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CN116253652A - Long-chain fatty acid ester derivative, pharmaceutically acceptable salt and pharmaceutical composition of tapentadol, and preparation method and application thereof - Google Patents

Long-chain fatty acid ester derivative, pharmaceutically acceptable salt and pharmaceutical composition of tapentadol, and preparation method and application thereof Download PDF

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CN116253652A
CN116253652A CN202111500496.5A CN202111500496A CN116253652A CN 116253652 A CN116253652 A CN 116253652A CN 202111500496 A CN202111500496 A CN 202111500496A CN 116253652 A CN116253652 A CN 116253652A
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tapentadol
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王振敏
郭菊春
赵娅迪
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Wuhan Siling Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups

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Abstract

The invention provides a long-chain fatty acid ester derivative of tapentadol, pharmaceutically acceptable salt, a pharmaceutical composition, a preparation method and application thereof. The long-chain fatty acid ester derivative of tapentadol is prepared by esterifying the phenolic hydroxyl of tapentadol through long-chain fatty acid. The pharmaceutical experiment result shows that the long-chain esterification of the tapentadol can improve the half-life period in the microsome metabolic process, and the plasma metabolic stability is also obviously improved, thus showing excellent slow-release long-acting effect. The long-chain fatty acid ester derivative of tapentadol, the pharmaceutically acceptable salt or the pharmaceutical composition thereof provided by the invention can be used for preparing analgesic drugs and relieving and treating pain of human or animal bodies, and has remarkable long-acting analgesic effect.

Description

Long-chain fatty acid ester derivative, pharmaceutically acceptable salt and pharmaceutical composition of tapentadol, and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmacy, in particular to a long-chain fatty acid ester derivative of tapentadol, pharmaceutically acceptable salt, a pharmaceutical composition, a preparation method and application thereof.
Background
Tapentadol hydrochloride (TapentadolHCl) is Johnson&Johnson and GrNovel oral analgesic, which is a single isomer form of (1R, 2R) and has formula C, is jointly developed by the company Mentha GmbH 14 H 24 ClNO, chemical name (1R, 2R) -3- (3-dimethyl-1-methyl-2-methylpropyl) -phenol Hydrochloride, quick release tablet was approved by the U.S. FDA for use in relief of moderate and severe acute pain at 2008, 11 months. Tapentadol is a novel dual-action central analgesic, realizes more effective analgesic effect through two complementary action mechanisms, is not only a mu opioid receptor agonist but also a norepinephrine reuptake inhibitor, has analgesic effect on various animal models of acute, inflammatory and chronic neuropathic pain, has the efficacy between morphine and tramadol, but is less prone to produce analgesic tolerance and dependency and less adverse reactions (such as nausea, vomiting and the like) and has small side effects compared with other opioid analgesics such as morphine, tramadol and the like. However, the first pass effect is obvious, and the dogs and rats have low oral absolute bioavailability of only 3% and 8% (clin.j.pain., 2008,4, 293), respectively, due to the broad first pass metabolism, which is much lower than that of human consumption, and the bioavailability of the human being after a single dose of tapentadol is 32% (Drugs Future,2006, 31, 1053).
For the purpose of long-acting, slow-release long-acting preparations have been studied from the point of view of pharmaceutics abroad. The U.S. Hui pharmaceutical factory (Wyeth-Ayerst) has developed an oral depot (EfexorXR) 1 day and has been marketed in 1997 and 1999 in the United kingdom, the U.S. and Argentina, respectively. The long-acting preparation is a slow release preparation containing venlafaxine, and no long-acting preparation for tapentadol exists at present.
In view of the foregoing, there is a need to design an improved long-chain fatty acid ester derivative of tapentadol to solve the above-mentioned problems.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a long-chain fatty acid ester derivative of tapentadol, pharmaceutically acceptable salt, a pharmaceutical composition, a preparation method and application thereof, and the long-chain esterification of tapentadol is used for improving the half-life period in the microsome metabolism process, remarkably improving the plasma metabolism stability and displaying excellent slow-release long-acting effect.
