WO2011079807A1

WO2011079807A1 - Dipropofol pyrophosphate dihydrogen ester and pharmaceutically acceptable salt, preparation process and application thereof

Info

Publication number: WO2011079807A1
Application number: PCT/CN2010/080513
Authority: WO
Inventors: 邹永; 孙洪宜; 魏文; 刘现可; 肖春芬
Original assignee: 西藏海思科药业集团股份有限公司
Priority date: 2009-12-30
Filing date: 2010-12-30
Publication date: 2011-07-07
Also published as: CN101768185B; CN101768185A

Abstract

Dipropofol pyrophosphate dihydrogen ester and pharmaceutically acceptable salt, preparation process and application thereof. The ester (2) is prepared by phosphorylating propofol with P₂O₅ as phosphorylating reagent in anhydrous organic solvent at 25-110°C for 2-8h under stirring, and condensing to obtain white solid. The title pharmaceutically acceptable salt is prepared by salifying ester (2) with base in organic solvent at 0-80°C for 1-5 h under stirring, filtering to obtain white solid. The process has the advantages of simple preparation process, high product yield and purity, low cost, and easily-accessible raw materials. The ester (2) and its pharmaceutically acceptable salt may be used to prepare the medical preparations as sedative, hypnotic and anesthetic, with stable property and good water solubility.

Description

Dipropionol dihydrogen pyrophosphate and pharmaceutically acceptable salt thereof, preparation method and application thereof

The invention relates to the field of medicinal chemical industry, in particular to a water-soluble prodrug, double propofol pyrophosphate and a salt thereof, a preparation method thereof and application thereof in preparing sedative hypnosis and anesthetic drugs. Background technique

Propofol (formula 1), also known as propofol, dexamethasone, chemically known as 2,6-diisopropylphenol, is a widely used systemic intravenous anesthetic. It has rapid onset, short duration of action, rapid recovery, less adverse reactions, no sequelae, wide application range (can be used for anesthesia induction, maintenance and assisted epidural anesthesia), easy to grasp and other excellent characteristics. However, since propofol is a fat-soluble compound and hardly soluble in water, its pharmacokinetic properties are poor. At present, intravenous administration is mainly carried out in the form of a fat emulsion, which has certain side effects such as injection pain, disorder of lipid metabolism and hyperlipidemia, digestive system adverse events and infection. Therefore, there is an urgent need in the clinic for a direct increase in the water solubility of propofol.

Precursor derivatization by the phosphation process can significantly increase the water solubility of propofol, and it is therefore possible to develop propofol prodrugs that are more suitable for clinical applications. Currently, propofol phosphated prodrugs have a methylene-linked fospropofol disodium and a directly linked propofol Phosphate Disodium. Both of these phosphate modification can improve the water solubility and improve the pharmacokinetic properties of propofol, but Fospropofol Disodium will release one molecule of formaldehyde during metabolism in the body (European Journal of Pharmaceutical Sciences, 2008, 34: 110-117), and thus is relatively unfavorable in terms of drug safety. 0 0

, II

0一 P II― ONa -0― P― ONa

I I

ONa ONa

Fospropofol disodium Propofol phosphate disodium

SUMMARY OF THE INVENTION It is an object of the present invention to provide a water-soluble propofol prodrug having a novel structure, i.e., dipropionol dihydrogen pyrophosphate and a salt thereof.

Another object of the present invention is to provide a process for producing the above-described dipropionol dihydrogen pyrophosphate and a salt thereof.

A further object of the present invention is to provide the use of the above-described dipropionol dihydrogen pyrophosphate and a salt thereof for the preparation of sedative hypnosis and anesthetics.

It is a still further object of the present invention to provide a sedative, hypnotic and anesthetic pharmaceutical composition.

