CN111349111A - Pentazocine prodrug, preparation method and application thereof - Google Patents

Pentazocine prodrug, preparation method and application thereof Download PDF

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CN111349111A
CN111349111A CN202010207219.4A CN202010207219A CN111349111A CN 111349111 A CN111349111 A CN 111349111A CN 202010207219 A CN202010207219 A CN 202010207219A CN 111349111 A CN111349111 A CN 111349111A
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pentazocine
prodrug
compound
pharmaceutically acceptable
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徐奎
刘逸凡
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ANHUI HEAL STAR PHARMACEUTICAL Co.,Ltd.
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Anhui Yixinming Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a pentazocine prodrug of a formula (I), a preparation method thereof and medical application of a pharmaceutical preparation containing the same, wherein R is hydrogen or deuterium. The prodrug compound of the invention has water solubility improved by more than 20 times at room temperature, is chemically stable, delays the onset time, prolongs the drug effect, generates the same parent drug blood concentration at lower dose, and has wide clinical application prospect.

Description

Pentazocine prodrug, preparation method and application thereof
One, the technical field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to pentazocine ester, a preparation method thereof, a pharmaceutical preparation containing the pentazocine ester and medical application of the pentazocine ester.
Second, background Art
Pentazocine was successfully marketed by the West Silerbore group of Siderlin, England (SteringW endotropgroup LTD) in 1967. Pentazocine (pentazocine, also known as tebuconazole, analgesin) 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 weaker 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, chemically (2R, 6R, 11R) -cis-1, 2,3,4, 5, 6-hexahydro-6, 11-dimethyl-3- (3-methyl-2-butenyl) -2, 6-methylene-3-benzazocine-8-ol, having the following structural formula:
Figure BDA0002421543970000011
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 morphine, and the analgesic effect of 30mg injected subcutaneously or intramuscularly is equivalent to 10mg of morphine. (ii) its respiratory depression is about 1/2 for 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.
The pentazocine hydrochloride tablet for oral administration is the only opioid receptor agonistic antagonistic analgesic which can be orally taken at present, and the oral administration has low bioavailability which is only about 18 to 22 percent due to the influence of first-pass metabolism.
Aiming at the transformation of the phenolic prodrug, a carbamate prodrug is formed by an ideal method, the structure can show good chemical stability, and is gradually metabolized into a raw drug in vivo through an enzymatic or non-enzymatic way to show reasonable pharmacokinetic behavior, and the carbamate prodrug successfully on the market, such as the dicarbamate prodrug of β 2-receptor agonist bambuterol terbutaline, has obviously prolonged action time, but the water solubility of the carbamate prodrug is reduced.
A drug that has superior biological activity and safety when tested in experimental models may be less active and/or more toxic when administered to a human subject. One of the possible reasons for this inconsistency is that the molecule may not reach the target site of action at therapeutic concentrations and/or accumulate to toxic levels in one or more tissues. This pharmacokinetic difference between in vitro and in vivo models, and between test species and humans, may significantly limit the therapeutic applications of certain compounds, creating challenges for drug development.
Physicochemical properties, therapeutically effective dose and route of administration can all affect the pharmacokinetic properties of the drug molecule. For a particular drug, the therapeutically effective dose is fixed. Nevertheless, variations in the route of administration may also allow for reduced drug dosages if the new route of administration provides higher bioavailability. For example, a drug that requires a high dose due to low oral bioavailability can be formulated for parenteral administration when it has suitable physicochemical properties, and can be administered at a lower dose due to its improved bioavailability. However, it is often only possible to use different routes of administration if the physicochemical properties of a given drug molecule are suitable for new dosage forms. The inherent physicochemical properties of many current drugs limit their use for oral administration, resulting in high doses and poor pharmacokinetic properties. Therefore, there have been attempts to modify the physicochemical properties of existing drugs and/or their formulations.
Poorly soluble drugs often exhibit poor bioavailability, which can hinder drug development or require administration of high doses to achieve therapeutically effective blood levels of the drug. For example, the trade name Tricor (fenofibrate) is marketed in the form of 300mg capsules. Reducing the particle size to a fine powder increases the solubility of the drug and allows the dose to be reduced to 200 mg. The formulation obtained by adding surfactant to the fine powder allows bioavailability similar to 300mg and 200mg total daily dose to be obtained with just 160mg dose of tablets. Another bioequivalent formulation of drug-containing nanoparticles can reduce the effective dose to 145 mg. Thus, bioavailability is increased by increasing its solubility, resulting in a significant reduction (over 100%) in the dose of Tricor. However, while there are some examples of improved solubility by reducing particle size, the inherent conditions of oral administration (e.g., the limited aqueous medium in the gastrointestinal tract) may limit the increase in bioavailability of certain drugs.
Another technique used to increase solubility is to prepare complexes of insoluble/poorly soluble drugs with easily soluble molecules such as cyclodextrins. Itraconazole, voriconazole and ziprasidone are examples of successful applications of this technology. However, this application typically requires a large excess of cyclodextrin relative to the amount of drug to be solubilized and does not result in the desired increase in solubility of the entire drug sample (e.g., dosages of l0mg itraconazole, 200mg voriconazole, or 20mg ziprasidone require 400mg, 3200mg, or 294mg of cyclodextrin, respectively).
Although the importance of developing new drugs should not be exaggerated, the ability to improve the physicochemical properties of existing drugs still has its advantages. Thus, there remains a clear unmet need for improved drugs, such as prodrugs of existing drugs.
Third, the invention
Prodrugs are bioreversible derivatives of drug molecules that release active prodrugs in vivo through enzymatic or chemical action, thereby exerting the desired pharmacological effects. In the process of discovery and development of medicines, the prodrug becomes a means for exactly improving the physicochemical property, the biological and pharmaceutical property and the pharmacokinetic property of a raw medicine. At present, 5 to 7 percent of drugs approved to be marketed worldwide can be classified as prodrugs, and the concept of prodrugs in the early stage of new drug research is more and more emphasized.
