Pentazocine prodrugs useful for long-acting injectable formulations, methods of making and uses

Abstract

The present application relates to the bispentazocine ester compound or its pharmaceutically acceptable salt shown in formula (I) and its preparation method; meanwhile, it also relates to its long-acting injection and preparation method and use in preparing various acute and chronic pain medicines.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a bispentazocine diacid ester compound or a pharmaceutically acceptable salt thereof and a preparation method thereof, and also relates to a composition of the compound and a preparation method thereof and a medical use thereof. BACKGROUND

[0002] Pain is a highly complex, heterogeneous, and dynamic process involving multiple interconnected neurotransmitters 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 mechanisms of body self-protection, which serves as a warning that there is harm or imminent danger to the body tissue and that it needs to be avoided and / or taken care of (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 can evolve into a chronic, debilitating disease. Chronic pain can develop even without identifiable tissue damage (Cleve Clin J Med 2023, 90(4): 245). Chronic pain is a major public health problem, with approximately 5020 million adults in the United States reporting that they feel pain most or all of the time. Despite its prevalence, this condition remains poorly understood and the treatment is unsatisfactory.

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

[0004]

[0005] Pentazocine is a cationic drug with high lipid solubility. Unlike other mixed opioid receptor agonists / antagonists such as butorphanol and nalbuphine, it is the only one of the three that can increase systolic blood pressure. Pentazocine is widely used in clinical practice, and a large number of studies have confirmed its exact analgesic effect and few adverse reactions.

[0006] The pharmacological effects and clinical applications of pentazocine are calculated by equivalent dose. The analgesic potency of this drug is 1 / 3 of that of morphine. The analgesic effect of 30 mg of pentazocine injected subcutaneously or intramuscularly is equivalent to that of 10 mg of morphine. Its respiratory depression is about 1 / 2 of that of morphine. When the dose is increased to more than 30 mg, the respiratory depression does not increase proportionally. When the dose is 60-90 mg, mental symptoms can occur, which can be antagonized by a large dose of naloxone. This drug can slow down the gastric emptying and delay the intestinal transport of the intestinal contents, but its excitatory effect on the sphincter of the biliary tract is weak, and the pressure in the biliary tract does not increase significantly. Its effects on the cardiovascular system are different from those of morphine. A large dose of this drug actually increases 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, thereby 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 also has a certain antagonistic effect on μ receptors, its addiction is very small, and it has been included in the non-narcotic drugs 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 development of withdrawal symptoms. It does not significantly antagonize the respiratory depression effect of morphine. It is suitable for various chronic severe pain. The absorption after oral administration and injection is good, and the peak blood concentration is reached at 0.25-1 hour after intramuscular injection. After oral administration, the first-pass elimination in the liver is significant, and less than 20% of the analgesic new enters the systemic circulation, so it takes 1-3 hours to reach the peak blood concentration after oral administration, and the effect lasts for more than 5 hours after oral administration.

[0007] Pentazocine has been used clinically for decades abroad, but only in recent years has it been used in China. There is still little clinical experience, especially in the application of postoperative analgesia, which is still in the exploratory stage and lacks large-sample multicenter clinical studies.

[0008] One of the challenges in providing an active pharmaceutical ingredient (API) in a long-acting injectable composition is to add a sufficient amount of the drug to maintain effective plasma levels of the API over a longer period of time (e.g., weeks or months) while keeping the total composition volume injectable at any time, single injection, converted to active treatment. This challenge becomes more difficult when the API is in the form of a prodrug, which therefore has a higher molecular weight than the parent API. In addition, the physicochemical properties of such a prodrug, including but not limited to chemical stability, physical stability, physical form, and solubility, are very important for its suitability for a long-acting injectable composition.

[0009] The long-acting injectable composition can be a solid suspension in an aqueous (liquid) composition or a suspension in an oily injectable. For example, a suspension of the API prodrug in an aqueous composition can be prepared for use in a long-acting composition. A prodrug that is highly lipophilic can also be dissolved in a specific oily base to be made, in such a system, 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 in therapeutic plasma concentrations over a longer period of time. In particular, a prodrug with low water solubility is important for long-acting injectable suspensions.

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

[0011] Long-acting analgesic action is particularly desirable for patients suffering from pain, such as postoperative pain, post-traumatic pain, and burn pain, which can last for about 3 days. Pentazocine has very 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 long-acting pentazocine action, thereby reducing the frequency of administration. In addition, there is a need for an alternative dosage form to overcome the problems associated with oral administration and to reduce the opportunity for abuse, so that the release of analgesics cannot be manipulated by patients or other external sources.

[0013] The present inventors have synthesized and reported the above two pentazocine prodrugs for oral administration to improve bioavailability and intestinal absorption. However, to the best of the applicant's knowledge, none of the known pentazocine esters has been used for long-acting injectable purposes for parenteral administration.

[0014] Patent documents of the present inventors:

[0015] CN111349111, a pentazocine prodrug, a preparation method thereof, and use thereof.