The object of the present invention is achieved by the following technical solutions provided by the present invention:

A dipropionol pyrophosphate dihydrogen ester of the formula (2) and any pharmaceutically acceptable

;

Formula (2)

The pharmaceutically acceptable optional salt of the above dipropionol dihydrogen pyrophosphate is a dipropofol pyrophosphate salt of the formula (3):

Wherein R is a pharmaceutically acceptable cation, preferably an alkali metal ion, an ammonium ion or a protonated amino acid.

The invention also provides a preparation method of the dipropionol pyrophosphate dihydrogen ester of the above formula (2), which comprises the following steps:

The propofol having the structure of formula (1) is stirred and reacted with a phosphorylating reagent in an anhydrous organic solvent at a temperature of 25 to 110 ° C for 2 to 8 hours, concentrated, and purified to obtain a double structure of the formula (2). Propofol dihydrogen pyrophosphate, as a white solid:

Formula 1)

The phosphorylating agent is preferably phosphorus pentoxide; the anhydrous organic solvent is preferably benzene, toluene, petroleum ether, chlorobenzene, chloroform, chloroform, 1,2-dichloroacetamidine. Or carbon tetrachloride, more preferably toluene.

Preferably, the weight ratio of the propofol to the anhydrous organic solvent is 1:3 to 1:20; the preferred reaction temperature is 80 ° C _{; and the} reaction time is preferably 4 hours.

Preferably, the molar ratio of propofol to phosphorus pentoxide is from 1:1 to 1:16, more preferably from 1:1 to 1:4. The present invention also provides a process for preparing a dipropionol pyrophosphate salt of the formula (3), which comprises the following steps:

The dipropionol pyrophosphate dihydrogen ester of the formula (2) is reacted in an organic solvent at 0 to 80 ° C for 1 to 5 hours with an alkali, the base being an inorganic base, an organic base or a base. Amino acid; reaction is completed If a white solid is precipitated, direct filtration can be carried out to obtain a propofol pyrophosphate salt of the formula (3); or, if the reaction solution is a clear solution, it is spin-dried to obtain a dipropofol coke in the form of a white solid. Phosphate salt.

Preferably, the preparation method of the double propofol pyrophosphate salt further comprises the following steps: the obtained white solid double C

Preferably, the weight ratio of the dipropionol dihydrogen pyrophosphate to the organic solvent is 1:5 to 1:40. The molar ratio of the dipropionol dihydrogen pyrophosphate to the base is preferably from 1:1 to 1:6, more preferably 1:2; the reaction temperature is preferably 25 ° C, and the reaction time is preferably 2.5 hours.

The organic solvent is preferably methanol or ethanol, more preferably ethanol; the inorganic base is preferably NaOH, Na ₂ C0 ₃ , NaHC0 ₃ , KOH or K ₂ C0 ₃ , more preferably NaOH; the organic base is preferably ammonia, A An amine, ethylamine, diethylamine, triethylamine or nicotinamide; the basic amino acid is preferably arginine, histidine or lysine; the organic solvent used for the recrystallization is preferably methanol, ethanol or acetone, Ethanol is preferred.

Optimal

ΟΝΡΙ

One ,

Type ( OONPI

(1) 2)

Organic solvents

Formula (2) (3)

Wherein: R is an alkali metal ion, an ammonium ion or a protonated amino acid.

The present invention also provides a pharmaceutical composition having anesthetic sedative and hypnotic action, comprising a therapeutically effective amount of said dipropionol dihydrogen pyrophosphate or a salt thereof as an active ingredient, and containing one or more pharmaceutics An acceptable carrier.

The dipropionol dihydrogen pyrophosphate or a salt thereof of the present invention, and the above pharmaceutical composition can be applied to the preparation of sedative hypnosis and anesthetic drugs.

For specific applications, it may be administered orally or orally. When not administered orally, it can be used often Formulation techniques, such as injections, ophthalmic preparations, dental preparations, and the like. When administered orally, the compound can be mixed with a conventional pharmaceutically acceptable carrier by conventional formulation techniques to prepare conventional solid preparations such as tablets, capsules, granules and the like.