ZL 201410252094.1 is a prodrug invented by the applicant to solve the oral first-pass effect of pentazocine, and has a good effect. But the pentazocine has poor water solubility and low bioavailability, and in the process of preparing the injection from the pentazocine, the process needs to be filled with nitrogen for protection, even a little oxygen is remained, the oxidation impurities exceed the standard in the long-term storage of the injection, and the extremely toxic impurities such as quinone compounds, polymers and the like are generated. The invention enhances the penetration capability and the first-pass effect of the medicine by improving the fat solubility of the raw medicine. At present, most of the prodrugs are used for enhancing the penetration capability of the drugs by improving the lipid solubility of the original drugs in clinic, and are recently used for improving the water solubility of the drugs. There is, however, a great unmet need for prodrugs, such as pentazocine, which are poorly adapted to the dependence of such analgesic drugs and to abuse of the prodrug.
The invention aims to make up the defects in the prior art and provides a pentazocine ester prodrug, which has the following structural formula:
Figure BDA0002421543970000041
wherein R is hydrogen or deuterium. When R is hydrogen, the structural formula is as follows:
Figure BDA0002421543970000042
when R is deuterium, the structural formula is as follows:
Figure BDA0002421543970000043
r is deuterium, a derivative of application No. 202010177342.6 of the present applicant's invention, having significant biological characteristics.
Since pentazocine is extremely difficult to dissolve in water, in the process of designing the prodrug, the water solubility of the target prodrug is improved greatly, a series of prodrugs with potential significance are synthesized, water solubility test is firstly carried out, for example, a DMSO saturated solution of a standard substance is prepared firstly, then a soluble mobile phase is diluted in a gradient manner, 5 standard substance solutions with different concentrations are prepared, and a standard curve of a compound is established by high performance liquid chromatography according to peak areas of the standard substance under different concentrations and the standard substance concentration; adding a certain amount of saturated solution of the compound into different buffer solutions, measuring peak areas after sample injection, and substituting into a standard curve to calculate the solubility of the compound in different buffer solutions. Thus, the present invention has been completed.
Another object of the present invention is to provide a process for the preparation of pentazocine prodrugs and pharmaceutically acceptable salts thereof. The preparation reaction formula is as follows:
Figure BDA0002421543970000051
wherein R is hydrogen or deuterium. When R is deuterium, the side chain synthesis method of step 11 is described in patent 202010177342.6 applied by the present inventor, further, the methylation reagent of step 1 is selected from
Figure BDA0002421543970000061
The target compound can be obtained with mild and high yield, when methyl iodide is selected, the toxicity is high, the side reaction is excessive, the reaction condition is severe, dimethyl sulfate and other similar methylation reagents are selected, the reaction is severe and incomplete, and the condition is severe; the hydrolysis and chlorination reagent in the step 2 is concentrated hydrochloric acid, the reaction temperature is selected from reflux temperature, and the extraction solvent is pentane or hexane; using sodium hydroxide or potassium hydroxide as the cyclized base in the step 3, and selecting pentane or hexane as an extraction solvent; the reducing reagent in the step 4 is selected from lithium aluminum hydride or sodium borohydride or potassium borohydride, preferably lithium aluminum hydride, and the reaction solvent is selected from n-hexane or n-heptane; the bromination in the step 5 is selected from the combination of lithium bromide and phosphorus tribromide, the reaction solvent and the extraction solvent are both selected from pentane, the reaction temperature is selected from-30 ℃ to-50 ℃, and the modes of diatomite assisted filtration and impurity removal and silica gel stirring and impurity removal are selected for post-treatment filtration, so that the method is simple and efficient; the reaction solvent in the step 6 is selected from polar aprotic solvents DMF and N-methyl pyrrolidone, and the reaction temperature is 70-100 ℃, preferably 85-95 ℃; the refining solvent is selected from methanol or ethanol, preferably ethanol; step 7, selecting a reaction solvent from methanol or ethanol, preferably ethanol, and selecting 80-90% hydrazine hydrate as a decomposition reagent; step 8, selecting sodium methoxide or sodium ethoxide as alkali, wherein the reaction temperature is selected from 30-35 ℃; step 9, selecting a water system with the pH value of 2.5-3.5 for the reaction system, wherein the temperature is 80-100 ℃, preferably 85-90 ℃, and the extraction solvent is pentane or hexane; the cyclization reagent in the step 10 is selected from 48% hydrobromic acid or 62% hydrobromic acid, the extraction solvent is selected from n-butyl alcohol, and the crystallization solvent is selected from acetone or a methanol-acetone mixed solvent; the alkaline reagent in the step 11 is triethylamine, the solvent is DMF or N-methylpyrrolidone, and the reaction temperature is 40-45 ℃; the acylating agent of step 12 is selected from triphosgene (phosgene solid) and the solvent is selected from toluene or dichloromethane, preferably toluene.
Still another object of the present invention is to provide a pentazocine prodrug and pharmaceutically acceptable salts thereof, which are hydrochloride and lactate. Pentazocine can be in various salts, but the hydrochloride or lactate salt has excellent desirable physicochemical properties.
Yet another object of the present invention is to provide a use of pentazocine prodrugs and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of diseases or conditions and/or symptoms of diseases or conditions treatable with pentazocine, wherein said ranges of use for diseases or conditions include: 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; analgesia for various cancer patients; the medicament may be for oral, topical, parenteral, sublingual, rectal, vaginal and intranasal administration, or the parenteral administration is selected from subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection and infusion, the oral administration comprising administration of an oral dosage form selected from: the prodrug is prepared into tablets, granules, capsules, sustained-release tablets and sustained-release capsules, wherein the dosage of the prodrug is 10 mg-40 mg.