In order to achieve the aim of the invention, the invention provides a long-chain fatty acid ester derivative of tapentadol, which has the following structural general formula:
Figure BDA0003401405380000021
wherein R represents a linear or branched alkyl group having 8 to 18 carbons, such as a derivative of the structure described by the formula:
Figure BDA0003401405380000022
Figure BDA0003401405380000031
Figure BDA0003401405380000041
as a further development of the invention, R represents a linear or branched alkyl radical having 8 to 11 carbon atoms.
As a further development of the invention, R represents a linear alkyl radical having 8 to 11 carbons.
As a further development of the invention, R represents a linear alkyl radical having 10 carbons.
The invention also provides a pharmaceutically acceptable salt of the long-chain fatty acid ester derivative of tapentadol, wherein the acid radical of the salt is inorganic acid or organic acid.
As a further improvement of the present invention, the inorganic acid is one of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid or hydroiodic acid;
the organic acid is one of dihydronaphthoic acid, formic acid, acetic acid, propionic acid, butyric acid, hydroxybutyric acid, malic acid, tartaric acid, amino acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trienesulfonic acid, camphorsulfonic acid, taurine citric acid, fumaric acid, maleic acid, citric acid, succinic acid, cholic acid or deoxycholic acid.
The invention also provides a preparation method of the long-chain fatty acid ester derivative of tapentadol, which comprises the steps of dissolving tapentadol and long-chain fatty carboxylic acid in an organic solvent, adding a dehydrating agent under the ice bath condition, and reacting to generate white precipitate; then adding pyridine catalyst, filtering and extracting to remove white precipitate after the reaction is completed, removing solvent, and passing through a silica gel column to obtain long-chain fatty acid ester derivative of tapentadol.
As a further improvement of the present invention, the dehydrating agent is Dicyclohexylcarbodiimide (DCC), 1-dimethylaminopropyl-3-Ethylcarbodiimide (EDC) or diisopropylcarbodiimide; the catalyst is dimethylaminopyridine, 2,4, 6-trimethylpyridine or pyridine.
The invention also provides a pharmaceutical composition comprising the long-chain fatty acid ester derivative of tapentadol or the pharmaceutically acceptable salt of tapentadol.
The invention also provides application of the long-chain fatty acid ester derivative of tapentadol or the pharmaceutically acceptable salt of tapentadol in preparing analgesic drugs.
The beneficial effects of the invention are as follows:
1. the long-chain fatty acid ester derivative of tapentadol provided by the invention adopts long-chain fatty acid to carry out esterification modification on phenolic hydroxyl groups of tapentadol, and experiments prove that compared with tapentadol, the compound and the medicinal salt thereof have outstanding advantages, can improve half-life period in the microsome metabolic process, remarkably improve plasma metabolic stability, show excellent slow-release long-acting effect, ensure that both the microsome half-life period and the human plasma half-life period can reach 8 hours, have inherent clearance rate lower than 20 mu L/min/mg, and have important significance for long-acting analgesia.
2. The long-chain fatty acid ester derivative of tapentadol, the pharmaceutically acceptable salt or the pharmaceutical composition thereof provided by the invention can be used for preparing analgesic drugs and relieving and treating pain of human or animal bodies, and has remarkable long-acting analgesic effect.
3. The long-acting principle achieved by the long-chain acyl-containing tapentadol prodrug is different from that of a long-acting preparation (Efexor XR), and the preparation method is simple, is easy to realize large-scale preparation, and has obvious practical application value and economic benefit.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail with reference to specific embodiments.
It should be further noted that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to aspects of the present invention are shown in the specific embodiments, and other details not greatly related to the present invention are omitted.