Without wishing to be bound by it, the basic principles of the invention can be understood as follows:

Dipropionol dihydrogen pyrophosphate or a salt thereof is a novel pyrophosphate ester prodrug. The method is designed to pyrophosphorize a free hydroxyl group in a drug molecule to obtain a dihydropyrophosphate or a salt thereof containing two propofols to improve the water solubility and pharmacokinetics of the parent drug. Nature, improve the medicinal properties. The pyrophosphate ester prodrug only improves the water solubility of the parent compound, improves its pharmacokinetic properties, does not change the pharmacological properties of the parent compound, does not introduce a toxic pharmacophore, and is due to the widespread presence of pyrophosphate structural units in the organism. The pyroesterification method, which hydrolyzes the enzyme of this structural unit, is endogenous in a sense. Therefore, the double propofol pyrophosphate salt can overcome the disadvantage that the water solubility of propofol is too low, while maintaining the physiological activity of propofol, and does not introduce substances harmful to the body.

Propofol is used as a raw material to react with phosphoric acid reagent phosphorus pentoxide to obtain dipropionol dihydrogen pyrophosphate; if necessary, dipropionol dihydrogen pyrophosphate and inorganic or organic base or alkaline The amino acid reaction is further purified to obtain a dipropofol pyrophosphate salt.

The invention has the following advantages and effects:

(1) The double propofol pyrophosphate salt designed and synthesized by the method of the invention has a new chemical structure, which makes the double propofol pyrophosphate salt have good water solubility, completely solves the lack of water solubility of propofol. The various problems brought about are stable at room temperature and under normal storage conditions.

(2) The pyrophosphate structural unit in the dipropionol pyrophosphate salt is an endogenous structural unit. After entering the body, propofol is released to function, and the pyrophosphate structural unit itself can be hydrolyzed by enzymes in the body, which is safe for the body.

(3) The method of the invention has mild reaction conditions, simple operation, low cost and easy availability of raw materials, low cost, green environmental protection, high yield, and easy scale preparation. DRAWINGS

Figure 1 is an iHNMR spectrum of dipropionol dihydrogen phosphate prepared in Example 1.

Figure 2 is a FAB-MS spectrum of dipropionol dihydrogen phosphate prepared in Example 1.

3 is a ³¹ P NMR spectrum of dipropionol dihydrogen phosphate prepared in Example 1.

4 is an iHNMR spectrum of the disodium propofol pyrophosphate disodium salt prepared in Example 7. Figure 5 is a ¹³ C NMR spectrum of the disodium propofol pyrophosphate disodium salt prepared in Example 7. Figure 6 is a FAB-MS spectrum of the disodium propofol pyrophosphate disodium salt prepared in Example 7.

Figure 7 is a ³¹ P NMR spectrum of the disodium propofol pyrophosphate disodium salt prepared in Example 7.

Figure 8 is an iHNMR spectrum of the dipropionol pyrophosphate diarginine salt prepared in Example 10.

Figure 9 is an ESI-MS spectrum of the dipropionol pyrophosphate diarginine salt prepared in Example 10.

Figure 10 is a ³¹ P NMR spectrum of the dipropionol pyrophosphate diarginine salt prepared in Example 10. Detailed ways

The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.

Example 1

1.42g (O.Olmol) P ₂ 0 ₅ and 10ml of anhydrous toluene were added to the reaction flask, heated to 80 ° C with stirring, and 1.78 g (O.Olmol) propofol was quickly added dropwise. The reaction was stirred for 4 hours. After the reaction was completed, the mixture was filtered while hot, and some of the solvent was evaporated. The remaining portion was allowed to stand for cooling, that is, a large amount of white solid was formed, which was filtered with suction and washed with anhydrous toluene to obtain dipropofol pyrophosphate dihydrogen ester. 1.86 g, melting point: 113-114 ° C, yield 74.69%.

