CN117603261A - Biphosphate derivative and preparation method and application thereof - Google Patents

Biphosphate derivative and preparation method and application thereof Download PDF

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CN117603261A
CN117603261A CN202311581173.2A CN202311581173A CN117603261A CN 117603261 A CN117603261 A CN 117603261A CN 202311581173 A CN202311581173 A CN 202311581173A CN 117603261 A CN117603261 A CN 117603261A
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fatty acid
biphosphate
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胡贝贝
李中秋
景永帅
孙世国
姚军
张永康
秦子尧
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Hebei University of Science and Technology
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Abstract

The invention relates to the technical field of compound preparation, and particularly discloses a biphosphate derivative, and a preparation method and application thereof. The structure of the phosphate derivative is shown as a formula (I). The invention designs and synthesizes a novel biphosphate derivative, which not only can retain the stronger bone targeting of BPs, but also does not affect other special functions of drug carriers, is a general bone targeting molecule suitable for being used as most of anti-bone tumor drug carriers, utilizes the bone affinity of the compound to construct a nano carrier with bone targeting drug release property, can realize the positioning release of anti-tumor drugs and reduce the anti-tumor drugsThe side effect caused by systemic release enhances the treatment effect, reduces the dosage of the medicine, and has higher potential application value in the field of preparation of the anti-bone tumor medicine.

