CN111217749A

CN111217749A - Deuterated pentazocine, preparation method, medical composition and application

Info

Publication number: CN111217749A
Application number: CN202010177342.6A
Authority: CN
Inventors: 徐奎; 刘逸凡
Original assignee: Anhui Yixinming Pharmaceutical Technology Co ltd
Current assignee: ANHUI HEAL STAR PHARMACEUTICAL Co.,Ltd.
Priority date: 2020-03-13
Filing date: 2020-03-13
Publication date: 2020-06-02
Also published as: WO2021180081A1

Abstract

The invention relates to deuterated pentazocine shown in a formula I and pharmaceutically acceptable salts thereof. The invention also provides a novel compound used as various acute and chronic pain easing medicines, a preparation method thereof and a pharmaceutical composition containing the compound. Compared with the non-deuterated pentazocine, the pentazocine has the advantages of improving pharmacokinetics, having better metabolic stability, prolonging the half-life period of the pentazocine and improving the bioavailability of the pentazocine.

Description

Deuterated pentazocine, preparation method, medical composition and application

One, the technical field

The invention relates to the field of medicine, in particular to deuterated pentazocine shown in a formula I, a pharmaceutically acceptable salt thereof, a preparation method, a medicinal composition and application thereof as an analgesic medicament for treating acute and chronic pain.

Second, background Art

Deuterium is essentially the same shape and volume as hydrogen in a drug molecule, and if hydrogen in a drug molecule is selectively replaced by deuterium, deuterated drugs will generally retain the original biological activity and selectivity. Meanwhile, experiments prove that the combination of carbon and deuterium bonds is more stable than carbon-hydrogen bonds, and the absorption, distribution, metabolism, excretion and other properties of certain drugs can be directly influenced, so that the curative effect, safety and tolerance of the drugs are improved. Therefore, if a certain specific carbon-hydrogen bond to be decomposed in the drug molecule is replaced by a corresponding carbon-deuterium bond, the decomposition process of the drug molecule can be delayed, so that the deuterium-substituted drug can act in the body for a longer time, and the effect of the drug molecule is better than that of the original drug. Such as: first clinical experiments show that the metabolism speed of venlafaxine and its deuterated compounds is half of that of venlafaxine, so that the venlafaxine has longer duration in vivo than venlafaxine and more obvious curative effect. This demonstrates to some extent the superiority of the deuterated products in treating diseases.

The follow-up medicine is the follow-up and supplement of the initial medicine and is an important aspect of new medicine creation. The optimization of the pioneer medicines is full and the patent coverage is wide, so that the space for researching and developing the follow-up medicines is reduced, and the medicine supervision department requires that the quality of new medicines is superior to or not inferior to the quality of the existing medicines of the same kind, so that the medicines have high risk and are placed in the market later.

Pentazocine was successfully marketed in 1967 by the wensber group of stirling in the uk. Pentazocine is a derivative of benzomorphan, has mixed agonistic and antagonistic effects on opioid receptors, mainly activates opioid kappa receptors, can activate sigma receptors at a larger dose, and has partial agonistic or weak antagonistic effect on mu receptors. The pentazocine is suitable for relieving moderate to severe pain, and has wide clinical application, such as intraoperative auxiliary analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment and the like. The pentazocine tablet for oral administration is the only opioid agonist antagonist analgesic that can be orally taken at present.

Pentazocine hydrochloride, chemically (2RS, 6RS, 11RS) -cis-1, 2, 3, 4, 5, 6-hexahydro-6, 11-dimethyl-3- (3-methyl-2-butenyl) -2, 6-methylene-3-benzazocin-8-ol, having the following structural formula:

pentazocine is a cationic drug with high lipid solubility. Pentazocine is different from other mixed opioid receptor agonist antagonists such as butorphanol, nalbuphine and the like, and is the only opioid receptor agonist antagonist capable of increasing systolic pressure in the three. The pentazocine has wide clinical application, and a large number of researches prove that the pentazocine has definite analgesic effect and few adverse reactions.