Example 2

2.84 g (0.02 mol) of P ₂ 0 ₅ and 10 ml of anhydrous toluene were placed in a reaction flask, and 1.78 g (O.10 mol) of propofol was rapidly added dropwise with stirring at 25 ° C, and the mixture was kept at a constant temperature. Stirring reaction was continued for 2 hours. After completion of the reaction, suction filtration was carried out, and a part of the solvent was evaporated. The remaining portion was allowed to stand for cooling, that is, a white solid was formed, which was filtered with suction and washed with anhydrous toluene to obtain a dipropofol dihydrogen phosphate dihydrogen ester 1.92 g. : 113-114 ° C, yield 77.11%.

Example 3

11.36g (0.08mol) P ₂ 0 ₅ and 50ml of anhydrous toluene were added to the reaction flask, heated to 110 ° C under stirring, and 1.78 g (O.Olmol) propofol was quickly added dropwise, and the temperature was dropped. Stirring reaction was continued for 8 hours. After completion of the reaction, the mixture was filtered while hot, and some of the solvent was evaporated. The remaining portion was allowed to stand for cooling, that is, a white solid was formed, which was filtered with suction and washed with anhydrous toluene to give dipropofol pyrophosphate dihydrochloride 1.62. g, melting point: 113-114 ° C, yield 65.06%.

Example 4

5.68 g (0.04 mol) of P ₂ 0 ₅ and 10 ml of anhydrous dichloromethane were added to the reaction flask, and the mixture was heated to reflux under reflux (about 45 ° C), and 1.78 g (O.10 mol) of propofol was rapidly added dropwise. Phenol, constant temperature after dropping Stirring reaction was continued for 3 hours. After the reaction was completed, the mixture was filtered while hot, and some of the solvent was evaporated. The remaining part was allowed to stand for cooling, that is, a white solid was formed, which was filtered with suction and washed with anhydrous dichloromethane to give dipropofol pyrophosphate. Hydrogen ester 1.51 g, melting point: 113-114 ° C, yield 60.64%.

Example 5

Add 1.42g (O.Olmol) P ₂ 0 ₅ and 10ml anhydrous trichloromethane to the reaction flask, heat to 80 ° C with stirring, and quickly add 1.78 g (O.Olmol) propofol, drop After the addition is completed, the reaction is continued for 6 hours. After the reaction is completed, the mixture is filtered while hot, and some of the solvent is dried. The remaining part is allowed to stand for cooling, that is, a white solid is formed, which is filtered with suction and washed with anhydrous chloroform. Phenol pyrophosphate dihydrogen ester 1.43 g, melting point: 113-114 ° C, yield 57.43%.

Example 6

1.42 g (O.Olmol) P ₂ 0 ₅ and 10 ml of anhydrous 1,2-dichloroacetamidine were added to the reaction flask, and the mixture was heated to reflux under reflux (about 84 ° C), and 1.78 g (O) was rapidly added dropwise. .Olmol) propofol, constant temperature after stirring, continue stirring for 4 hours, the reaction is completed, heat filtration, some of the solvent is spin-dried, and the rest is allowed to stand for cooling, that is, a white solid is formed, and suction is filtered and anhydrous is used. After washing with 2-dichloroethane, 1.31 g of dipropionol pyrophosphate dihydroester was obtained, melting point: 113-114 ° C, yield 52.61%.

Example 7

2.49 g (0.005 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, stirred and dissolved at room temperature, and 0.60 g (0.015 mol) of sodium hydroxide was slowly added dropwise to the reaction flask. A 10 ml solution of absolute ethanol was added dropwise over about 0.5 hours, and a large amount of white solid formed during the addition. After completion of the dropwise addition, the reaction was further stirred at room temperature for 2 hours, and filtered to obtain a white solid of dipropionol pyrophosphate disodium salt. The solid was recrystallized from ethanol to give a white solid (yield: 2.17 g, mp.