[0016] Application No. 202510157222.2, a pentazocine glycolate benzoate and a preparation method and use thereof.

[0017] Therefore, there is still a need in the art to develop a suitable pharmaceutical composition to enable pentazocine to exhibit long-acting analgesic action. SUMMARY

[0018] Pentazocine ordinary tablets (TALWIN ) oral drug dissolution is slow or not completely dissolved, and due to the influence of first-pass metabolism, the bioavailability is lower, only about 18%~22%, and the metabolism is extensive, and large post-marketing surveillance surveys show that the gastrointestinal side effects are extremely large. Pentazocine injection Although intravenous drugs have high bioavailability, intravenous injection has a short half-life in the body and a short average residence time, which can lead to an increase in the number of doses, resulting in reduced patient compliance, lower bioavailability, and limited clinical application. In addition, the short duration of action of immediate-release injection limits its use to 3-4 hours, and the duration of postoperative pain relief is short. Therefore, the design and preparation of suitable pentazocine formulations to extend the duration of action meet the clinical needs.

[0019] Based on the above, the applicant tried to extend the duration of action of pentazocine. In the present application, several pharmaceutical compositions containing pentazocine ester derivatives and a selected oil carrier are prepared. These compositions have been shown to exhibit long-acting analgesia for up to several days (e.g., 3 to 5 days).

[0020] The present application modifies the structure of pentazocine to prepare a prodrug with long-acting properties. This type of drug is prepared into an intramuscular, subcutaneous or intravenous preparation by formulation means, which forms a drug depot in the body after intramuscular, subcutaneous or intravenous injection, and the drug is slowly, continuously and stably released from the depot and converted into pentazocine, thereby exerting a long-acting effect. The present application uses the following technical solutions to achieve this:

[0021] The present application aims to overcome the shortcomings in the prior art and provides a bis-pentazocine ester compound or a pharmaceutically acceptable salt thereof represented by formula (I):

[0022]

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

[0024] Another object of the present application is to provide a preparation method of bis-pentazocine ester, which comprises esterification of pentazocine with sebacoyl chloride in an organic solvent and a base acid-binding agent, and the reaction formula is as follows:

[0025]

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

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

[0028] As a known technology, this technology has been successfully used in clinically marketed drugs, such as flupentixol decanoate (FDA, Injectable solutions. Gelders reported in International Clinical Psychopharmacology, (1986) Vol.1, 1-11, and CNHinko et al. reported in Neuropharmacology, (1988) Vol.27, 475-483, the formulation of controlled-release formulations containing decanoate in injectable oils (such as sesame oil or soybean oil), which prolongs the stabilizing effect of the formulation, allowing the dosing interval to be extended from 2 to 4 times a day to 1 to 2 times a month; another example is fluphenazine decanoate injection (FDA, ), TRNorman in

[0029] International Clinical Psychopharmacology, (1987) Vol.2, 299-305 reported the preparation of fluphenazine decyl ester from fluphenazine. CNHinko reported the preparation of an ester of nipectic acid in Neuropharmacology, (1988), Vol.27, 475-483. CLBroekkamp...

[0030] The Journal of Pharmacy and Pharmacology (1988) Vol.40, 434-437 reported the preparation of nicotinylmorphine ester from morphine. JVJoshi et al. reported a prodrug of norethindrone heptaate in Steroids (1989) Vol.53, 751-761, which can be formulated with longer dosing intervals of up to 2 months.

[0031] However, due to unknown factors present in nature, sometimes the drug of interest is released rapidly from the oil vehicle. For example, testosterone has been found to be released rapidly from a suspension of testosterone for intramuscular administration (T. Tanaka (1974), Chemical & Pharmaceutical Bulletin, Vol. 22, pp. 1275-1284). H. A. C. Titulaer reported that artemisinin was added to parenteral oils to form various dosage forms for intramuscular, intravenous, oral or rectal administration. However, the drug was released rapidly 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 rate and extent of release from dosage forms for parenteral administration were very irregular and variable.

[0032] Based on the foregoing studies, dosage forms containing a drug composition suspended or dissolved in an oil vehicle do not necessarily exhibit longer duration of therapeutic utility. In general, any attempt to incorporate a drug of interest into an oil vehicle for the purpose of obtaining a long-acting dosage form requires consideration of the physical solubility, stability and release rate of the drug of interest from the vehicle.

[0033] Based on the foregoing, in order to achieve the goal of extending the duration of action of pentazocine, the present inventors provide a long-acting pharmaceutical composition comprising a pentazocine ester derivative of formula (I) and pharmaceutically acceptable adjuvants, preferably the long-acting pharmaceutical composition is for injection.

[0034] It is another object of the present application to provide a pharmaceutical composition comprising:

[0035]

[0036] wherein the injection oil is selected from the group consisting of 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 application also provides that the long-acting injection suspension aid is selected from one or more of sodium carboxymethyl cellulose, aluminum stearate; the dispersing agent is selected from one or more of Tween 80, lecithin, glycerol monostearate; and the antioxidant is selected from one or more of benzyl alcohol, vitamin E.