The pharmacological action and clinical application of the pentazocine are calculated according to equivalent dose, the analgesic effect of the pentazocine is 1/3 of that of morphine, and the analgesic effect of 30mg injected subcutaneously or intramuscularly is equivalent to that of 10mg of morphine. The respiratory depression is about 1/2 of that of morphine; the respiratory depression effect is not enhanced in proportion by increasing the dosage to be more than 30 mg; when the dosage is 60-90 mg, the mental symptoms can be produced, and the naloxone with large dosage can resist the mental symptoms. The medicine can slow down gastric emptying and delay the time of conveying intestinal contents by an intestinal canal, but has weak excitation effect on biliary sphincter and unobvious rise of pressure in biliary tract. The effect on the cardiovascular system is different from that of morphine, but the large dose of morphine can increase the heart rate and increase the blood pressure. For patients with coronary heart disease, intravenous injection can increase average aortic pressure and left ventricular end diastolic pressure, thereby increasing the amount of heart work. The medicine can increase the level of noradrenaline in blood plasma, which is related to the function of the medicine to excite the cardiovascular system. Because the drug has a certain function of antagonizing mu receptors, the drug has little addiction, and non-narcotic drugs are listed in the drug administration of many countries. The composition can reduce analgesic effect of morphine; withdrawal symptoms can be promoted in patients who have developed tolerance to morphine. It has no obvious effect of antagonizing morphine in inhibiting respiration. Is suitable for various chronic severe pains, has good absorption after oral administration and injection, and reaches the peak value of blood concentration 0.25 to 1 hour after intramuscular injection. After oral administration, the first-pass elimination in the liver is obvious, and the pain easing effect entering the systemic circulation is less than 20%, so that the peak value of the blood concentration can be reached within 1-3 hours after oral administration, and the effect lasts for more than 5 hours after oral administration.

The clinical experience of the pentazocine applied abroad has been decades, but the pentazocine is applied only in recent years in China, the clinical experience is still few, especially the application of postoperative analgesia is still in the exploration stage at present, and the clinical research of large samples and multiple centers is still lacked.

Deuterium is a stable form of nonradioactive isotope of hydrogen, also known as deuterium. In the isotopic distribution of natural hydrogen, the abundance of deuterium is 0.015%. Deuterium has very low toxicity and contains about 10g of deuterium in adult bodies.

Many drugs have been hampered in their widespread use or limited in their use in certain indications by the presence of poor absorption, distribution, metabolism and/or excretion (ADME) properties. In addition to formulation technology and prodrug strategies, deuterium modification is also a viable approach to improve the properties of drug ADME. On the one hand, deuterium-substituted drugs generally retain the original biological activity if the hydrogen in the drug molecule is selectively replaced by deuterium, since deuterium is essentially the same shape and volume as hydrogen in the drug molecule. On the other hand, because the carbon-deuterium bond is lower than the vibration zero energy of the carbon-hydrogen bond and is more stable than the carbon-hydrogen bond, the hydrogen atom in the drug molecule is replaced by the deuterium atom, so that the decomposition process of the deuterium atom can be delayed, the acting time of the deuterated drug in vivo is longer, the purpose of changing the drug metabolism speed is achieved, and the pharmacokinetics and the pharmacodynamics of the drug are improved or the drug metabolism toxicity is reduced. For example, deutetrabenazine is approved by Auspex company by FDA in 2017, treats chorea such as central nervous disease Huntington's disease and is the first deutero drug approved by FDA in the world. Tetrabenazine is a compound known in the 50 th 20 th century, with oral tetrabenazine being oxidatively demethylated in the liver by CYP2D6, the first pass effect resulting in low bioavailability. The metabolic link is the oxidation of C-H of methoxy. Because the C-D bond is stronger than C-H, and the kinetic isotope effect (kH/kD is 6.5) is utilized, the deutetrabenazine is developed, deuteration is only carried out at the metabolic site, the metabolic stability is improved, and the dosage is reduced.

However, due to the complex metabolic processes of biological systems, the pharmacokinetic properties of drugs in the body are influenced by various factors and show corresponding complexity. The change in pharmacokinetic properties of deuterated drugs represents a great chance and unpredictability compared to corresponding non-deuterated drugs. Deuteration at some sites, not only does not prolong the half-life, but may shorten it, deteriorating its pharmacokinetic properties; on the other hand, hydrogen at some positions on a drug molecule is also not easily deuterated due to steric hindrance and the like, so that the deuteration of the drug is not random and a site capable of deuteration is unpredictable.