In addition, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention provides a long-chain fatty acid ester derivative of tapentadol, which has the following structural general formula:
Figure BDA0003401405380000061
wherein R represents a linear or branched alkyl group having 8 to 18 carbons. Preferably, R represents a linear or branched alkyl group containing 8 to 11 carbons. More preferably, R represents a linear alkyl group containing 8 to 11 carbons. More preferably, R represents a linear alkyl group having 10 carbons. The experimental result shows that the long-chain esterification of the tapentadol can improve the half-life period in the microsome metabolic process, remarkably improve the plasma metabolic stability and show excellent slow-release long-acting effect.
The invention also provides a pharmaceutically acceptable salt of the long-chain fatty acid ester derivative of tapentadol, wherein the acid radical of the salt is inorganic acid or organic acid.
Wherein the inorganic acid is one of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid or hydroiodic acid; the organic acid is one of dihydronaphthoic acid, formic acid, acetic acid, propionic acid, butyric acid, hydroxybutyric acid, malic acid, tartaric acid, amino acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trienesulfonic acid, camphorsulfonic acid, taurine citric acid, fumaric acid, maleic acid, citric acid, succinic acid, cholic acid or deoxycholic acid.
The invention also provides a preparation method of the long-chain fatty acid ester derivative of tapentadol, which comprises the steps of dissolving tapentadol and long-chain fatty carboxylic acid in an organic solvent, adding a dehydrating agent under the ice bath condition, and reacting to generate white precipitate; then adding pyridine catalyst, reacting for 10-30h, filtering and extracting to remove white precipitate, removing solvent, and passing through silica gel column to obtain long-chain fatty acid ester derivative of tapentadol.
Specifically, detection by TLC (dichloromethane: methanol 15:1 (volume ratio), addition of 2 drops of aqueous ammonia) showed that the reaction was complete, and after removal of the white precipitate by filtration, the solution was extracted with 5% aqueous citric acid (25 ml×3), and then with saturated aqueous sodium chloride (30 ml×3), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered, evaporated to dryness to give an oil, which was passed through a silica gel column, eluent (petroleum ether: ethyl acetate=10:1 (volume ratio)), to give a colorless oil.
The dehydrating agent is Dicyclohexylcarbodiimide (DCC), 1-dimethylaminopropyl-3-Ethylcarbodiimide (EDC) or diisopropylcarbodiimide; the catalyst is dimethylaminopyridine, 2,4, 6-trimethylpyridine or pyridine. The organic solvent is anhydrous dichloromethane.
The invention also provides a pharmaceutical composition, which comprises the long-chain fatty acid ester derivative of tapentadol or the pharmaceutically acceptable salt of tapentadol, excipient, pharmaceutical auxiliary materials and the like.
The long-chain fatty acid ester derivative of tapentadol, the pharmaceutically acceptable salt or the pharmaceutical composition thereof provided by the invention can be used for preparing analgesic drugs and relieving and treating pain of human or animal bodies, and has remarkable long-acting analgesic effect.
Example 1
Example 1 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenylnonanoate (1) prepared as follows:
in a 100mL eggplant-shaped bottle, 0.50g (2.26 mmo) of tapentadol and 0.46g (2.9 mmo) of pelargonic acid were added, and after dissolving in 15mL of anhydrous methylene chloride, the mixture was stirred in an ice bath. A solution of 0.69g (3.34 mmol) of N, N-Dicyclohexylcarbodiimide (DCC) and 5mL of anhydrous methylene chloride was added to gradually form a white precipitate, and after 2 hours of ice bath reaction, 0.1g of N, N-Dimethylaminopyridine (DMAP) was added as a catalyst, and after ice bath removal, the mixture was stirred at room temperature for 24 hours, and the reaction was found to be complete by TLC (methylene chloride: methanol 15:1, 2 drops of aqueous ammonia were added).