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 key points of the invention are as follows:
1) compared with the original medicine, the water solubility is improved by more than 20 times, which is beneficial to the disintegration and dissolution of solid preparations and the liquid preparation of liquid preparations;
2) the chemical property is stable, the phenolic hydroxyl is substituted by prodrug groups, the oxidation is avoided, and the preparation can be stored for a long time;
3) the biological property is stable, and the retention time of the pentazocine in the body is prolonged;
4) preventing abuse of pentazocine;
5) improves bioavailability and delays drug action time.
Fourth, detailed description of the invention
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.
Example 1 Synthesis of pentazocine prodrug (Compound 1)
Figure BDA0002421543970000071
1. Synthesis of 2-acetyl-2-methyl-butyrolactone (intermediate 1)
N2Protection, 2-acetylbutyrolactone (51g, 0.4mol) in 400ml of anhydrous dichloromethane was added dropwise to [ Me containing 400ml of dichloromethane2Cl][Al(OTeF5)4](0.8mol) to the solution, stirring overnight at room temperature, filtering, washing the solid with a suitable amount of dichloromethane several times, concentrating under reduced pressure to obtain 51.7g of light yellow oil,the yield thereof was found to be 91.0%.
2. Synthesis of 5-chloro-3-methylpentane-2-one (intermediate 2)
2-acetyl-2-methyl-butyrolactone (51g, 0.359mol), concentrated hydrochloric acid (128ml, 32%, 1.07mol), distilled water 150ml, carefully heating until gas stops, collecting distillate 140ml after distillation of the reaction compound, adding distilled water 90ml into the residue, collecting distillate 80ml after distillation, separating the organic layer, extracting the aqueous layer with pentane (3 × 100ml), drying with calcium chloride, concentrating under reduced pressure, collecting the fraction 69-71 ℃/19mmHg, obtaining colorless oily substance 44.5g, yield 92.1%.
3. Synthesis of 1- (1-methylcyclopropyl) ethan-1-one (intermediate 3)
5-chloro-3-methylpentane-2-one (44.0g, 0.327mol), sodium hydroxide (20.2g, 0.505mol) and 26ml of water are heated and refluxed for 2h, 50ml of water is added, heating and refluxing are continued for 1.5h until the water-ketone is separated, an organic layer is distilled out, the organic layer is separated, saturated potassium carbonate is added into a water layer, an aqueous solution is extracted by pentane, the organic layers are combined, dried by anhydrous magnesium sulfate and concentrated under reduced pressure, and a fraction at 121-124 ℃ is collected to obtain 20g of colorless oily matter, wherein the yield is 62.8%.
4. Synthesis of 1- (1' -methylcyclopropyl) ethanol (intermediate 4)
N2Under protection, at 0 ℃, 200ml of anhydrous hexane solution of 1- (1-methylcyclopropyl) ethane-1-ketone (18g, 0.183mol) is dropped into 70ml of anhydrous hexane solution of lithium aluminum hydride (7g, 0.185mol), the temperature is maintained and stirring is carried out for 2h, 24ml of saturated sodium sulfate is added for quenching, filtration is carried out, hexane is washed for a plurality of times, hexane layers are combined, anhydrous sodium sulfate is dried, diatomite is filtered, and reduced pressure concentration is carried out, so that 18g of colorless oily matter is obtained, and the yield is 99.0%.
5. Synthesis of (E) -5-bromo-3-methylpentyl-2-ene (intermediate 5)
1- (1' -methylcyclopropyl) ethanol (15g, 0.15mol) and 2,4, 6-collidine (20ml, 0.14mol) were added to 380ml of dry pentane at-30 ℃, lithium bromide (33g, 0.38mol) was added, the suspension was cooled to-50 ℃, phosphorus tribromide (15ml, 0.15mol) was added, the temperature was raised to 0 ℃ within 1h while maintaining stirring for 5h, 23ml of 2,4, 6-collidine and 100ml of water were added, the aqueous layer was extracted with pentane (4 × 150ml), and washed with 100ml of saturated sodium carbonate and 100ml of hydrochloric acid in this order, dried over anhydrous sodium sulfate, filtered with celite, and concentrated under reduced pressure to give 15.2g of colorless oil in 61.8% yield.
6. Synthesis of intermediate 6
(E) -5-bromo-3-methylpentyl-2-ene (15g, 0.092mol), phthalimide potassium salt (18.7g, 0.1mol) and 75ml of DMF, stirring at 90 ℃ for reaction for 15h, cooling slightly, concentrating the reaction solution under reduced pressure, adding 100ml of water to the residue, extracting with dichloromethane (4 × 150ml), concentrating the dichloromethane layer, and recrystallizing with anhydrous ethanol to obtain 20g of a white solid with a yield of 95%.
7. Synthesis of (E) -3-methylpentyl-3-en-1-amine hydrochloride (intermediate 7)
Adding the intermediate 6(18g, 0.079mol) into 180 percent absolute ethyl alcohol, dripping 50ml of ethanol solution of 85 percent hydrazine hydrate (1.5 times), refluxing for 2 hours, cooling to room temperature, adding water to dissolve solid, adding concentrated hydrochloric acid, stirring for 0.5 hour, evaporating the ethanol, adding water, filtering, washing the solid, extracting the filtrate by using dichloromethane to remove impurities, adjusting the pH of a water layer to be more than 10 by using sodium hydroxide, extracting by using dichloromethane, washing by using water, washing by using brine, concentrating, dissolving in the absolute ethyl alcohol, adding hydrochloric acid to form salt, and obtaining 9.43g with the yield of 88 percent.