Example 8

2.49 g (0.005 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, and while stirring at 0 ° C, 0.53 g (0.005 mol) of sodium carbonate was slowly added dropwise to the reaction flask. 10 ml of absolute ethanol solution was added dropwise in about 0.5 hours, and a large amount of white solid was formed during the dropwise addition. After the dropwise addition was completed, the reaction was continuously stirred for 1 hour, and filtered to obtain a white solid of dipropionol pyrophosphate disodium salt. The solid was recrystallized from methanol to give white white solid (yield: 1.08 g, mp.

Example 9

2.49 g (0.005 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, and while stirring at 80 ° C, 2.1 g (0.025 mol) of sodium hydrogencarbonate was slowly added dropwise to the reaction flask. 20ml of water The ethanol solution was added dropwise over about 1 hour, and a large amount of white solid was formed during the addition. After the dropwise addition, the reaction was further stirred for 4 hours, and filtered to obtain a white solid of dipropionol pyrophosphate disodium salt. The solid was recrystallized from acetone to give a white white solid: 1.36 g, m.p.

Example 10

0.498 g (0.01 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, and 0.348 g (0.002 mol) of arginine was slowly added dropwise to the reaction flask under stirring at room temperature. Appropriate amount of ethanol-water solution, the addition is completed in about 1 hour, the stirring reaction is continued for 3 hours, and the mixture is dried by suction filtration to obtain a white solid of 0.63 g of dipropofol pyrophosphate diarginine salt. Melting point: 183-185° C, yield 74.46%.

Example 11

0.498 g (0.01 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, and 0.292 g (0.002 mol) of lysine was slowly added dropwise to the reaction flask under stirring at room temperature. Appropriate amount of ethanol-water solution, complete the dropwise addition in about 1 hour, continue to stir the reaction for 3 hours after the addition, and then spin dry to obtain double propofol pyrophosphate dilysine salt white solid 0.56 g, melting point: 173-174 ° C, yield 70.88%.

Example 12

0.498 g (0.01 mol) of dipropionol dihydrogen pyrophosphate and 10 ml of absolute ethanol were added to the reaction flask, and 0.310 g (0.002 mol) of histidine was slowly added dropwise to the reaction flask under stirring at room temperature. Appropriate amount of ethanol-water solution, complete the dropwise addition in about 1 hour, continue to stir the reaction for 3 hours after the addition, and then spin-dry to obtain 0.53 g of dipropofol pyrophosphate dihistidine white solid. Melting point: 204-206° C, yield 65.59%.

The structural spectra of the compounds obtained in the respective examples are shown in Figures 1-10, and the structural formula and spectral data of the obtained compounds are as follows:

1. Examples 1-6 Dihydrogen esters:

The spectral data of dipropionol pyrophosphate dihydrogen ester is as follows: ifiNMR (400 MHz, CD ₃ COCD ₃ , 5/ppm _: J/Hz): 1.16, 1.18 (d, 24H, J=6.8), 3.51-3.58 (m, 4H), 7.14 (m, 6H); ³¹ PNMR (400MHz, D ₂ 0, δ/ppm, 85% H ₃ P0 ₄ ) : -16.6; FAB-MS: m/z 499 [M+l]+, 521 [M+Na] ⁺ o 2, buy the application of 7-9 double disodium salt

The spectral data of the disodium propofol pyrophosphate disodium salt are as follows: ifiNMR (400 MHz, CD ₃ COCD ₃ , δ/ppm, J/Hz): 1.11, 1.12 (d, 24H, J=6.8), 3.50-3.56 ( m, 4H), 7.09-7.14 (m, 6H); ¹³ CNMR (400MHz, D ₂ 0, δ/ppm) : 25.6, 29.2, 126.6, 127.7, 144.4, 149.9; ³¹ PNMR (400MHz, D ₂ 0, δ /ppm, 85% H ₃ P0 ₄ ): -14.3 (s); MS (FAB): m/z 543 [M+l] ⁺ , 565 [M+Na] ⁺ o

3. Example 10 Double propofol pyrophosphate diarginine salt

The spectral data of the dipropionol pyrophosphate diarginine salt is as follows: iHNMR (400 MHz, D ₂ 0 δ/ppm): 1.08 (d, 24H), 1.52-1.62 (m, 4 Η), 1.75-1.80 (m , 4Η), 3.08 (t, 4Η) 3.48-3.58 (m, 4H) , 3.61 (t, 2H) , 7.03-7.09 (m, 6H) ; ³¹ PNMR (400MHz, D ₂ 0 δ/ppm, 85% H ₃ P0 ₄ ) : -14.2; ESI-MS: m/z 846 M ⁺ , 498, 177.