After removing the white precipitate of N, N-dicyclohexylurea by filtration, the remaining solution was extracted with 5% aqueous citric acid (25 ml×3), then with saturated aqueous sodium chloride (30 ml×3), the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered, and the dichloromethane was evaporated to dryness to give an oil, which was passed through a silica gel column, and an eluent (petroleum ether: ethyl acetate=10:1) to give a colorless oil. The reaction formula is as follows:
Figure BDA0003401405380000071
the nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.04-6.97(m,3H),4.25(t,J＝5.0HZ,2H),2.45-2.41(m,1H),2.14(s,6H),1.94-1.44(m,7H),1.35-1.30(m,10H),0.95-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 362.1([M+H] + )。
example 2
Example 2 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyl decanoate (2) which differs from example 1 in that decanoic acid is used instead of nonanoic acid as a starting material, the remainder being substantially the same as in example 1 and not described here in detail.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.30-7.28(m,1H),7.04-6.98(m,3H),4.26(t,J＝5.0HZ,2H),2.45-2.40(m,1H),2.15(s,6H),1.94-1.46(m,7H),1.35-1.31(m,12H),0.95-0.88(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 376.1([M+H] + )。
example 3
Example 3 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyl undecanoate (3) which differs from example 1 in that undecanoic acid is used instead of pelargonic acid as starting material, otherwise the procedure is substantially the same as in example 1 and is not repeated here.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.32-7.29(m,1H),7.04-6.96(m,3H),4.26(t,J＝5.0HZ,2H),2.46-2.41(m,1H),2.15(s,6H),1.94-1.46(m,7H),1.35-1.32(m,14H),0.96-0.89(m,6H),0.74(t,J＝5.0HZ,3H).MS(ESI)m/z 390.1([M+H] + )。
example 4
Example 4 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyldodecanoate (4) which differs from example 1 in that dodecanoic acid is used instead of nonanoic acid as a starting material, and otherwise is substantially the same as in example 1 and is not described here again.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.35-1.31(m,16H),0.97-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 404.1([M+H] + )。
example 5
Example 5 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyltridecanoate (5) which differs from example 1 in that tridecanoic acid is used instead of pelargonic acid as starting material, otherwise the procedure is substantially as in example 1 and is not repeated here.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,18H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 418.1([M+H] + )。
example 6
Example 6 provides 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyltetradecanoate (6) which differs from example 1 in that tetradecanoic acid is used instead of nonanoic acid as a starting material, and otherwise is substantially the same as in example 1 and is not described here again.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,20H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 432.1([M+H] + )。
example 7
Example 7 provides 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenylpentadecanoate (7) with the difference compared to example 1 that pentadecanoic acid is used instead of nonanoic acid as starting material, otherwise the same as in example 1 are not described here again.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,22H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 446.1([M+H] + )。
example 8
Example 8 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyl palmitate (8) which differs from example 1 in that hexadecanoic acid is used instead of nonanoic acid as starting material, the remainder being substantially the same as in example 1 and not described here.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,24H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 460.1([M+H] + )。
example 9
Example 9 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyl heptadecanoate (9) which differs from example 1 in that heptadecanoic acid is used instead of nonanoic acid as a starting material, otherwise substantially the same as in example 1 and will not be described here again.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,26H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 474.1([M+H] + )。
example 10
Example 10 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenylstearate (10) which differs from example 1 in that octadecanoic acid is used instead of nonanoic acid as starting material, the remainder being substantially the same as in example 1 and not described here.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,28H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 488.1([M+H] + )。
example 11
Example 11 provides a 3- ((2 r,3 r) -1- (dimethylamino) -2-methylpent-3-yl) phenyl nonadecanoate (11) which differs from example 1 in that nonadecanoic acid is used instead of nonanoic acid as starting material, the remainder being substantially the same as in example 1 and not described here again.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )δ7.31-7.29(m,1H),7.05-6.96(m,3H),4.25(t,J＝5.0HZ,2H),2.47-2.41(m,1H),2.14(s,6H),1.93-1.49(m,7H),1.38-1.31(m,30H),0.98-0.89(m,6H),0.75(t,J＝5.0HZ,3H).MS(ESI)m/z 502.1([M+H] + )。
pharmacological property test
1. Metabolic stability test in microsomes
Experimental system
(1) Stock solutions of the compounds to be tested and the positive control were prepared at a concentration of 10mM using DMSO (dimethyl sulfoxide) as a diluent, and then all stock solutions were diluted with 70% acetonitrile to a working concentration of 0.25 mM;
(2) The cofactor used in the test was NADPH (reduced amidic adenine dinucleotide phosphate) regeneration system consisting of 6.5mM NADP (nicotinamide adenine dinucleotide phosphate), 16.5mM G-6-P (glucose-6-phosphate), 3U/mL G-6-P D (glucose-6-phosphate dehydrogenase);
(3) The quencher consists of acetonitrile containing tosyl butyramide and propanol (used as internal standard);
(4) The buffer used in the test was 100mM phosphate buffer containing 3.3mM MgCl 2 ；
(5) The mixture contained 0.2mg/mL liver microsomal protein and 1 μm test compound/positive control and incubated in 100mM potassium phosphate buffer.