8. Synthesis of methyl p-methoxyphenyl glycidate (intermediate 8)
At the temperature of 5-10 ℃, dripping a mixture of p-methoxybenzaldehyde (20.5g, 0.15mol) and methyl chloroacetate (16.5g, 0.16mol) into a solution of ethanol 45ml and sodium methoxide (9.7g, 0.195mol), raising the temperature to 30-35 ℃, stirring for 2h, concentrating under reduced pressure, adding water, stirring for 1h, filtering, and drying under vacuum at the temperature of 30-35 ℃ to obtain 27.5g, wherein the yield is 88.1%, and mp: 85.7 to 87.5 ℃.
9. Synthesis of intermediate 9
Intermediate 7(6.8g, 0.05mol), 1N HCl (53.5ml), water (196ml) (pH ≈ 3), mixing, adding intermediate 8(10.5g, 0.05mol), heating to 85-90 ℃, stirring for reaction for 36h, cooling to room temperature, filtering to remove impurities, extracting the solution with an appropriate amount of pentane to remove organic impurities, basifying with 50% potassium carbonate to pH 7-8, standing, precipitating crystals, filtering, washing with water to obtain intermediate 9(6.9g) as a white solid, yield 55.1%, mp: 140 to 141 ℃.
10. Synthesis of intermediate 10
Heating the intermediate 9(6.4g, 0.0257mol) and 48% hydrobromic acid 15g to 130 ℃, refluxing for 25h, concentrating under reduced pressure to dryness after the reaction is finished, adding ammonia water to adjust the pH of the residue to 10-11, extracting with n-butyl alcohol, separating, washing with saturated saline (10ml × 4), concentrating under reduced pressure to dryness, adding acetone, refluxing for 1-2 h, slowly cooling to 5-10 ℃, stirring for 1-2 h, filtering, and washing with acetone to obtain a white powdery solid intermediate 10(4.9g), wherein the yield is 87.2%, and the mp is 232-234 ℃.
11. Synthesis of intermediate 11
The preparation method comprises the following steps of heating intermediate 10(4.8g, 0.022mol), 25ml of N-methylpyrrolidone, 2.1ml of triethylamine, 3-bromo-3-methyl-2-butene (3.6g, 0.0242mol), stirring for 6h at 40-45 ℃, supplementing 1ml of triethylamine if the intermediate 10 does not react completely, cooling to room temperature after the reaction is finished, adding 20ml of water and 3g of sodium chloride, stirring for 10min, extracting with dichloromethane (20ml of × 4), washing with saturated saline (10ml of × 2), concentrating to dryness, adding 15ml of acetone, stirring for 1h at-5-0 ℃, filtering, washing a solid with acetone, drying for 3h at 65-70 ℃ in vacuum, and obtaining 5.4g of white crystalline powdery intermediate 11 pentazocine with the yield of 86.1%.
12. Synthesis of intermediate 12
Cooling the intermediate 11(5.0g, 17.5mmol), toluene 50ml and N, N-diethylaniline (2.6g, 17.5mmol) to-5-0 ℃, dropwise adding a toluene solution of solid phosgene (10.5g, 35mmol) under stirring, stirring at room temperature for 6h, heating to 50-55 ℃, stirring for 1h, cooling to room temperature, filtering with diatomite, washing the solid with an appropriate amount of toluene, combining the filtrates, washing with 0.1N hydrochloric acid (3 × 30ml), washing with a saturated saline solution (2 × 30ml), concentrating under reduced pressure to dryness, adding N-hexane to the residue, stirring for 1h, filtering, washing the filtrate with an appropriate amount of N-hexane, drying at vacuum 55-60 ℃ for 2h to obtain a white powdery solid 4.8g with a yield of 79%.
13. Synthesis of intermediate 13
31ml of toluene and 6ml of triethylamine of di-tert-butyl phosphate (3.15g, 0.015mol), cooling to-5-0 ℃, dripping 45ml of toluene solution of intermediate 12(4.5g, 0.013mol) under stirring, heating to 30-35 ℃, stirring for 1.5h after dripping, cooling to room temperature, filtering, washing the filtrate with water (2 × 30ml), saturated sodium carbonate solution (2 × 30ml) and saturated salt water in sequence, drying with anhydrous sodium sulfate, filtering with diatomite, concentrating the filtrate under reduced pressure, adding 40ml of pentane into the residue, heating to 35-40 ℃, adding 5ml of 0.1N sodium hydroxide solution, stirring for 10min, cooling to room temperature, standing for layering, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness to obtain 3.85g of white powdery solid with yield of 78.8%.
14. Synthesis of pentazocine prodrug (Compound 1)
Intermediate 13(3.75g, 7.18mmol), trifluoroacetic acid 11g, dichloromethane 90ml, triethylamine 5ml, stirring at room temperature for 3h, filtering, washing the filtrate with water (2 × 20ml), saturated sodium carbonate solution (2 × 20ml) and saturated brine in sequence, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, refining the solid with methanol-methyl isobutyl ketone (1:1) to obtain white crystalline solid 2.5g, yield 85.1%, HPLC content 98.7%.
Figure BDA0002421543970000101
Pentazocine prodrug (Compound 1) (Y200312-E02)1H-NMR(500MHz，CDCl3/TMS，ppm)：
Figure BDA0002421543970000111
Pentazocine prodrug (Compound 1) (Y200312-E02)13C-NMR(CDCl3)：
Figure BDA0002421543970000112
Figure BDA0002421543970000121
XRD spectroscopic data for pentazocine prodrug (compound 1) (Y200312-E02):
Figure BDA0002421543970000122
example 2 Synthesis of deuterated pentazocine prodrug (Compound 2)
Figure BDA0002421543970000131
The same as example 1, wherein intermediate 11 was synthesized using [4,4' -2H6]-1-bromo-3-methyl-2-butene [ synthetic method see patent of invention applied by applicant: 202010177342.6 example 1]Instead of 1-bromo-3-methyl-2-butene, 2.3g of deuterated pentazocine prodrug (compound 2) was conveniently prepared, with an HPLC content of 99.1%.