At present, people continuously try to develop deuterated drugs so as to find more effective therapeutic drugs for diseases. However, the research on deuterated pentazocine is relatively rare at present, and it is not yet clear which hydrogen is replaced by neon to be more beneficial for the efficacy.

The invention expects to obtain a class of deuterated drugs of metabolites with good pharmacokinetic properties, reduced dosage and reduced toxic and side effects by carrying out deuteration on pentazocine compounds.

Third, the invention

The applicant researches pentazocine from 2014, and after dozens of synthesis and pilot study from the fact that the applicant obtains a project from national amphetate department, the applicant finally reports the drug imitation registration of the bulk drugs and the injection. In the study of the pentazocine metabolic pathway, the pathway of the liver drug enzyme CYP450 and the like at the presumed metabolic site is as follows:

based on our laboratory findings and the literature teasing, current methods have the potential to prevent metabolism at these sites. Other sites on the molecule may also undergo transformations that result in metabolites with hitherto unknown pharmacology/toxicology. Limiting the production of these metabolites has the potential to reduce the risk of administration of such drugs and may even allow for increased dosages and/or increased efficacy.

The invention aims to provide deuterated pentazocine and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the novel compound and application of the novel compound in treating acute and chronic pain analgesics.

Specifically, the invention provides deuterated pentazocine shown in the following general formula I and pharmaceutically acceptable salts thereof:

the invention also provides a preparation method of the deuterated pentazocine and pharmaceutically acceptable salts thereof, which is characterized by comprising the following technical route:

wherein intermediate 1 of step 4: intermediate 2: the molar ratio of sodium bicarbonate is 1:1.1: 0.9.

The invention also provides deuterated pentazocine and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are hydrochloride and lactate.

Wherein deuterated pentazocine as the hydrochloride salt is used in the development of an oral formulation comprising an oral dosage form selected from the group consisting of: tablet, granule, capsule, sustained-release tablet and sustained-release capsule

Wherein deuterated pentazocine as lactate is used in the development of a formulation for parenteral administration, wherein said parenteral administration is selected from the group consisting of subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection and infusion.

The invention also provides a medicinal composition of the deuterated pentazocine and pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers, and the medicinal composition also comprises an additional therapeutic agent selected from one of naloxone hydrochloride, acetaminophen and aspirin. Further, the pharmaceutical composition is applied to the preparation of various acute and chronic pain easing medicaments, wherein the range of acute and chronic pain easing medicaments comprises the following components: analgesia of various surgical anesthetics, anesthesia induction, intraoperative anesthesia and postoperative analgesia; postoperative analgesia in various operating departments; analgesia of various endoscopic surgeries; analgesia of painless induced abortion; relieving pain for various cancer patients.

As used herein, "deuterated" refers to a compound or group wherein one or more hydrogens are replaced with deuterium. Deuterium can be mono-, di-, poly-, or fully substituted. In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content ((0.015%, more preferably > 50%, more preferably > 75%, more preferably > 95%, more preferably > 97%, more preferably > 99%, more preferably > 99.5%).

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The invention provides a deuterated pentazocine derivative by structurally modifying pentazocine and introducing deuterated hydrogen into the pentazocine, so that the pharmacokinetic property of the medicament is improved, the half-life period of the pentazocine is prolonged, and the bioavailability is improved. Has good social benefit and wide market application prospect.

Fourth, detailed description of the invention

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Example 1: preparation of deuterated pentazocine

1) Step 1: [4,4' -²H₆]Preparation of ethyl (E) -3-methyl-2-butenoate

Triethyl phosphonoacetate (39.3g, 0.176mol), dried tetrahydrofuran (350ml), cooled to-5-0 deg.C, slowly added n-butyllithium (0.16mol, 2.5M n-hexane solution) dropwise, gradually warmed to room temperature and stirred until bubbling stops, deuterated acetone (7.5g, 0.117mol) in 70ml of dried tetrahydrofuran solution is added to the phosphonic acid anion solution, the mixture was stirred at room temperature for 4-4.5 h, the end point was identified by TLC (pentane/ether: 2:1), then, 22mL of a saturated ammonium chloride solution was added to quench, the aqueous layer was extracted with isopropyl ether, the organic layers were combined, washed with brine (30mL × 3), dried over anhydrous magnesium sulfate, the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (pentane/diethyl ether ═ 2:1) to obtain 13.6g of the objective compound as a pale yellow oil, yield 86.6%, GC content 97.8%.