Experimental method
(1) A 0 minute sample was prepared by adding 80 μl aliquots of each incubation mixture to 300 μl of quenching reagent to precipitate the protein. The sample was vortexed and then an aliquot of 20. Mu.L of NADPH regeneration system was added.
(2) The reaction was started by adding 130. Mu.L of NADPH regeneration system to 520. Mu.L of each incubation mixture. The final incubation conditions reached in 650 μl were: 0.2mg/mL microsomal protein, 1. Mu.M test substance/positive control, 1.3mM NADP,3.3mM 6-phosphoglucose, 0.6U/mL 6-phosphoglucose dehydrogenase.
(3) The mixture was incubated with gentle shaking in a 37℃water bath. 100. Mu.L aliquots of each mixture were transferred to clean 96-well plates at 5, 10, 30, 60 minutes, which contained 300. Mu.L of quencher to precipitate the protein, followed by centrifugation (5000 Xg, 10 minutes).
(4) 100. Mu.L of the supernatant was placed in a 96-well assay plate into which 300. Mu.L of ultrapure water was previously added, and then analyzed by LC-MS/MS.
Metabolic conditions of the Compounds of Table 1 in microsomes
Figure BDA0003401405380000121
Enzymatic kinetic parameters of the compounds of Table 2
Figure BDA0003401405380000122
As is evident from the results shown above, the microsomes of the compound of the present invention have a slow metabolic process and can maintain a high residual rate after 60 minutes, especially the compounds obtained in examples 1 to 4, wherein 3- ((2R, 3R) -1- (dimethylamino) -2-methylpent-3-yl) phenyldodecanoate obtained in example 4 remains the most after 60 minutes.
As can be seen from Table 2, the compound of the present invention has a longer half-life (up to about 8 hours) in the microsome metabolism process, and the clearance rate is relatively low, which indicates that the compound of the present invention has good microsome metabolism stability, and can maintain the effective blood concentration in the body for a longer time, thereby exerting a durable analgesic effect. Among them, the intrinsic clearance of example 1 was the smallest, the half-life of example 3 was the longest, but the intrinsic clearance was slightly higher; examples 6 and 8 have a longer half-life and lower intrinsic clearance.
2. Human plasma metabolic stability test
Experimental system
(1) Stock solutions of test compounds and positive controls were prepared at a concentration of 10mM using DMSO as diluent. The stock solution of the positive control was then diluted with 50% acetonitrile to a working concentration of 0.2mM, and the stock solution of the test compound was then diluted with 50% acetonitrile to a working concentration of 1 mM.
(2) The quencher consisted of acetonitrile containing tosyl butyramide and propranolol (used as internal standard).
Experimental method
(1) Positive control and test article working solutions (in duplicate) were added to human plasma and concentrated to 1. Mu.M and 5. Mu.M, respectively.