GC-MS(m/z)：415.6。
Example 3 Synthesis of pentazocine prodrug (Compound 1)
1. Synthesis of 2-acetyl-2-methyl-butyrolactone (intermediate 1)
N2Protection, 2-acetylbutyrolactone (510g, 4mol) in 4L anhydrous dichloromethane was added dropwise to [ Me containing 4L dichloromethane2Cl][Al(OTeF5)4](8mol) solution, room temperature stirring overnight, filtering, solid with appropriate amount of dichloromethane washing, vacuum concentration, light yellow oily matter 523g, yield 91.8%.
2. Synthesis of 5-chloro-3-methylpentane-2-one (intermediate 2)
2-acetyl-2-methyl-butyrolactone (520g, 3.4mol), concentrated hydrochloric acid (1.3L, 32%, 10.7mol), 1500ml of distilled water, carefully heating until the gas stops, collecting 1400ml of distillate after the reaction compound is distilled, adding 900ml of distilled water into the residue, collecting 800ml of distillate after distillation, separating an organic layer, extracting an aqueous layer with pentane (3 × 500ml), drying calcium chloride, concentrating under reduced pressure, collecting 69-71 ℃/19mmHg of fraction, obtaining 448g of colorless oily substance, and obtaining the yield of 91.7%.
3. Synthesis of 1- (1-methylcyclopropyl) ethan-1-one (intermediate 3)
5-chloro-3-methylpentane-2-one (440g, 3.27mol), potassium hydroxide (283g, 5.05mol) and 260ml of water are heated and refluxed for 2h, 500ml of water is added, heating and refluxing are continued for 1.5h until the water-ketone is separated, an organic layer is distilled, the organic layer is separated, saturated potassium carbonate is added into a water layer, an aqueous solution is extracted by pentane, the organic layers are combined, dried by anhydrous magnesium sulfate and concentrated under reduced pressure, and fractions at 121-124 ℃ are collected to obtain 211g of colorless oily matter with the yield of 63.6%.
4. Synthesis of 1- (1' -methylcyclopropyl) ethanol (intermediate 4)
N2Under protection, 2100ml of anhydrous hexane solution of 1- (1-methylcyclopropyl) ethan-1-one (210g, 2.14mol) was added dropwise to 700ml of anhydrous hexane solution of sodium borohydride (92.8g, 2.59mol) at 0 ℃, stirred for 2h while maintaining the temperature, quenched with 250ml of saturated sodium sulfate, filtered, washed with hexane several times, combined hexane layers were dried over anhydrous sodium sulfate, filtered with celite, and concentrated under reduced pressure to obtain 209g of colorless oil with a yield of 99.0%.
5. Synthesis of (E) -5-bromo-3-methylpentyl-2-ene (intermediate 5)
1- (1' -methylcyclopropyl) ethanol (195g, 1.95mol) and 2,4, 6-collidine (260ml, 1.82mol) were added to 4L of dry pentane at-30 deg.C, lithium bromide (429g, 4.94mol) was added, the suspension was cooled to-50 deg.C, phosphorus tribromide (195ml, 1.95mol) was added, the temperature was raised to 0 deg.C within 1 hour while maintaining stirring for 6 hours, 300ml of 2,4, 6-collidine and 1300ml of water were added, the aqueous layer was extracted with pentane (4 × 600ml), and then washed with 1000ml of saturated sodium carbonate and 1000ml of hydrochloric acid in this order, dried over anhydrous sodium sulfate, filtered with celite, and concentrated under reduced pressure to obtain 198.6g of colorless oil with a yield of 62.1%.
6. Synthesis of intermediate 6
(E) -5-bromo-3-methylpentyl-2-ene (195g, 1.196mol), phthalimide potassium salt (243g, 1.3mol) and 980ml of DMF, stirring at 90 ℃ for reaction for 18h, cooling slightly, concentrating the reaction solution under reduced pressure, adding 1300ml of water to the residue, extracting with dichloromethane (4 × 650ml), concentrating the dichloromethane layer, and recrystallizing with absolute ethanol to obtain 264g of a white solid with a yield of 95.1%.
7. Synthesis of (E) -3-methylpentyl-3-en-1-amine hydrochloride (intermediate 7)
Adding the intermediate 6(252g, 1.1mol) into 2600ml of absolute ethanol, dripping 700ml of ethanol solution of 85% hydrazine hydrate (1.5 times), refluxing for 2h, cooling to room temperature, adding water to dissolve the solid, adding concentrated hydrochloric acid, stirring for 1h, evaporating ethanol, adding water, filtering, washing the solid with water, extracting the filtrate with dichloromethane to remove impurities, adjusting the pH of a water layer to be more than 10 with sodium hydroxide, extracting with dichloromethane, washing with water, washing with brine, concentrating, dissolving in absolute ethanol, adding hydrochloric acid to form salt, and obtaining 136g with the yield of 88.7%.
8. Synthesis of methyl p-methoxyphenyl glycidate (intermediate 8)
At the temperature of 5-10 ℃, dripping a mixture of p-methoxybenzaldehyde (205g, 1.5mol) and methyl chloroacetate (165g, 1.6mol) into a solution of ethanol 45ml and sodium methoxide (97g, 1.95mol), heating to 30-35 ℃, stirring for 2h, concentrating under reduced pressure, adding water, stirring for 1h, filtering, and vacuum drying at the temperature of 30-35 ℃ to obtain 281g, wherein the yield is 88.4%, and mp: 86.7 to 87.9 ℃.