¹H-NMR(500MHz，CDCl₃/TMS，ppm)：

δ：5.61(s,1H),4.10(q,J＝11.9Hz,2H),1.22(t,J＝11.9Hz,3H)；

¹³C-NMR：165.9，154.2，115.1，59.1，14.2；

GC-MS(m/z)：134。

2) Step 2: [4,4' -²H₆]Preparation of (E) -3-methyl-2-butenol

[4,4'-²H₆]Ethyl-3-methyl-2-butenoate (13.4g, 0.1mol), 50ml tetrahydrofuran solution, cooled to-5-0 ℃, 150ml dry tetrahydrofuran solution of lithium aluminium hydride (4.0g, 0.105mol) was added dropwise with stirring, stirred at-5-0 ℃ for 0.5h, then stirred at room temperature for 45min, 80ml isopropyl ether was added, a mixture of 100g sodium sulfate and 30ml water was added at-5-0 ℃, stirred at room temperature for 0.5h, an additional 100g anhydrous sodium sulfate was added to remove water, filtered, the solid was washed with isopropyl ether and purified by flash column chromatography (pentane/diethyl ether 2:1) to give 6.8g of the target compound as a colorless oil, yield 74%, GC content 96.9%.

¹H-NMR(500MHz，CDCl₃/TMS，ppm)：

δ：5.33(t,J＝11.5,1H),4.04(d,J＝11.5Hz,2H),2.76(s,OH)；

¹³C NMR(CDCl₃)：135.3,123.7,59.1；

GC-MS(m/z)：92.18

3) And step 3: [4,4' -²H₆]Preparation of (E) -1-bromo-3-methyl-2-butene (intermediate 1)

[4,4'-²H₆]-3-methyl-2-butenol (6.5g, 0.07mol), 250mL of dry dichloromethane, adding boron tribromide (6.75mL, 0.07mol) through a syringe at 0 ℃, stirring at 5-0 ℃ for 30min, then stirring at room temperature for 30min, quenching reaction by ice, washing a dichloromethane layer by using brine (30mL multiplied by 3), drying by anhydrous magnesium sulfate, concentrating to dryness, distilling and purifying a crude product to obtain the [4,4' -²H₆]10.0g of (E) -1-bromo-3-methyl-2-butene (intermediate 1) were obtained as a colorless oil in a yield of 92.1% and a GC content of 98.5%.

¹H-NMR(500MHz，CDCl₃/TMS，ppm)：

δ：5.53(t,J＝14Hz,1H),3.98(d,J＝14Hz,2H)；

¹³C-NMR(CDCl₃)：140.2,121.4,29.5；

GC-MS(m/z)：155.0

4) And 4, step 4: preparation of deuterated pentazocine

Starting material 2(11.5g, 0.0528mol), which was made by the same company, was dissolved in 40ml of DMF, 4.39g (0.0522mol) of sodium bicarbonate was added, the mixture was stirred and heated to 105 to 110 ℃, and [4,4' -²H₆]9.0g (0.058mol) of 1-bromo-3-methyl-2-butene (intermediate 1) in 9mL of DMF was added dropwise, the mixture was stirred for 1 hour while maintaining the temperature, after the completion of TLC identification, the mixture was cooled to room temperature, filtered, concentrated to dryness under reduced pressure, 50mL of dichloromethane and 20mL of water were added to the residue, 5mL of triethylamine was added thereto, the mixture was stirred for 10 minutes, allowed to stand for layering, the organic layer was washed with brine (30mL × 3), dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, 10mL of acetone was added to the residue, stirred at-5 to 0 ℃ for 1 hour, filtered, the solid was washed with an appropriate amount of cold acetone, and dried at 60 ℃ to 65 ℃ for 5 hours under vacuum to obtain 10.9g of deuterated pentazocine as a white crystalline powder, yield was 71%, and HPLC content was 99.2%.