(2) A 0 minute sample was prepared by adding 80 μl aliquots of each incubation mixture to 320 μl of quenching reagent to precipitate the protein.
(3) The mixture was incubated in a 37 ℃ water bath with gentle shaking. 80. Mu.L aliquots of each mixture were transferred to clean 96-well plates at 0, 1h, 2h, 3h, 4h, 5h, 6h, 7h and 8h, which contained 320. Mu.L quencher to precipitate the protein, followed by centrifugation (4000 Xg, 15 min).
(4) 80. Mu.L of the supernatant was placed in a 96-well assay plate with 160. Mu.L of ultrapure water added in advance, and then analyzed by LC-MS/MS.
Table 3 results of test for human plasma Metabolic stability of Compounds
Figure BDA0003401405380000131
Figure BDA0003401405380000141
As can be seen from Table 3, the compounds of the present invention can maintain a high concentration for a long period of time in the human plasma metabolism process, and the compounds of examples 1 and 8 can maintain a residual rate above the normal residual rate after 8 hours, which indicates that the compounds of the present invention have good plasma metabolism stability, and can maintain an effective blood concentration in vivo for a long period of time, thereby exerting a long analgesic effect.
Example 12
Preparation of pharmaceutical compositions in the form of tablets
Table 4 tablet ingredients
Figure BDA0003401405380000142
Sieving the raw materials with 80 mesh sieve for use, weighing the active ingredients, microcrystalline cellulose, lactose and povidone K30 according to the proportion shown in Table 4, adding into a high-speed mixing preparation machine, stirring at low speed, mixing well, adding a proper amount of purified water, stirring at low speed, cutting at high speed, granulating, drying at 60 ℃ for 3h, and sieving with 24 mesh sieve to obtain granules; and adding the sodium carboxymethyl starch, the silicon dioxide and the magnesium stearate in the prescribed amount, mixing, and tabletting by a rotary tablet press.
Example 13
Preparation of capsule (230 mg) pharmaceutical composition
Table 5 capsule ingredients
Figure BDA0003401405380000143
Figure BDA0003401405380000151
Sieving the raw materials with 80 mesh sieve for use, weighing the active ingredients, lactose, starch and povidone K30 according to the proportion in table 5, adding into a high-speed mixing preparation machine, stirring at low speed, mixing uniformly, adding a proper amount of purified water, stirring at low speed, cutting at high speed, granulating, drying at 60 ℃ for 3h, and sieving with 24 mesh sieve to obtain granules; then adding the prescribed amount of silicon dioxide and magnesium stearate, mixing, and filling the capsule by a capsule filling machine.
Example 14
Preparation of injection (5 mL) pharmaceutical composition
Table 6 injection ingredients
Figure BDA0003401405380000152
Weighing active ingredients, lactose and sodium chloride according to the proportion in Table 6, dissolving the active ingredients, lactose and sodium chloride by using water for injection, preparing 0.1mol/L solution of sodium citrate by using water for injection, dripping the solution into the solution, monitoring the pH value to 6.8-7.0, and stopping dripping to obtain a medicine aqueous solution; filtering the above aqueous solution with a filter membrane, drying, aseptically pulverizing, and packaging to obtain injection.
In conclusion, the long-chain fatty acid ester derivative of tapentadol provided by the invention has the advantages that the phenolic hydroxyl group of tapentadol is esterified and modified by long-chain fatty acid, so that the half-life period in the microsome metabolism process can be improved, the plasma metabolism stability is also obviously improved, the excellent slow-release long-acting effect is shown, the half-life period of both the microsome and human plasma can be up to 8 hours, the inherent clearance rate is lower than 20 mu L/min/mg, and the tapentadol long-acting analgesic preparation has important significance for long-acting analgesia. The long-chain fatty acid ester derivative of tapentadol, the pharmaceutically acceptable salt or the pharmaceutical composition thereof can be used for preparing analgesic drugs and relieving and treating pain of human or animal bodies, and has remarkable long-acting analgesic effect.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. The long-chain fatty acid ester derivative of tapentadol is characterized by having the following structural general formula:
Figure FDA0003401405370000011
wherein R represents a linear or branched alkyl group having 8 to 18 carbons.