9. Synthesis of intermediate 9
Intermediate 7(136g, 1mol), 1N HCl (1070ml) and water (3950ml) (pH is approximately equal to 3), mixing, adding intermediate 8(210g, 1mol), heating to 85-90 ℃, stirring for reaction for 36h, cooling to room temperature, filtering to remove impurities, extracting the solution with a proper amount of pentane to remove organic impurities, basifying the solution with 50% potassium carbonate to pH 7-8, standing, precipitating crystals, filtering, washing with water to obtain white solid intermediate 9(143g), yield 57.1%, mp: 141-142 ℃.
10. Synthesis of intermediate 10
Heating the intermediate 9(140g, 0.565mol) and 330g of 48% hydrobromic acid to 130 ℃, refluxing for 28h, concentrating under reduced pressure to dryness after the reaction is finished, adding ammonia water to adjust the pH of the residue to 10-11, extracting with n-butanol, separating, washing with saturated saline (250ml × 4), concentrating under reduced pressure to dryness, adding acetone, refluxing for 1-2 h, slowly cooling to 5-10 ℃, stirring for 1-2 h, filtering, and washing with acetone to obtain a white powdery solid intermediate 10(112g), wherein the yield is 90.6% and the mp is 232-234 ℃.
11. Synthesis of intermediate 11
Heating the intermediate 10(110g, 0.506mol), DMF 580ml, triethylamine 49ml, 1-bromo-3-methyl-2-butene (82.8g, 0.557mol), stirring for 6h at 40-45 ℃, supplementing 25ml triethylamine if the intermediate 10 does not react completely, cooling to room temperature after the reaction is finished, adding 470ml of water and 50g of sodium chloride, stirring for 10min, extracting with dichloromethane (250ml × 4), washing with saturated saline (250ml × 2), concentrating to dryness, adding 360ml of acetone, stirring for 1h at-5-0 ℃, filtering, washing the solid with acetone, drying at 65-70 ℃ in vacuum for 4h to obtain the white crystalline powder intermediate 11 pentazocine 124g with the yield of 86.0%.
12. Synthesis of intermediate 12
Cooling the intermediate 11(122g, 0.427mol), 1300ml of toluene and N, N-diethylaniline (58g, 0.427mol) to-5-0 ℃, dropwise adding 240ml of a toluene solution of solid phosgene (256g, 0.854mol) while stirring, stirring at room temperature for 7h, heating to 50-55 ℃, stirring for 1h, cooling to room temperature, filtering with kieselguhr, washing the solid with an appropriate amount of toluene, combining the filtrates, washing with 0.1N hydrochloric acid (3 × 400ml), washing with saturated brine (2 × 300ml), concentrating under reduced pressure to dryness, adding N-hexane into the residue, stirring for 1h, filtering, washing the filtrate with an appropriate amount of N-hexane, drying for 2h under vacuum of 55-60 ℃ to obtain 118g of white powdery solid with a yield of 79.3%.
13. Synthesis of intermediate 13
31ml of toluene and 6ml of triethylamine of di-tert-butyl phosphate (3.15g, 0.015mol), cooling to-5-0 ℃, dropwise adding 1200ml of toluene solution of intermediate 12(117g, 0.338mol) under stirring, heating to 30-35 ℃, stirring for 2h, cooling to room temperature, filtering, washing the filtrate with water (2 × 300ml), saturated sodium carbonate solution (2 × 300ml) and saturated salt solution in sequence, drying with anhydrous sodium sulfate, filtering with diatomite, concentrating the filtrate under reduced pressure, adding 900ml of pentane into the residue, heating to 35-40 ℃, adding 130ml of 0.1N sodium hydroxide solution, stirring for 10min, cooling to room temperature, standing for layering, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness to obtain 100g of white powdery solid with yield of 78.9%.
14. Synthesis of pentazocine prodrug (Compound 1)
Intermediate 13(97.5g, 0.187mol), trifluoroacetic acid 286g, dichloromethane 2400ml, triethylamine 130ml, stirred at room temperature for 3h, filtered, the filtrate was washed with water (2 × 30ml), saturated sodium carbonate solution (2 × 30ml) and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the solid was purified with methanol-methylisobutylketone (1:1) to give 65g of white crystalline solid with a yield of 85.0% and an HPLC content of 99.2%.
Example 4 Synthesis of deuterated pentazocine prodrug (Compound 2)
The same as example 1, wherein intermediate 11 was synthesized using [4,4' -2H6]-1-bromo-3-methyl-2-butene [ synthetic method see patent of invention applied by applicant: 202010177342.6 example 1]Instead of 1-bromo-3-methyl-2-butene, 67.8g of deuterated pentazocine prodrug (compound 2) was conveniently prepared, with an HPLC content of 98.1%.
Example 5 preparation of pentazocine prodrug (Compound 1) capsules
Prescription:
Figure BDA0002421543970000161
1000 capsules are prepared, the content of each capsule is 50mg, and the weight of the content of the capsule is about 142.0 mg.
The preparation process comprises the following steps:
taking the microcrystalline cellulose, the calcium hydrophosphate dihydrate and the sodium carboxymethylcellulose fine powder with the prescription amount, mixing the fine powder with the raw material medicine fine powder, and grinding the mixture for 30 minutes at the same time to fully and uniformly mix the mixture. And preparing a soft material by taking a proper amount of a 40% ethanol solution of 5% polyvinylpyrrolidone as an adhesive, sieving with a 20-mesh sieve, granulating, drying at 50-60 ℃ for 30 minutes, adding magnesium stearate, mixing uniformly, determining the content to be qualified, and filling into a No. 3 empty capsule shell to obtain the capsule.
Comparative example 6 preparation of primary grinding pentazocine capsules
[https://www.medicines.org.uk/emc/search？q＝Pentazocine]
Recipe for Mylan pharmaceutical company:
Figure BDA0002421543970000171
1000 capsules are prepared, the content of each capsule is 50mg, and the weight of the content of the capsule is about 282.0 mg.
