmaceutical composition according to any one of claims 5 to 7 for preparing various drugs for acute and chronic pain.

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