4. Example 11 Double propofol pyrophosphate dilysine salt

The spectral data of the dipropionol pyrophosphate dilysinate salt are as follows: iHNMR (400 MHz, D ₂ 0 δ/ppm): 1.08 (d, 24H), 1.41 (m, 4 Η), 1.61 (t, 4 Η), 1.87 (m, 4Η), 2.92 (t, 4Η) 3.52-3.57 (m, 4H), 3.88 (t, 2H), 7.13 (m, 6H); ³¹ PNMR (400MHz, D ₂ 0, 5/ppm _: 85% H ₃ P0 ₄ ) : -14.2; ESI-MS : m/z 790 M+, 498, 146.

5, real two histidine

The spectral data of the dipropionol pyrophosphate dihistidine salt is as follows: iHNMR (400 MHz, D ₂ 0, δ/ppm): 1.09 (d, 24H), 3.06-3.20 (m, 4H), 3.47-3.54 ( m, 4H), 3.87-3.90 (dd, 2Η), 7.07 (s, 2Η), 7.12 (m, 6Η), 8.02 (s, 2Η); ³¹ PNMR (400MHz, D ₂ 0, δ/ppm, 85%) H ₃ P0 ₄ ) : -14.2; ESI-MS: m/z 808 M ⁺ , 498, 155.

Formulation Example h Injection

Take 25.0 mg of dipropionol pyrophosphate disodium salt and add it to 20 ml of 5% glucose solution at 15-20 ° C. After stirring the solution, add 10 mg of needle to activated carbon, stir for 10 minutes, filter and decarbonize; use 0.45 μηι Filter the membrane, filter with 0.22μηι filter, add 5% glucose solution to the total amount of 100ml, determine the content, check the clarity, fill the 100ml infusion bottle, press the aluminum cap and sterilize at 121 °C for 20min.

Formulation Example 2: Injection

25.0 mg of dipropionol pyrophosphate diarginine salt was added to 20 ml of a 5% glucose solution at 15-20 ° C. After stirring the solution, 10 mg of the needle was added with activated carbon, stirred for 10 minutes, and decarburized by filtration; Filter through 0.45μηι filter, filter with 0.22μηι filter, add 5% glucose solution to total 100ml, determine the content, check the clarity, fill into 100ml infusion bottle, press plug aluminum cap, sterilize at 121 °C 20min.

Formulation Example 3 : Injection

The double propofol pyrophosphate disodium salt is dried under vacuum at 35~40 ° C to obtain a sterile powder, which is divided into 25 mg/bottle, 50 mg/bottle, 75 mg/bottle, lOOmg/bottle under sterile conditions. A sterile powder injection formulation of propofol pyrophosphate disodium salt.

Formulation Example 4: Injection

The double propofol pyrophosphate diarginine salt is dried under vacuum at 35~40 ° C to obtain a sterile powder, which is divided into 25 mg/bottle, 50 mg/bottle, 75 mg/bottle, lOOmg/bottle under aseptic conditions. A sterile powder injection preparation of dipropionol pyrophosphate diarginine salt is obtained. Formulation Example 5: Capsule

25.0 mg of the dipropofol pyrophosphate disodium salt solid powder was thoroughly mixed with 15.0 mg of lactose, and the mixture was filled in a capsule of 40.0 mg/capsule to obtain an oral capsule.

Formulation Example 6: Capsule

25.0 mg of a double propofol pyrophosphate diarginine solid powder was thoroughly mixed with 15.0 mg of lactose, and the mixture was filled in a capsule of 40.0 mg/capsule to obtain an oral capsule.