[0038] It is yet another object of the present application to provide a method for preparing the long-acting injection, comprising the steps of:

[0039] 1) Take the prescribed amount of suspending agent into the oil for injection, heat and stir until dissolved, stop heating when the oil solution is clear and transparent golden yellow, and let cool to room temperature;

[0040] 2) Add the prescribed amount of dispersing agent and antioxidant to the oil in step 1, and stir until uniform;

[0041] 3) Add the raw drug of the compound of formula (I) to step 2 in portions, stir while adding, and mix until uniform, then add oil for injection to the volume;

[0042] 4) Put the uniform mixture in step 3 into a ball mill for grinding, preferably at a speed of 700-900 rpm;

[0043] Further preferably, grind for 3 minutes and stop for 5 minutes per cycle;

[0044] Further preferably, grind for a total of 5 cycles;

[0045] 5) Fill the solution in step 4 into a vial, ampoule or pre-filled syringe, fill the headspace with nitrogen, and seal;

[0046] 6) Sterilize at high temperature to obtain the product, preferably at a temperature of 100-130℃, and further preferably at 121℃.

[0047] Another object of the present application is the use of the compound or pharmaceutical composition thereof in the preparation of various acute and chronic pain medications.

[0048] The gist of the present application is:

[0049] The compound has good solubility and is suitable for preparation into an injection solution. The compound has good stability and is essentially non-toxic to normal human liver cells. Animal efficacy experiments and safety experiments show that the compound has good efficacy and a long-lasting analgesic effect, and does not cause obvious irritation to local tissues, showing good safety and tolerability. Animal pharmacokinetic experiments show that the compound has a long half-life and can achieve a long-acting release effect. BRIEF DESCRIPTION OF DRAWINGS

[0050] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the specific embodiments or prior art description will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0051] Figure 1 The structural formula of pentazocine didecanoate.

[0052] Figure 2The hydrogen spectrum of pentazocine bis-decanedioate ester.

[0053] Figure 3 The carbon spectrum of pentazocine bis-decanedioate ester.

[0054] Figure 4 The IR of pentazocine bis-decanedioate ester. DETAILED DESCRIPTION

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

[0056] The present application will be further explained and described below in conjunction with specific embodiments.

[0057] Example 1:

[0058]

[0059] 100 mg pentazocine, 35 mg triethylamine and 20 ml dichloromethane were added into a 50 ml reaction bottle, cooled to 0-5 ℃, and 42 mg sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10 ℃. After dropwise addition, 20-25 ℃ reaction was carried out for 2 hours, and spot plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed. 20 ml purified water was washed once, dried, concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50) to obtain 0.19 g of light yellow oil, HPLC 97.84%, yield: 75.6%.

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

[0061] 1 H-NMR (400MHz, 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] 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 Double bond s 1643,1608,1583 Benzene ring skeleton C=C stretching vibration Benzene ring w, s, s 1492 C-H bending vibration Methylene group s 1375,1325 C-H bending vibration Methyl group m, s 1139 C-O stretching vibration Ar-O-C (phenolic hydroxyl group) s 1072,1012 Ring breathing vibration Cyclohexyl group s, s 902,844 =C-H out-of-plane bending vibration 1, 2, 4-trisubstituted benzene s, s

[0066] IR:

[0067] Example 2:

[0068] 2g pentazocine, 0.71g triethylamine and 30ml dichloromethane were added into a 50ml flask, cooled to 0-5°C, 0.84g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10°C. After dropwise addition was completed, 20-25°C reaction for 2.5 hours, the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed, 30ml purified water was washed once, dried, concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50), 4.18g light yellow oil was obtained, yield: 81%.

[0069] Example 3:

[0070] 10g pentazocine, 3.55g triethylamine and 200ml dichloromethane were added into a 500ml flask, cooled to 0-5°C, 4.19g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10°C. After dropwise addition was completed, 20-25°C reaction for 4 hours, the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed, 200ml purified water was washed once, dried, concentrated, and the residue was added to 200ml isopropyl ether, 0-5°C stirring for 1h, filtered, and the filtrate was concentrated, 19.3g light yellow oil was obtained, yield: 75.0%.

[0071] Example 4:

[0072] 1 g pentazocine, 0.45 g DIPEA and 20 ml dichloromethane were added to a 50 ml reaction flask, cooled to 0-5 °C, and 0.42 g sebacoyl chloride was added dropwise, the temperature of which was not more than 10 °C. After the addition was completed, it was reacted at 20-25 °C for 2 hours, and the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed. It was washed once with 20 ml purified water, dried, concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50) to obtain 1.53 g of a yellowish oil, with a yield of 79.1%.

[0073] Example 5:

[0074] 1 g pentazocine, 0.28 g pyridine and 20 ml dichloromethane were added to a 50 ml reaction flask, cooled to 0-5 °C, and 0.42 g sebacoyl chloride was added dropwise, the temperature of which was not more than 10 °C. After the addition was completed, it was reacted at 20-25 °C for 1 hour, and the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed. It was washed once with 20 ml purified water and once with 20 ml 2N hydrochloric acid, dried, concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50) to obtain 1.53 g of a yellowish oil, with a yield of 79.1%.