¹H-NMR(500MHz，CDCl₃/TMS，ppm)：

¹³C-NMR(CDCl₃)：

IR: (Fourier transform Infrared Spectroscopy, Bruker Tensor 27 type)

MS: (high resolution time-of-flight mass spectrometry ES + Mass Spectrometry and ES-Mass Spectroscopy)

Peak m/z	Ion m/z	Strength (%)	Resolving attribution
				222.1	C₁₂H₁₂ D₆NOH⁺	8
224.2	C₁₂H₁₄ D₆NOH⁺	45	223.2C₁₂H₁₄ D₆NO(II)
				225.2		10
272.2	C₁₉H₂₁ D₆NOH⁺	100	291.2C₁₉H₂₁ D₆NO(I)
				293.2		22

Peak m/z	Ion m/z	Strength (%)	Resolving attribution
				222.1	C₁₄H₁₂₈ D₆NO^-	88	223.1C₁₄H₁₃ D₆NO^-(III)
223.1		10
				290.1	C₁₉H₂₀D₆NO^-	100	291.1C₁₉H₂₁ D₆NO
291.1		15

Example 2: preparation of deuterated pentazocine

1) Step 1: [4,4' -²H₆]Preparation of ethyl (E) -3-methyl-2-butenoate

Triethyl phosphonoacetate (51g, 0.23mol), dried tetrahydrofuran (420ml), cooled to-5-0 deg.C, slowly added n-butyllithium (0.2mol, 2.5M n-hexane solution) dropwise, gradually warmed to room temperature and stirred until bubbling stops, deuterated acetone (9.8g, 0.15mol) in 80ml of dried tetrahydrofuran solution is added to the phosphonic acid anion solution, the mixture was stirred at room temperature for 4-4.5 h, the end point was identified by TLC (pentane/ether: 2:1), then, 30mL of a saturated ammonium chloride solution was added to quench, the aqueous layer was extracted with isopropyl ether, the organic layers were combined, washed with brine (30mL × 3), dried over anhydrous magnesium sulfate, the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (pentane/diethyl ether ═ 2:1) to obtain 17.9g of the objective compound as a pale yellow oil, yield 87.0%, GC content 98.3%.

¹H-NMR(500MHz，CDCl₃/TMS，ppm)：

2) Step 2: [4,4' -²H₆]Preparation of (E) -3-methyl-2-butenol

[4,4'-²H₆]-ethyl-3-methyl-2-butenoate (17.5g, 0.13mol), 50ml tetrahydrofuran solution, cooled to-5-0 ℃, added dropwise with stirring 190ml of dried tetrahydrofuran solution of lithium aluminium hydride (5.2g, 0.14mol), stirred at-5-0 ℃ for 0.5h, then stirred at room temperature for 45min, added with 100ml isopropyl ether, added with a mixture of 130g sodium sulfate and 50ml water at-5-0 ℃, stirred at room temperature for 0.5h, added with a further 130g anhydrousSodium sulfate was removed with water, filtered, the solid was washed with isopropyl ether and purified by flash column chromatography (pentane/diethyl ether ═ 2:1) to give 8.9g of the title compound as a colorless oil, 74/7% yield, 97.5% GC content.

[4,4'-²H₆]-3-methyl-2-butenol (8.5g, 0.091mol), 290mL of dry dichloromethane, adding boron tribromide (8.78mL, 0.091mol) through a syringe at 0 ℃, stirring at 5-0 ℃ for 30min, then stirring at room temperature for 30min, quenching reaction by ice, washing a dichloromethane layer by using saline (30mL multiplied by 3), drying by anhydrous magnesium sulfate, concentrating to dryness, and distilling and purifying a crude product to obtain the [4,4' -²H₆]13.3g of (E) -1-bromo-3-methyl-2-butene (intermediate 1) was a colorless oil, yield 92.7%, GC content 98.9%.

4) And 4, step 4: preparation of deuterated pentazocine

Starting material 2(15g, 0.069mol), which is made by the company, is dissolved in 55ml DMF, 5.7g (0.068mol) of sodium bicarbonate is added, the temperature is raised to 105-110 ℃ by stirring, and [4,4' -²H₆]11.7g (0.075mol) of 1-bromo-3-methyl-2-butene (intermediate 1) in 12mL of DMF was added dropwise, the mixture was stirred for 1 hour while maintaining the temperature, after the TLC identification, the mixture was cooled to room temperature, filtered, concentrated to dryness under reduced pressure, the residue was added with 90mL of dichloromethane and 30mL of water, 8mL of triethylamine was added, the mixture was stirred for 10 minutes, allowed to stand for layering, the organic layer was washed with brine (30mL × 3), dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, the residue was added with 15mL of acetone, stirred for 1 hour at-5 to 0 ℃, filtered, the solid was washed with an appropriate amount of cold acetone, and dried for 5 hours at 60 ℃ to 65 ℃ under vacuum to obtain 14.2g of deuterated pentazocine as a white crystalline powder, the yield was 71.4%, and the HPLC content was 99.7%.