Formulation Example 7: Tablet

25.0 mg of a double propofol pyrophosphate disodium salt solid powder was uniformly mixed with lg glucose, 10 g of corn starch, and 1.5 g of a 5% corn starch paste, and the mixture was granulated by a wet granulation method. Then, lg magnesium stearate was added, and an oral preparation was obtained by a tableting method.

Formulation Example 8: Tablet

25.0 mg of a solid powder of dipropionol pyrophosphate diarginine salt was uniformly mixed with lg glucose, 10 g of corn starch, and 1.5 g of a 5% corn starch paste, and the mixture was granulated by a wet granulation method. Then, lg magnesium stearate was added, and an oral preparation was obtained by a tableting method.

Formulation Example 9: Granules

25.0 mg of dipropionol pyrophosphate disodium salt, 20 mg of dextrin and 40 mg of sucrose were mixed, granulated by a wet method, thoroughly dried at 60 ° C, and obtained by dispensing.

Formulation Example 10: Granules

25.0 mg of dipropionol pyrophosphate diarginine salt, 20 mg of dextrin and 40 mg of sucrose were mixed, granulated by wet method, thoroughly dried at 60 ° C, and obtained by dispensing.

Water solubility determination

O.lmg of dipropionol pyrophosphate salt was placed in three test tubes under normal temperature and normal pressure, respectively, and Ιμΐ distilled water was added to the test tube one by one, and shaken while adding, and the compound was recorded when the compound was completely dissolved. The volume of water added. The water solubility of the dipropionol pyrophosphate salt was greatly improved, and the solubility was: double propofol pyrophosphate disodium salt 76.5 mg/ml (16 ° C), double propofol pyrophosphate Ester diarginine salt 40.5mg/ml (16°C), dipropionol pyrophosphate dilysine salt 36.4mg/ml (16°C), dipropionol pyrophosphate dihistidine 32.8mg/ml (16 °C) (The solubility of propofol in pure water is only 146mg/L) o

Determination of stability in aqueous solution:

Prepared 5mg/ml propofol pyrophosphate disodium salt, propofol pyrophosphate diamino acid reconstituted salt The solution was allowed to stand at room temperature for 28 days in the dark, and was followed by TLC and NMR. No hydrolyzate or other decomposition products were found.

Pharmacodynamic test:

The dipropofol pyrophosphate salt was formulated into an aliquot of an aqueous solution, which was filtered through a 0.2 μm sterile membrane and used for animal injection.

1. Pharmacodynamic experiments of dipropionol pyrophosphate disodium salt:

The tail vein injection study of mice showed that the doses required to start anesthesia were 2.6 ± 2.5, 4.3 ± 1.5, 2.1 ± 0.8 min, respectively, at doses of 25, 50, and 75 mg/kg, respectively. It is 13.4 士 3.3, 23·9±5·6, 36.1 7.8 min.

The study of tail vein injection in rats showed that the doses required to start anesthesia were 10.2±2.7, 6.6±1.8, 3.9±0.9 min, respectively, at doses of 100, 150, and 200 mg/kg, respectively. It is 8.2 3.6, 13.1 6.7, 17.5 9.1 min.

2. Pharmacodynamic experiments of dipropionol pyrophosphate diarginine salt:

The tail vein injection study of mice showed that the doses required to start anesthesia were 8.5±2.1, 4.9±1.3, 2.3±0.8 min, respectively, at doses of 25, 50, and 75 mg/kg, respectively. The other lj is 11.5 ± 4.1, 19.2 ± 6.9, 31.1 ± 8.9 min.

The study of tail vein injection in rats showed that the doses required to start anesthesia were 11.5±2.7, 7.5±1.8, 4.7±0.9 min, respectively, at doses of 100, 150, and 200 mg/kg, respectively. It is 7.6 士 3.1, 11·3±6·3, 15.5 8.7 min.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and modifications may be made without departing from the spirit and scope of the invention. Simplifications, which are equivalent replacement means, are included in the scope of the present invention.