[0075] Example 6:

[0076] 2 g pentazocine, 0.71 g triethylamine and 30 ml toluene were added to a 50 ml reaction flask, cooled to 0-5 °C, and 0.84 g sebacoyl chloride was added dropwise, the temperature of which was not more than 10 °C. After the addition was completed, it was reacted at 20-25 °C for 2.5 hours, and the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed. It was filtered, the filtrate was concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50) to obtain 4.02 g of a yellowish oil, with a yield of 78.3%.

[0077] Example 7:

[0078] 1 g pentazocine, 0.28 g pyridine and 20 ml toluene were added to a 50 ml reaction flask, cooled to 0-5 °C, and 0.42 g sebacoyl chloride was added dropwise, the temperature of which was not more than 10 °C. After the addition was completed, it was reacted at 20-25 °C for 1 hour, and the plate (developing agent: MeOH: DCM = 1:20) showed that the reaction was completed. It was filtered, the filtrate was concentrated, and passed through a silica gel column (developing agent: MeOH: DCM = 1:50) to obtain 1.39 g of a yellowish oil, with a yield of 72.2%.

[0079] Example 8:

[0080] 1 g pentazocine, 0.45 g DIPEA and 20 ml dichloromethane were added into a 50 ml flask, cooled to 0-5 °C, 0.42 g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10 °C. After dropwise addition was completed, 20-25 °C was reacted for 2 hours, the plate was spotted (developing agent: MeOH: DCM = 1:20) to show that the reaction was completed, filtered, the filtrate was concentrated, and the silica gel column (developing agent: MeOH: DCM = 1:50) was used to obtain 1.65 g of light yellow oil, yield: 85.5%.

[0081] Example 9:

[0082] 1 g pentazocine, 0.45 g DIPEA and 20 ml dichloromethane were added into a 50 ml flask, cooled to 0-5 °C, 0.42 g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10 °C. After dropwise addition was completed, 20-25 °C was reacted for 2 hours, the plate was spotted (developing agent: MeOH: DCM = 1:20) to show that the reaction was completed, filtered, the filtrate was concentrated, and the silica gel column (developing agent: MeOH: DCM = 1:50) was used to obtain 1.65 g of light yellow oil, yield: 85.5%.

[0083] Example 10:

[0084] 1 g pentazocine, 0.45 g DIPEA and 20 ml dichloromethane were added into a 50 ml flask, cooled to 0-5 °C, 0.42 g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10 °C. After dropwise addition was completed, 20-25 °C was reacted for 2 hours, the plate was spotted (developing agent: MeOH: DCM = 1:20) to show that the reaction was completed, filtered, the filtrate was concentrated, and the silica gel column (developing agent: MeOH: DCM = 1:50) was used to obtain 1.65 g of light yellow oil, yield: 85.5%.

[0085] Example 11:

[0086] 1 g pentazocine, 0.45 g DIPEA and 20 ml dichloromethane were added into a 50 ml flask, cooled to 0-5 °C, 0.42 g sebacoyl chloride was added dropwise, the temperature of dropwise addition was not more than 10 °C. After dropwise addition was completed, 20-25 °C was reacted for 2 hours, the plate was spotted (developing agent: MeOH: DCM = 1:20) to show that the reaction was completed, filtered, the filtrate was concentrated, and the silica gel column (developing agent: MeOH: DCM = 1:50) was used to obtain 1.65 g of light yellow oil, yield: 85.5%.

[0087] Example 12:

[0088] 1 g pentazocine, 0.28 g pyridine and 20 ml acetonitrile were added to a 50 ml reaction flask, cooled to 0-5 °C, and 0.42 g sebacoyl chloride was added dropwise, the temperature of which was not more than 10 °C. After the dropwise addition was completed, the reaction was carried out at 20-25 °C for 1 hour, and the reaction was shown to be completed by spotting (developing agent: MeOH: DCM = 1:20). Filtration was carried out, and the filtrate was concentrated to dryness, yielding 1.31 g of a yellowish oil, with a yield of 67.87%.

[0089] Comparative Example 1:

[0090] Sebacoyl chloride was replaced with decanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.09 g of decanoic acid pentazocine ester, with a yield of 59.0%.

[0091] Comparative Example 2:

[0092] Sebacoyl chloride was replaced with dodecanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.22 g of dodecanoic acid pentazocine ester, with a yield of 83.3%.

[0093] Comparative Example 3:

[0094] Sebacoyl chloride was replaced with nonanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.16 g of nonanoic acid pentazocine ester, with a yield of 66.3%.

[0095] Comparative Example 4:

[0096] Sebacoyl chloride was replaced with octanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.13 g of octanoic acid pentazocine ester, with a yield of 55.0%.

[0097] Comparative Example 5:

[0098] Sebacoyl chloride was replaced with hexanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.14 g of hexanoic acid pentazocine ester, with a yield of 62.0%.