As seen from the prescription of the original medicine, the water solubility of pentazocine is extremely poor, the solubilizer sodium dodecyl sulfate is used in the prescription, the pentazocine is easy to oxidize, the sodium metabisulfite is also used in the prescription for oxidation resistance, and the compound has obvious superiority in physical and chemical properties.
Example 7 preparation of deuterated pentazocine prodrug (Compound 2) tablet
Prescription:
Figure BDA0002421543970000172
the preparation process comprises the following steps:
taking 25.0g of raw material of the deuterated pentazocine prodrug (compound 2), grinding, and sieving with a 200-mesh sieve for later use; respectively drying 90.0g of microcrystalline cellulose, 10.0g of sodium carboxymethyl starch and 8.0g of calcium hydrogen phosphate dihydrate at 80 ℃, and sieving by a 120-mesh sieve for later use; the deuterated pentazocine prodrug and calcium hydrophosphate dihydrate are uniformly stirred, the obtained solid is ground and sieved by a 120-mesh sieve, and then the solid is mixed with microcrystalline cellulose and fine powder of sodium carboxymethyl starch, ground and sieved by a 100-mesh sieve to be fully and uniformly mixed. And preparing the mixture into a soft material by taking a proper amount of 40% ethanol solution of 3% polyvinylpyrrolidone as a binding agent, sieving with a 20-mesh sieve, granulating, drying at 40 ℃ for 30 minutes, granulating, adding 2.0g of magnesium stearate, uniformly mixing, tabletting and coating to obtain the tablet.
Comparative example 8 preparation of primary pentazocine tablets
[https://www.medicines.org.uk/emc/search？q＝Pentazocine]
Recipe for Mylan pharmaceutical company:
Figure BDA0002421543970000181
as seen from the prescription of the original medicine, the water solubility of pentazocine is extremely poor, the solubilizer sodium dodecyl sulfate is used in the prescription, the pentazocine is easy to oxidize, the sodium metabisulfite is also used in the prescription for oxidation resistance, and the compound has obvious superiority in physical and chemical properties.
Example 9 preparation of injection solution of pentazocine prodrug (Compound 1)
Prescription:
Figure BDA0002421543970000182
the preparation process comprises the following steps:
weighing the pentazocine prodrug (compound 1), placing the pentazocine prodrug in a container, adding 800ml of water for injection, adding an appropriate amount of sodium chloride to adjust osmotic pressure ratio to about 1, adjusting pH value to 4.0-5.0 by using 0.1N hydrochloric acid or 0.1N sodium hydroxide, adding water for injection to scale, detecting a sampling intermediate product, filtering the qualified product by using a 0.22 mu m microporous filter membrane, filling the filtered product into 1ml ampoule bottles, filling 1ml of the product into each bottle, sealing the bottles, sterilizing the bottles by flowing steam at 121 ℃ for 30 minutes, cooling, inspecting by a lamp, packaging the finished product and warehousing the finished product to obtain the pentazocine prodrug.
Comparative example 10 preparation of pentazocine injection
Prescription:
Figure BDA0002421543970000191
the preparation process comprises the following steps:
weighing pentazocine, placing the pentazocine in a container, adding 800ml of water for injection, adding lactic acid, heating to 50-60 ℃, stirring for 30min to dissolve, adding an appropriate amount of sodium chloride to adjust osmotic pressure ratio to about 1, adjusting pH value to 4.0-5.0 by using lactic acid, adding water for injection to scale, detecting a sampling intermediate product, filtering after qualified products by using a 0.22 mu m microporous filter membrane, filling nitrogen, filling into 1ml of ampoule bottles, filling 1ml of each bottle, sealing, sterilizing by using circulating steam at 121 ℃ for 30min, cooling, inspecting by using a lamp, packaging and warehousing finished products.
In the process of the pentazocine injection, a large amount of lactic acid is required to be added to form lactate, the pH value is adjusted by using the lactic acid, and finally nitrogen is filled for protection to marginally make oxidation impurities in the process qualified.
Example 11 solubility test
The solubility is measured according to the method of the national pharmacopoeia 2015 edition at the room temperature of 23 ℃.
Item pH1.2 pH4.0 pH6.8 Water (W)
Compound 1 105mg/ml 78mg/ml 49mg/ml 21mg/ml
Compound 2 124mg/ml 83mg/ml 54mg/ml 23mg/ml
Pentazocine 48mg/ml 11mg/ml 0.3mg/ml 0.8mg/ml
It can be seen that the water solubility of the present invention is increased by more than 20 times.
Example 12 chemical stability test
1. Stability in pure Water
The compound was prepared as an aqueous solution at a concentration of 2.5mg/ml and divided into two portions (sample 1, sample 2) which were stored in test tubes, respectively.
1) Sampling 24h,72h,7d, 14d and 30d after the sample 1 is placed at normal temperature, and analyzing by HPLC;
2) the sample 2 was kept in hot water at 70 ℃ and then sampled for 30min, 1h, 2h, 3h and 6h for HPLC analysis.
Figure BDA0002421543970000201
The results of the experiments show that the aqueous solutions of compound 1 and compound 2 were not decomposed after being left at room temperature for 30 days and heated at 70 ℃ for 6 hours, and it was found from the above experiments that the target compounds were very stable in pure water, were not decomposed even under heating, and that pentazocine was very poor in stability.
2. Stability in physiological saline
The compound was prepared as an aqueous solution of physiological saline at a concentration of 2.0mg/ml, and divided into two portions (sample 1, sample 2) which were stored in test tubes, respectively. Under the same conditions as 1, the results also showed that the physiological saline aqueous solutions of compound 1 and compound 2 were not decomposed after being left at room temperature for 30 days and heated at 70 ℃ for 6 hours, whereas pentazocine was poor in stability.