Claims

Right to demand

Equation ( ² ).

2. A bis-propofol pyrophosphate salt, which is a pharmaceutically acceptable arbitrary salt of dipropionol pyrophosphate dihydrogenate according to claim 1, which has the structure shown in formula (3):

(3)

Wherein R is a pharmaceutically acceptable cation.

The dipropionol pyrophosphate salt according to claim 2, wherein: R is an alkali metal ion, an ammonium ion or a protonated amino acid.

A method for preparing a dipropionol pyrophosphate dihydrogen ester according to claim 1, which comprises the steps of:

The propofol of the formula (1) is stirred and reacted with a phosphorylating reagent in an anhydrous organic solvent at a temperature of 25 to 110 ° C for 2 to 8 hours, concentrated, and purified to obtain a double structure of the formula (2). Propofol dihydrogen pyrophosphate, as a white solid:

Formula 1)

The preparation method according to claim 4, wherein: the phosphorylating agent is phosphorus pentoxide; and the anhydrous organic solvent is benzene, toluene, petroleum ether, chlorobenzene or dichloromethane. , chloroform, 1,2-dichloroacetic acid or carbon tetrachloride; the molar ratio of propofol to phosphorus pentoxide is 1:1 to 1:16; the propofol and The anhydrous organic solvent has a weight ratio of 1:3 to 1:20.

The preparation method according to claim 5, wherein: the propofol is stirred and reacted with phosphorus pentoxide in an anhydrous organic solvent at a temperature of 80 ° C for 4 hours; The water organic solvent is toluene; the molar ratio of propofol to phosphorus pentoxide is 1:1~1:4.

The method for producing a dipropionol pyrophosphate salt according to claim 2 or 3, which comprises the steps of:

The dipropionol pyrophosphate dihydrogen ester of the formula (2) is reacted in an organic solvent at 0 to 80 ° C for 1 to 5 hours with an alkali, the base being an inorganic base, an organic base or Basic amino acid; if the reaction is completed, if it is precipitated as a white solid, it can be directly filtered to obtain a double propofol pyrophosphate salt of the formula (3); or, if the reaction solution is a clear solution, it is dried to obtain a white solid. A form of dipropionol pyrophosphate salt.

The method according to claim 7, further comprising the step of: recrystallizing the obtained white solid dipropionol pyrophosphate salt to obtain a white crystal of dipropionol pyrophosphate salt.

9. The preparation method according to claim 8, wherein: the molar ratio of the dipropionol dihydrogen pyrophosphate to the base is 1:1 to 1:6; The weight ratio of the dihydroxyl pyrophosphate to the organic solvent is from 1:5 to 1:40.

The preparation method according to claim 9, wherein: the dipropionol dihydrogen phosphate is reacted with an alkali in an organic solvent at a temperature of 25 ° C for 2.5 hours; The molar ratio of dipropionol dihydrogen pyrophosphate to the base is 1:2.

The preparation method according to any one of claims 8 to 10, wherein the organic solvent is methanol or ethanol; and the inorganic base is NaOH, Na ₂ C0 ₃ , NaHC0 ₃ , KOH or K ₂ C0 ₃ ; The organic base is ammonia, methylamine, ethylamine, diethylamine, triethylamine or nicotinamide; the basic amino acid is L-arginine, L-histidine or L-lysine; The organic solvent used for the recrystallization is methanol, ethanol or acetone.

12. A pharmaceutical composition having anesthetic sedative and hypnotic effects, comprising: a therapeutically effective amount of the dipropionol dihydrogen phosphate of claim 1 or an effective amount of claim 2 or 3 The dipropionol pyrophosphate salt is the active ingredient and contains one or more pharmaceutically acceptable carriers.

The use of the dipropionol pyrophosphate dihydrogenate according to claim 1, or the propofol pyrophosphate according to claim 2 or 3, for the preparation of sedative hypnosis and anesthetics.