[0099] Comparative Example 6:

[0100] Sebacoyl chloride was replaced with dodecanoyl chloride, and the preparation method was the same as in Example 1, yielding 0.18 g of dodecanoic acid pentazocine ester, with a yield of 67.2%.

[0101]

[0102] These typical long-acting prodrugs, among which sebacic acid pentazocine ester, are particularly significantly non-obvious long-acting.

[0103] Example 13: Investigation of solubility in oil

[0104] In the invention of the oil phase, typical representatives of the compounds of the invention were selected, and the screening was as follows:

[0105]

[0106]

[0107] The results show that the sesame oil is superior to other injection oils.

[0108] The following compounds are each formulated into a 90mg / ml sesame oil solution, and the solubility thereof is observed, and further investigation is made as to whether an oil suspension can be prepared for medicinal use.

[0109]

[0110]

[0111] Conclusion: The pentazocine didecanedioate of the present application is most suitable for further drug development.

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

[0113] Preparation process:

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

[0115] 2) Add the prescribed amount of dispersant and antioxidant to the oil of step 1 and stir until uniform;

[0116] 3) Add the pentazocine didecanedioate to step 2 in portions, stirring while adding, and mix until uniform, then add injection oil to volume;

[0117] 4) Put the initial suspension of step 3, which is mixed uniformly, into a ball mill and grind at a speed of 700-900 rpm, grind for 3 minutes per cycle and stop for 5 minutes, for a total of 5 cycles;

[0118] 5) Fill the solution of step 4 into a vial, ampoule or pre-filled syringe, and seal with a nitrogen headspace;

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

[0120] Table 1: Injection prescription

[0121]

[0122]

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

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

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

[0126] Take 1ml dichloromethane, ethanol, benzyl alcohol, NMP, ethyl acetate, acetone, acetonitrile, pyridine, THF in 1.5ml EP tube, add excess pentazocine didecanedioic acid ester, vortex for 30min, ultrasonic for 5min, in 20℃ constant temperature oscillation water bath, oscillation speed 90RPM, take sample every 24h until equilibrium. Each time take supernatant, 12000r / min centrifugation for 3min, take 0.1ml supernatant, dilute with methanol, then use high performance liquid chromatograph for sample analysis, take sample to direct dissolution until complete equilibrium.

[0127] Table 2: Apparent solubility of pentazocine didecanedioic acid ester in different organic solvents

[0128]

[0129] The solubility in different organic solvents shows that the polarity of pentazocine didecanedioic acid ester is very small, and at the same time, it retains the polarity containing N, which can significantly realize long-acting, and provides basis for long-acting solvent selection.

[0130] 2. Solubility detection in simulated human buffer.

[0131] The purpose of the present application is long-acting injection, and the active ingredient of its metabolism is pentazocine. Referring to the solubility determination method in <General Rules> of Chinese Pharmacopoeia 2020 Edition, the precursor drug and its metabolite pentazocine are detected, and the specific solubility difference is shown in the following table:

[0132] Table 3: Solubility of pentazocine didecanedioic acid ester in simulated human buffer

[0133]

[0134] The solubility of pentazocine didecanedioic acid ester in water is very low, which belongs to a poorly soluble drug, and its solubility decreases with the increase of pH. The above results show that the solubility of pentazocine didecanedioic acid ester in aqueous solution is very low. According to Noyes-Whitney equation, the dissolution rate of the drug is positively correlated with the solubility. Therefore, the dissolution rate of pentazocine didecanedioic acid ester in water may also be slow. The slow dissolution rate is beneficial to the realization of slow release, which meets the principle of long-acting metabolism.

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

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

[0137] An excess of pentazocine bisdecaenoate was dispersed in different dissolution media to obtain the corresponding supersaturated solutions, which were placed in 10 ml test tubes with stoppers, and shaken at 90 rpm for 72 h in a 37°C constant temperature water bath. The solubility was measured every 24 h. When measuring the solubility, the supernatant was filtered with a 0.45 μm microporous filter, 2 ml of the initial filtrate was discarded, and 1 ml of the subsequent filtrate was used for sample analysis by high performance liquid chromatography. The solubility of pentazocine bisdecaenoate in different dissolution media was calculated by the external standard method. The whole process was carried out quickly, and after the sample was taken out, further dilution was carried out in a 37°C water bath to prevent the influence of temperature change on the solubility.

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

[0139]

[0140]

[0141] The solubilization of surfactants to poorly soluble drugs is achieved by forming micelles. When the concentration of surfactants exceeds the critical micelle concentration, the solubility of poorly soluble drugs is significantly improved. With the increase of its concentration, the solubilization of poorly soluble drugs increases linearly, and the long-term concentration dependence is consistent.

[0142] Example 16: Stability test.