Example 13 in vitro stability test
1. Artificial intestinal juice incubation system
Pipetting 1 μ L of each compound stock solution with a micropipette, adding into 99 μ L of artificial intestinal fluid pre-incubated for 5min, mixing well, incubating in a cell constant temperature heater at 37 deg.C, paralleling 3 groups, taking out EP tube for 0,1,2,3,4h, adding 400 μ L of glacial acetonitrile containing internal standard rapidly to terminate reaction, vortexing for 1min, and centrifuging (13500r min)-1At 4 deg.C for 10min, collecting supernatant, blowing with nitrogen gas, adding 100 μ L of chromatographic methanol, vortexing for 1min, and centrifuging (13500r min)-1At 4 deg.C for 10min, and collecting supernatant to be tested. The results are as follows:
stability of Compounds in Artificial intestinal fluid (n ═ 3)
Compound (I) Ke (Rate of Elimination) t1/2(h) elimination half-life CLint(L·h-1·g-1) Clearance rate
Compound 1 0.45±0.0032 3.37±0.161 6.97±0.45
Compound 2 0.47±0.0038 3.39±0.170 7.06±0.48
Pentazocine 0.34±0.0074 3.63±0.142 6.47±0.38
2. Rat blank plasma incubation system
Sucking 99 mu L of rat blank plasma by a micropipette, pre-incubating in a cell constant temperature heater at 37 ℃ for 5min, adding 1 mu L of methanol stock solution of each compound, incubating, taking out samples at time points of 0, 5, 10, 15, 30, 60 and 120min respectively, adding 400 mu L of glacial acetonitrile containing an internal standard to terminate the reaction, and processing according to the item '1', wherein the results are as follows:
stability of the Compounds in rat blank plasma (n ═ 3)
Compound (I) Ke (Rate of Elimination) t1/2(h) elimination half-life CLint(L·h-1·g-1) Clearance rate
Compound 1 0.13±0.0011 7.43±0.51 384.2±13.84
Compound 2 0.14±0.0015 7.58±0.47 375.7±14.07
Pentazocine 0.36±0.0047 2.47±0.31 690.3±16.52
3. Rat liver microsome incubation system
The final volume of the incubation system was 100. mu.L, containing 99. mu.L rat liver microsomes (protein concentration 1mg/mL), β -NADPH (2mmol/L), and 1. mu.L of the target compound methanol stock solution 1. mu.L. the microsomes were preincubated with β -NADPH for 5min prior to adding the target compound for co-incubation, samples were taken at time points 0, 3, 5, 10, 15, 30, 60, and 120min, respectively, and 400. mu.L of glacial acetonitrile containing an internal standard was added to terminate the reaction and was treated under "1" with the following results:
stability of Compounds in rat liver microsomes (n ═ 3)
Compound (I) Ke (Rate of Elimination) t1/2(h) elimination half-life CLint(L·h-1·g-1) Clearance rate
Compound 1 0.13±0.0042 8.05±0.36 278.4±10.47
Compound 2 0.14±0.0037 8.78±0.43 285.9±11.56
Pentazocine 0.28±0.0085 3.86±0.10 497.3±13.58
The results show that: the half-life of the compound 1 and the compound in rat blank plasma and rat liver microsome is more than 2 times longer than that of pentazocine.
Example 14 pharmacokinetic testing
Healthy male Wistar rats 9 with a weight of 210-260 g were selected and randomly divided into A, B, C groups of 3 rats each. Single cycle gavage was given with compound 1 in group a, compound 2 in group B and pentazocine in group C, all at 30 mg/kg. 0.4mL of blood was taken from orbital veins of rats before (0h) and 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 12 or 24h after administration, placed in heparinized EP tubes, centrifuged for 5min (5000rpm), plasma separated, and frozen in a freezer at-20 ℃ to be tested. The fluconazole is taken as an internal standard, and the measurement results are as follows through tandem mass spectrometry:
Figure BDA0002421543970000221
the test shows that: upon gavage administration of the compounds of the invention, both Cmax and AUC of tapentadol in the blood were significantly increased, but both Cmax and AUC of the pentazocine glucuronic acid conjugate were significantly decreased. The bioavailability of the compound 1 is remarkably improved from 19% to 43%, and the bioavailability of the compound 2 is remarkably improved from 19% to 52%. Therefore, after the compound is administrated, the blood concentration of the pharmacological active form pentazocine can be obviously improved, and the blood concentration of the inactive pentazocine glucuronic acid conjugate in the body can be obviously reduced.

Claims (10)

1. A pentazocine prodrug of formula (i) and pharmaceutically acceptable salts thereof:
Figure FDA0002421543960000011
wherein R is hydrogen or deuterium.
2. The process for the preparation of pentazocine prodrugs and pharmaceutically acceptable salts thereof according to claim 1, characterized by the following technical scheme:
Figure FDA0002421543960000021
wherein R is hydrogen or deuterium.
3. The process for the preparation of pentazocine prodrugs and pharmaceutically acceptable salts thereof according to claim 2, characterized in that: the methylating agent of step 1 is selected from
Figure RE-FDA0002496058440000022
。
4. The pentazocine prodrug and the pharmaceutically acceptable salts thereof according to claims 1-3, characterized in that: the pharmaceutically acceptable salt is hydrochloride and lactate.
5. Use of a pentazocine prodrug of formula (i) and pharmaceutically acceptable salts thereof in the preparation of a medicament for treating a disease or condition and/or symptoms of a disease or condition treatable with pentazocine.
6. The use according to claim 5, wherein the range of uses for the disease or condition comprises: 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.
7. The use according to claim 5 or 6, wherein the medicament is for oral, topical, parenteral, sublingual, rectal, vaginal and intranasal administration.
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 use according to claim 5, wherein the prodrug dose is between 10mg and 40 mg.
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