Example 3: preparation of deuterated pentazocine hydrochloride

Dissolving deuterated pentazocine (20.4g, 0.07mol) in 100ml of methanol, heating to 45-50 ℃, dropwise adding a 15% hydrogen chloride methanol solution while stirring until the pH value of the solution is 3-4, stirring for 10min, cooling to-5-0 ℃, crystallizing for 2h, filtering, and washing the solid with methanol to obtain 20.8g of white crystalline powder with the yield of 91.1%.

Example 4: preparation of deuterated pentazocine lactate

Deuterated pentazocine (20.4g, 0.07mol) is dissolved in 100ml isopropanol, lactic acid (7.2g, 0.08mol) is added while stirring when the temperature is raised to 55-60 ℃, the temperature is maintained and the stirring is carried out for 30min, then the mixture is cooled to room temperature and stands for crystallization for 2h, the mixture is filtered, and the solid is washed by isopropanol to obtain 21.4g white crystalline powder with the yield of 79.1%.

Example 5: preparation of deuterated pentazocine injection

Prescription:

the preparation process comprises the following steps:

a) weighing the compound of example 1 or example 4, lactic acid and sodium chloride according to the formula amount, and adding 80% of water for injection to dissolve;

b) adding 0.6% of active carbon for injection needles, keeping the temperature at 50-60 ℃, stirring for 30min, filtering and decarburizing to obtain filtrate;

c) cooling to room temperature, adjusting the pH value to 3.5-5.5 by using 0.1N sodium hydroxide if necessary, adding water for injection to full amount, and measuring the content and the pH value of an intermediate; after being qualified

d) Filtering with 0.22 μm microporous membrane, bottling in 2ml ampere bottle, and filling N₂And encapsulating each capsule by 1ml, and sterilizing at 121 ℃ for 30min under hot pressure to obtain a finished product of the deuterated pentazocine injection.

Example 6: preparation of deuterated pentazocine hydrochloride/naloxone hydrochloride tablets

Specification: 25mg/0.25mg (25mg deuterated pentazocine/0.25 mg naloxone)

Prescription:

specification: 50mg/0.5mg (50mg deuterated pentazocine/0.5 mg naloxone)

Prescription:

the preparation process comprises the following steps:

firstly, pretreatment, namely, respectively crushing the raw materials and the auxiliary materials and sieving the crushed raw materials and the auxiliary materials with a 100-mesh sieve for later use.

② total mixing, namely, uniformly mixing the naloxone hydrochloride and the microcrystalline cellulose, adding other auxiliary materials, finally adding magnesium stearate to increase the fluidity, uniformly mixing, adding other auxiliary materials, and uniformly mixing.

and thirdly, tabletting, namely directly tabletting, wherein the temperature between tabletting is 20-25 ℃, and the relative humidity is controlled at 35-45%.

Example 7: in vitro liver microsome stability assay

Liver microsome stability assays were performed as lmg/mL liver microsome protein in NADPH-producing system (2.2mM NADPH,25.6mM glucose 6-phosphate, 6 units/mL glucose 6-phosphate dehydrogenase, and 3.3mM magnesium chloride) in 2% sodium bicarbonate. The test compound was prepared as a solution in 25% acetonitrile-water, which was added to the assay mixture (final assay concentration 3ug/mL) and incubated at 37 ℃. The final concentration of acetonitrile in the assay should be < 1%. Aliquots (60ul) were removed at 0, 15, 30, 45, 60, 120min and diluted with ice cold acetonitrile (300ul, with internal standard compound dissolved) to terminate the reaction. The samples were centrifuged at 12000RPM for 10min to precipitate the proteins. The supernatant was transferred to a microcentrifuge tube and stored for LC/MS analysis for test compound degradation half-life. It was thus found that the deuterated pentazocine determined here had an increased half-life compared to pentazocine. The results are as follows:

compound (I)	Pentazocine	Deuterated pentazocine	Deuterated pentazocine hydrochloride	Deuterated pentazocine lactate
					Percentage of metabolism	36.2％±2.5％	7.9％±1.6％	8.4％±1.3％	8.6％±1.1％

The results show that: pentazocine is metabolized by 36.2% within 120min, and deuterated pentazocine hydrochloride, deuterated pentazocine hydrochloride and deuterated pentazocine lactate are metabolized by 7.9%, 8.4% and 8.6% respectively, and in turn, the metabolic stability of the deuterated pentazocine is far greater than that of the pentazocine.