[0143] 1. Accelerated test:

[0144] Pentazocine bisdecaenoate will be used as a raw material for the preparation of suspension injection in the future, so the storage problem is very critical. During storage, other impurities may be introduced or generated, affecting the use of the raw material, so the stability of the raw material of the present application is investigated. According to the ICH Guideline for Stability Testing of New Drug Substances and Products, an accelerated test was conducted to investigate the effects of temperature, humidity, and light on the raw material. The conditions were set as follows: temperature 40 ± 2°C, humidity 75% ± 5%, light 4500 lx, and sampling every 10 days. The results are shown in the following table.

[0145] Table 5: Stability test results of pentazocine bisdecaenoate

[0146]

[0147] Conclusion: As shown in the table, the raw material of the application is relatively stable under the relevant conditions, and no obvious impurities are generated, so the raw material can be stored at room temperature after preparation.

[0148] 2. Heating stability research under nitrogen protection:

[0149] The sample obtained by the melting method was precisely weighed at 10 mg, dissolved with pure acetonitrile to 50 ml, diluted 10 times with mobile phase B, and 20 μl was injected into the high performance liquid chromatograph to record the chromatogram, and the percentage content was calculated by the external standard method.

[0150] Table 6: Results of heating stability research under nitrogen protection

[0151]

[0152] Conclusion: After heating the sample to a high temperature of 230°C under nitrogen protection and then cooling to room temperature, the pethidate ester of didecanedioic acid is very stable, and the pethidate monodecanoate is unstable.

[0153] Example 17: Experimental research on in vitro cytotoxicity of normal human liver cells.

[0154] 1. Experimental materials:

[0155] 1.1 Cell: L02 cell, which is a human liver cell strain;

[0156] 1.2 Drug: Pethidate ester of didecanedioic acid, HPLC purity 97.84%;

[0157] 1.3 Reagents and instruments: Modified RPMI-1640 medium, penicillin-streptomycin double-antibiotic 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 electric heating constant temperature water bath, RT-2100C type enzyme marker analyzer.

[0158] 2. Experimental method:

[0159] 2.1 Preparation of reagents:

[0160] 2.1.1 Preparation of MTT: 0.5 g of MTT was weighed with a precision balance and placed in a 50 mL volumetric flask, appropriate PBS was added, 40-50°C water bath was used, and shaking was performed until dissolution was complete. PBS was added to the calibration mark to prepare a 10 mg / kg solution, which was filtered with a 0.22 μm microporous filter to remove bacteria, and then stored in a 4°C refrigerator in the dark.

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

[0162] 2.1.3 Preparation of the compound of the present application The DMSO is used to prepare the mother liquor of the medicine, and then diluted with the culture solution to the concentration of the medicine used, and the final concentration of DMSO is controlled to be ≤0.1%.

[0163] 2.2 Culture of LO2 cells The human normal LO2 cells are placed in 25 cm 2 cell culture bottles, 4-5 mL of RPMI-1640 culture solution containing 10% FBS is added, and the cells are cultured in a 37°C cell culture box with 5% CO2 saturated humidity. The culture solution is replaced every 2 days, the cell growth is observed every day, and the cells are passaged or frozen when the cells are 80% confluent. The cells of 5-7 generations are used for formal test.

[0164] 2.3 Grouping and administration The experiment is divided into a normal cell control group, and different concentrations of the administration group of the present application are set according to the results of the pre-experiment, and the concentrations are 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0 and 375.0 μmol / L.

[0165] 2.4 MTT colorimetric determination of liver cells The LO2 cells in the logarithmic growth phase are prepared into a cell suspension of 5.0×103 / mL, inoculated in a 96-well plate, and a normal control group is set. The administration group of the present application with different concentrations of 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0 and 375.0 μmol / L is set. After 24 h of culture, the culture solution is aspirated, washed with PBS for 2-3 times, and the above-mentioned different concentrations of the compound of the present application are added, 8 replicate wells are set for each concentration, and the plate is cultured in a 37°C, 5% CO2 incubator. After 24, 48 and 72 h of culture, MTT solution is added at each time point, and the plate is cultured in the dark for 4 h. After 4 h, the upper culture medium is aspirated, 150 L of DMSO solvent is added to each well to dissolve the thiazolyl blue crystals, and the plate is shaken gently to make the dissolution uniform. The absorbance value of each well is measured by a microplate reader at 490 nm. The absorbance value of each well is proportional to the number of cells, and the two are positively correlated. The experiment is repeated for 3 times. The cell viability rate is calculated as follows: cell viability rate (%) = absorbance (OD490) of each group × 100 / absorbance (OD490) of the control group.

[0166] 2.5 Statistical analysis All data are represented by mean ± standard deviation, and the data are processed by SPSS 17.0 statistical software package. The t test is used for statistical analysis, the paired t test is used for self-comparison, the unpaired t test is used for comparison between groups, and the test standard is P<0.05.

[0167] 3. Experimental results:

[0168] Table 7 Experimental results of dodecanedioic acid pentazocine ester in vitro cytotoxicity of normal human hepatocytes

[0169]

[0170] Conclusion: After 72 hours of administration of the present application at different concentrations, the OD values of the cells in each group showed a growth trend, but the growth rate decreased, indicating that the cells were still in the growth stage and the growth rate was inhibited. The different concentrations of the present application had no inhibitory effect on the cells, and the survival rate of the cells was greater than 90% compared with the normal group. Within the range of 1.25-375.0 μmol / L, the present application had almost no inhibitory effect on cell growth and was non-toxic to cells.