2. Long-chain fatty acid ester derivatives of tapentadol according to claim 1, characterized in that R represents a linear or branched alkyl group containing 8 to 11 carbons.
3. Long-chain fatty acid ester derivatives of tapentadol according to claim 2, characterized in that R represents a linear alkyl group containing 8 to 11 carbons.
4. Long-chain fatty acid ester derivatives of tapentadol according to claim 2, characterized in that R represents a linear alkyl group containing 10 carbons.
5. A pharmaceutically acceptable salt of a long chain fatty acid ester derivative of tapentadol according to any one of claims 1 to 4, wherein the acid radical of the salt is an inorganic or organic acid.
6. The pharmaceutically acceptable salt of a long chain fatty acid ester derivative of tapentadol according to claim 5, wherein the mineral acid is one of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid or hydroiodic acid;
the organic acid is one of dihydronaphthoic acid, formic acid, acetic acid, propionic acid, butyric acid, hydroxybutyric acid, malic acid, tartaric acid, amino acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trienesulfonic acid, camphorsulfonic acid, taurine citric acid, fumaric acid, maleic acid, citric acid, succinic acid, cholic acid or deoxycholic acid.
7. A process for the preparation of long chain fatty acid ester derivatives of tapentadol as claimed in any one of claims 1 to 4, characterized in that tapentadol and long chain fatty carboxylic acid are dissolved in an organic solvent and then added with a dehydrating agent under ice bath conditions to react to form white precipitate; then adding pyridine catalyst, filtering and extracting to remove white precipitate after the reaction is completed, removing solvent, and passing through a silica gel column to obtain long-chain fatty acid ester derivative of tapentadol.
8. The method for preparing long-chain fatty acid ester derivatives of tapentadol according to claim 7, wherein the dehydrating agent is dicyclohexylcarbodiimide, 1-dimethylaminopropyl-3-ethylcarbodiimide or diisopropylcarbodiimide; the catalyst is dimethylaminopyridine, 2,4, 6-trimethylpyridine or pyridine.
9. A pharmaceutical composition comprising a long chain fatty acid ester derivative of tapentadol according to any one of claims 1 to 4 or a pharmaceutically acceptable salt according to any one of claims 5 to 6.
10. Use of a long-chain fatty acid ester derivative of tapentadol according to any one of claims 1 to 4 or a pharmaceutically acceptable salt according to any one of claims 5 to 6 for the preparation of an analgesic drug.
CN202111500496.5A 2021-12-09 2021-12-09 Long-chain fatty acid ester derivative, pharmaceutically acceptable salt and pharmaceutical composition of tapentadol, and preparation method and application thereof Pending CN116253652A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1706813A (en) * 2004-06-09 2005-12-14 中国人民解放军军事医学科学院放射医学研究所 Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use
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CN102065852A (en) * 2007-11-23 2011-05-18 普罗泰克医药公司 Tapentadol compositions
US20130046012A1 (en) * 2010-04-28 2013-02-21 Lacer, S.A. New compounds, synthesis and use thereof in the treatment of pain
CN105037180A (en) * 2015-04-19 2015-11-11 安徽省逸欣铭医药科技有限公司 Central-analgesic novel compound having double effects, preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1706813A (en) * 2004-06-09 2005-12-14 中国人民解放军军事医学科学院放射医学研究所 Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use
CN101426485A (en) * 2006-04-28 2009-05-06 格吕伦塔尔有限公司 Pharmaceutical composition comprising 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and an NSAID
CN102065852A (en) * 2007-11-23 2011-05-18 普罗泰克医药公司 Tapentadol compositions
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