Example 8: oral drug blood concentration in SD rat

Accurately weighing a proper amount of the compound in the embodiment 1-3, dissolving the compound with CMC-Na solution to respectively prepare 15mg/mL solution for animal gavage administration, and filtering and sterilizing the solution before administration, wherein the administration dose is 30 mg/Kg. Approximately 0.10mL of blood, EDTAK, was drawn through the orbit after each animal was anesthetized with isoflurane₂Anticoagulation, the PO group collection time points were: 15min, 30min, lh, 2h, 4h, 6h, 8h and 24h after intragastric administration. And the plasma was centrifuged within 1 hour (centrifugation conditions: 3000 rpm, 15min, 6 ℃). Taking the supernatant, injecting and analyzing.

And detecting by adopting a positive ion mode in the LC-MS-MS analysis. The concentration-time data is calculated by DAS 3.0 pharmacokinetic software and a statistical moment method to obtain a main absorption kinetic parameter T of the rat after gavage administration of the compound_1/2(h)、AUC(0-t)(h ng mL^-1)、AUC(0-∞)(h ng mL^-1) And the like. The results are as follows:

compound (I)	Pentazocine	Deuterated pentazocine	Deuterated pentazocine hydrochloride	Deuterated pentazocine lactate
					T1/2	3.41±0.13	4.76±0.24	4.89±0.16	4.75±0.20
AUC(0-t)	2107±433	1689±375	1674±369	1702±358
					AUC(0-∞)	2274±532	2766±471	2853±502	2809±497

The results show that: deuterated pentazocine, deuterated pentazocine hydrochloride andthe half-life of the lactic acid deuterated pentazocine is respectively prolonged by 39.6 percent, 43.4 percent and 39.3 percent, and the AUC (0- ∞) under the time curve (h ng mL)^-1) The area values increased by 21.6%, 25.5% and 23.5%, respectively. It is shown that the deuterated pentazocine of the invention has good pharmacokinetic properties.

Claims

1. A deuterated pentazocine of formula (I) and pharmaceutically acceptable salts thereof:

2. the process for the preparation of deuterated pentazocine and pharmaceutically acceptable salts thereof according to claim 1, characterized by the following technical scheme:

3. the process of claim 2, wherein the deuterated pentazocine and pharmaceutically acceptable salts thereof are prepared by: intermediate 1 of step 4: intermediate 2: the molar ratio of sodium bicarbonate is 1:1.1: 0.9.

4. The deuterated pentazocine and pharmaceutically acceptable salts thereof according to claims 1-3, wherein: the pharmaceutically acceptable salt is hydrochloride and lactate.

5. A pharmaceutical composition containing deuterated pentazocine and pharmaceutically acceptable salts thereof as described in claims 1-4 and pharmaceutically acceptable carriers, and application of the pharmaceutical composition in preparation of various acute and chronic pain-relieving drugs.

6. The use of claim 5, wherein the medicament further comprises an additional therapeutic agent selected from one of naloxone hydrochloride, acetaminophen, aspirin.

7. The method of any one of claims 1-6, wherein administration is by a route selected from the group consisting of: oral, topical, parenteral, sublingual, rectal, vaginal and intranasal.

8. The method of claim 7, wherein the parenteral administration is selected from the group consisting of subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection, and infusion.

9. The method of claim 7, wherein the oral administration comprises administering an oral dosage form selected from the group consisting of: tablet, granule, capsule, sustained release tablet and sustained release capsule.

10. The pharmaceutical composition for use according to claim 5, wherein the range of acute and chronic pain relievers includes: analgesia of various surgical anesthetics, anesthesia induction, intraoperative anesthesia and postoperative analgesia; postoperative analgesia in various operating departments; analgesia of various endoscopic surgeries; analgesia of painless induced abortion; relieving pain for various cancer patients.