[0171] Example 18: In vivo pharmacodynamic evaluation.

[0172] 1. Experimental animals:

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

[0174] 2. Experimental method:

[0175] 2.1 Model preparation:

[0176] The model group rats were established to have inflammatory pain model of rat foot swelling by subcutaneous injection of 100 μL complete Freund's adjuvant on the left foot of the rats, and the injection site was massaged after injection to promote absorption. The day of modeling was set as day 0.

[0177] 2.2 Grouping:

[0178] The experimental animals were divided into 4 groups according to the basic nociceptive threshold, 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 the use of animals in pain research.

[0179] 2.3 Determination of nociceptive threshold:

[0180] According to the principle of Von frey fiber determination of rat mechanical response threshold, the Von Frey nociceptive tester is used to measure the nociceptive value of the injected foot of the experimental animal, the measurement site is between the second and third toe of the foot bottom, and the nociceptive pain threshold (PWT) causing the positive paw withdrawal of the rat is used to represent. In this experiment, the positive paw withdrawal of the rat is judged as rapid lifting or shaking. The test site of the blank control group is consistent with that of the model group. The parallel experimental method of each group is adopted for each measurement. In a quiet environment, the rats to be measured are placed in the iron cage. After each rat adapts to the environment of the iron cage for 10 minutes, the nociceptive pain threshold is determined. Each determination is five times, and each interval is 5 minutes. The minimum pressure value causing the positive reaction is taken as the nociceptive threshold (PWT) of the animal.

[0181] 2.4 Dosing regimen:

[0182] The rats receive 100 μL of complete Freund's adjuvant (CFA) in the subcutaneous tissue of the foot. The nociceptive pain threshold is measured before CFA injection and used as the baseline PWT. The pain threshold of the injection site of the rat is determined every day after CFA injection until the pain threshold of the rat is reduced to the minimum, and the drug can be administered. The rats can be dosed on the 5th day after CFA administration. According to the experimental grouping, the experimental group uses the long-acting injection of Example 14 injection No. 1 (dissolved in sesame oil) (low, medium and high doses are 3 mg / kg, 4.5 mg / kg and 6 mg / kg, respectively), the positive control group is pentazocine immediate-release injection (dissolved in sesame oil, with benzyl alcohol 1.2%) (1.5 mg / kg), the blank control group is long-acting injection without drug (sesame oil + benzyl alcohol 1.2%), and the negative control group uses normal saline (0.2 mL per rat). The injection of each group is injected into the subcutaneous tissue of the foot of the rat, and the nociceptive pain threshold is determined according to the conditions in item 2.3 after administration. The determination time is before administration, 1 h, 2 h, 3 h, 6 h, 24 h, 30 h, 48 h, 54 h and 72 h after administration, so as to compare the changes of the nociceptive pain threshold of 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 application has a significantly prolonged drug effect duration compared with pentazocine immediate-release injection, indicating that the long-acting injection has a long-acting analgesic effect.

[0188] Example 19: Evaluation of the irritability experiment.

[0189] 30 SD rats (200 ± 10 g) were randomly divided into five groups: blank control group, didecanedioic acid pentazocine ester group, pentazocine decanoate group, bis-pentazocine nonanedioate group, bis-pentazocine undecanedioate group. The right hind foot of rats in five groups were injected with normal saline and didecanedioic acid pentazocine ester solution, pentazocine decanoate solution, bis-pentazocine nonanedioate solution, bis-pentazocine undecanedioate solution, respectively, 0.1 mL (the solution of the above compounds was prepared according to the method of Example 14 No. 1, i.e. compound 90 mg, benzyl alcohol 1.2% (w / v), sesame oil to the volume, prepared into a solution with a concentration of 90 mg / ml) was observed and recorded the first time of licking foot and the total licking foot time within 30 min.

[0190] Table 9: Initial licking foot time

[0191]

[0192] Table 10: Total licking foot time

[0193]

[0194] Conclusion: The average initial licking foot time of the blank control group and the didecanedioic acid pentazocine ester group was 16.7 min and 17.5 min, respectively, and there was no significant difference between the two groups. Within half an hour of administration, the average licking foot time of the didecanedioic acid pentazocine ester group was longer than that of the control group. It showed that the didecanedioic acid pentazocine ester group had less irritation and high safety. On the contrary, the average licking foot time of the pentazocine decanoate group, bis-pentazocine nonanedioate group, and bis-pentazocine undecanedioate group was shorter than that of the control group, which had partial irritation.

[0195] Example 20: Pharmacokinetic study in rats in vivo.

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

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

[0198] 2. Preparation of plasma samples:

[0199] Blank plasma sample: The blank plasma of rats was taken, after thawing, 100 μL was accurately measured in a 1.0 mL centrifuge tube, 600 μL of 4% glacial acetic acid methanol was added, vortex mixed for 5 min, centrifuged at 9000 rpm for 10 min to precipitate the protein, the supernatant was taken into a 1.0 mL centrifuge tube, and was evaporated at 40°C. Methanol was added to the residue for redissolution, vortex oscillation for 6 min, ultrasonic for 15 min, and centrifuged at 13000 rpm for 20 min, and the supernatant was the blank plasma sample solution.

[0200] Plasma sample after administration: The plasma of rats after administration was taken, after thawing, 100 μL was accurately measured in a 1.0 mL centrifuge tube, 10 μL of internal standard methadone 1 μg / mL (dissolved in methanol) was added, vortex mixed for 1 min. 600 μL of 4% glacial acetic acid methanol was added, vortex mixed for 5 min, centrifuged at 9000 rpm for 1 min to precipitate the protein, the supernatant was taken into a 1.0 mL centrifuge tube, and was evaporated at 40°C. Methanol was added to the residue for redissolution, vortex oscillation for 6 min, ultrasonic for 15 min, and centrifuged at 13000 rpm for 20 min after the drug was fully dissolved, and the supernatant was the plasma sample solution after administration.

[0201] 3. Administration scheme and sample collection:

[0202] Twelve rats were randomly divided into two groups, 6 rats in each group, and were respectively injected with the oil suspension of injection solution No. 1 of Example 14 of the application at a dose of 7 mg / kg. At 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48 h, 96 h, 144 h, 192 h, 240 h after administration, blood was collected from the orbital vein of the rats, about 0.25 mL each time, added to a heparin sodium treated anticoagulant tube, centrifuged at 4000 rpm for 10 min, the upper plasma was separated and stored at -20°C for analysis and detection.

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

[0204] The plasma sample after administration was treated according to the method under 2. Preparation of plasma sample, and was injected according to the chromatographic conditions under 1. Analysis method of high performance liquid chromatography in vivo, the peak area ratio of the main drug to the internal standard peak was substituted into the standard curve to calculate the blood drug concentration, and the results were processed by Phoenix software to calculate the related pharmacokinetic parameters.

[0205] 5. Results:

[0206] Table 11: Results of pharmacokinetic study of dodecanedioic acid pentazocine ester in rats in vivo

[0207] Parameter Unit Pentazocine bisdecaate 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 this invention can be slowly, continuously, and stably released in vivo and converted into pentazocine, thereby exerting a long-lasting effect. Simultaneously, the stable release achieves a long-lasting release effect.

[0209] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions 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 compound of pentazocine diester represented by the formula (I) or its pharmaceutically acceptable salt: ###0001### (I) wherein n is 2. wherein: comprising the following steps:

2. A process for the preparation of the bis-pentazocine ester compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized by: The compound of pentazocine diester is prepared by esterification of pentazocine with diacyl chloride in the presence of organic solvent and base acid binding agent, the reaction formula is as follows: wherein n is the same as defined in claim 1. The compound of claim 1 and other pharmaceutically acceptable adjuvants.

3. A pharmaceutical composition, characterized by The compound of claim 1 and other pharmaceutically acceptable adjuvants.

4. The pharmaceutical composition of claim 3, wherein The injection oil is selected from the group consisting of olive oil, corn oil, sesame oil, peanut oil, almond oil, coconut oil, poppy seed oil, cottonseed oil and castor oil.

5. The pharmaceutical composition of claim 4, characterized in that: The injection oil is selected from the group consisting of sesame oil.

6. The pharmaceutical composition of claim 4, characterized in that: The suspending agent is selected from the group consisting of sodium carboxymethyl cellulose, aluminum stearate, one or more thereof; the dispersing agent is selected from the group consisting of tween 80, lecithin, glycerol monostearate, one or more thereof; the antioxidant is selected from the group consisting of benzyl alcohol, benzyl benzoate, vitamin E, one or more thereof.

7. The pharmaceutical composition of claim 4, wherein: comprising the following steps:

8. A process for the preparation of a pharmaceutical composition as claimed in claim 4, characterized in that: 1) A prescribed amount of suspending agent is added to the injection oil, heated while stirring to dissolve, stop heating when the oil solution is clear and transparent golden yellow, and let it cool to room temperature; 2) Add a prescribed amount of dispersing agent and antioxidant to the oil of step 1, and stir until uniform; 3) Add the compound of formula (I) raw material to step 2 in portions, stirring while adding, mix well, and then add injection oil to volume; 4) Put the well-mixed initial suspension of step 3 into a ball mill for grinding; 5) Fill the solution of step 4 into a vial, ampoule or pre-filled syringe, fill the headspace with nitrogen, and seal; 6) High temperature sterilization, and the product is ready. The pharmaceutical composition is administered by intramuscular injection.

9. The pharmaceutical composition of claim 4, wherein:

10. Use of the compound of claim 1 or the pharmaceutical composition of any one of claims 4-7 for the preparation of a medicament for the treatment of various acute and chronic pain. ​

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