Description

Biphosphate derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of compound preparation, in particular to a biphosphate derivative, and a preparation method and application thereof.
Background
Malignant tumors are one of the most serious diseases recognized by the world to be harmful to human health, about 1810 ten thousand new cases are reported by the world and the number of deaths caused by malignant tumors is up to 960 ten thousand, and the number of deaths is increased every year according to the world health organization report. Among them, the third highest incidence rates are lung cancer (11.6%), breast cancer (11.6%) and prostate cancer (7.1%). With the development of malignant tumors in vivo, the tumors themselves can cause failure of tissue and organs, and most deaths are due to metastasis of the tumors.
Bone is a common part of various tumor metastasis, and 65% -80% of patients with advanced prostate cancer and breast cancer can have cancer bone metastasis, and the bone metastasis rate of liver cancer, lung cancer, kidney cancer and bladder cancer can also reach 30% -40%. In particular, malignant bone tumors are accompanied with various complications such as bone pain, osteolysis, pathological fracture, hypercalcemia and the like, which bring great pain to patients and consume a great deal of medical resources.
Because bone tissue hardness is high, permeability is poor and physiological and biochemical processes are special, medicines are difficult to transport to focus positions by general administration, and effective treatment concentration can be achieved in bone tissues by adding medicine dosage through systemic administration, so that not only is the medicine treatment coefficient reduced and the treatment cost increased, but also serious toxic and side effects are caused to non-bone tissues or organs of patients. Therefore, the design of the novel bone targeting molecule with high selectivity and the development of the targeting administration route and the therapeutic means for resisting bone tumor have great significance for the treatment of bone tumor which is a difficult problem in the current medical world and the improvement of the life quality of patients.
Disclosure of Invention
In order to solve the problems, the invention provides a biphosphate derivative, and a preparation method and application thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a phosphate derivative has a structure shown in a formula (I):
wherein n is 10-18.
The existing biphosphate bone targeting molecule is modified by Biphosphate (BPs) aiming at a certain component in a drug delivery system, if the component of the drug delivery system is changed, the targeting molecule can not be suitable for a new system, and the universality of the targeting molecule is greatly limited. How to balance the relation between the specificity and the universality of the targeting molecule structure is also a key problem for searching bone targeting molecules, and in addition, the molecular mechanism of the targeting molecule after BPs modification and the combination of the rest carrier materials is not clear at present, so that qualitative theoretical guidance can not be provided for the type design of various drug carriers.
In order to solve the problems, the invention designs and synthesizes a novel biphosphate derivative which can not only keep the bone targeting property of BPs stronger, but also not affect other special functions of drug carriers, is a general bone targeting molecule suitable for being used as most of anti-bone tumor drug carriers, utilizes the bone affinity of the compound to construct a nano carrier with bone targeting drug release property, can realize the positioning release of anti-tumor drugs, reduces side effects caused by the systemic release of the anti-tumor drugs, enhances the treatment effect, reduces the dosage of drugs, and has higher potential application value in the preparation field of the anti-bone tumor drugs.
The biphosphate derivative provided by the invention bonds the biphosphate with the fatty acid compound through the amide bond, so that the pharmacological activity and the targeting characteristic of the biphosphate can be reserved to the greatest extent, and the longer tail end carbon chain can endow the compound with stronger hydrophobic characteristic and self-assembly characteristic, so that the compound can self-assemble when reaching a certain concentration to form liposome, vesicle and the like with inward hydrophobic end and outward hydrophilic end, thereby being capable of being used as a carrier of hydrophilic or lipophilic antitumor drugs, being applicable to most antitumor drugs, being capable of meeting the dual requirements of targeting and universality, being a carrier targeting molecule of the antitumor drug with higher potential application value, and having extremely high practical value.
Preferably, the structural formula of the biphosphate derivative is:
the invention relates to a phospholipid-like bone targeting molecule which takes biphosphate as a polar head group and takes a long carbon chain as a hydrophobic tail, and the phospholipid-like bone targeting molecule has an amphiphilic group, so the phospholipid-like bone targeting molecule has stronger self-assembly capability, can self-assemble to form nano carriers such as liposome, vesicle, micelle, nanoparticle and the like at a certain concentration, and can be used as an ideal carrier material for controllable release of anti-tumor active ingredients. In particular, the novel bone targeting molecule provided by the invention has a structure similar to that of phospholipid, so that the novel bone targeting molecule has higher compatibility with liposome materials such as phospholipid, cholesterol and the like, and can form stable bone targeting liposome, so that the antitumor drug has better biocompatibility and targeting property.
The invention also provides a preparation method of the biphosphate derivative, which comprises the following steps:
step a, in an inert solvent, carrying out esterification reaction on a fatty acid compound shown in a formula (II) and N-hydroxysuccinimide to obtain a fatty acid ester compound shown in a formula (III);
and b, carrying out amidation reaction on the fatty acid ester compound shown in the formula (III) and alendronate sodium in a polar solvent under alkaline conditions to obtain the compound shown in the formula (I). The specific reaction route is as follows:
further, the preparation method of the biphosphate derivative specifically comprises the following steps:
step a, adding a fatty acid compound shown in a formula (II), N-hydroxysuccinimide and a catalyst into an inert solvent, reacting for 20-24 hours at the temperature of 2-8 ℃, adding water, filtering, washing and drying to obtain the fatty acid ester compound shown in the formula (III);
step b, dissolving a fatty acid ester compound shown in a formula (III) in a polar solvent to obtain a fatty acid ester compound solution; dissolving alendronate in an alkaline solution to obtain an alendronate solution;
slowly adding the fatty acid ester compound solution into the alendronate solution at 20-30 ℃ for reaction for 20-24 h, extracting, filtering and drying to obtain the compound shown in the formula (I).
The preparation process of the biphosphate derivative provided by the invention is simple, raw materials are easy to obtain, and the biphosphate derivative is suitable for large-scale industrial production and application.
Preferably, in the step a, the inert solvent is at least one of N, N-dimethylformamide, dichloromethane or acetic acid.
Further preferably, in step a, the inert solvent is N, N-dimethylformamide.
The preferable reaction solvent can promote the reaction of the fatty acid compound and N-hydroxysuccinimide to be fully carried out, and the yield of the fatty acid ester is improved.
Preferably, in step a, the catalyst is at least one of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazole) -N, N '-tetramethylurea hexafluorophosphate, N' -dicyclohexylcarbodiimide or N, N-diisopropylethylamine.
Further preferred, in step a, the catalyst is 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine.
The preferred catalyst can improve the reactivity of the fatty acid compound and N-hydroxysuccinimide, improve the reaction efficiency and obviously improve the yield of the fatty acid ester.
Preferably, in step a, the washing agent used in the washing is ethyl acetate.
The crude product of the fatty acid ester prepared in the step a is yellow in appearance, and colored impurities in the crude product of the fatty acid ester can be sufficiently removed by adopting ethyl acetate as a detergent, so that the quality of a fatty acid ester product is improved.
Preferably, in the step a, the molar ratio of the fatty acid compound to the N-hydroxysuccinimide is 1:1.2-1:2.
The preferable ratio of the fatty acid compound to the N-hydroxysuccinimide can improve the conversion rate of the reaction and reduce the reaction cost.
Preferably, in step a, the molar ratio of the fatty acid compound to the catalyst is from 1:5.5 to 1:7.
Further preferably, in step a, the molar ratio of the fatty acid compound to 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate is 1:1.5-1:2, and the molar ratio of the fatty acid compound to N, N-diisopropylethylamine is 1:4-1:5.
The addition amount of the catalyst is preferable, and the reaction cost can be effectively reduced on the premise of ensuring the yield and the reaction efficiency of the fatty acid ester.
Preferably, in step b, the polar solvent is tetrahydrofuran.
Preferably, in the step b, the alkaline solution is sodium hydroxide solution with the mass concentration of 3% -8%.
Preferably, in step b, the alendronate is alendronate sodium.
Preferably, in step b, the molar ratio of the fatty acid active ester compound to alendronate is from 1:0.8 to 1:1.
Preferably, in the step b, the concentration of the fatty acid ester compound solution is 0.5mol/L to 1.0mol/L.
Preferably, in the step b, the volume ratio of the sodium hydroxide solution to the polar solvent is 5:1-5:2.
Experiments prove that the volume ratio of the sodium hydroxide solution to the polar solvent has a great influence on the yield of the target product, and when the ratio of a certain solvent is too large, the collision probability of fatty acid ester and alendronate sodium in the solution can be reduced, so that the reaction cannot be fully carried out. The preferred volume ratio of sodium hydroxide solution to polar solvent can effectively increase the yield of the target product.
Illustratively, in step b, the fatty acid ester compound solution is added dropwise to the alendronate sodium solution.
Further, the dropping speed of the fatty acid ester compound solution is 1mL/min-1.5mL/min.
The invention also provides application of the biphosphate derivative in preparing an anti-bone tumor medicament.
The biphosphate derivative provided by the invention can be self-assembled to form liposome, vesicle and the like, is used as a carrier of an anti-bone tumor drug, can encapsulate the anti-tumor drug, is used as a specific targeting molecule to guide the anti-tumor drug into a specific targeting part, can lead the drug to be carried for targeting and then degrade and release the drug, avoids killing normal cells of an organism, improves the active targeting of the preparation, enhances the curative effect of the drug, reduces the toxic and side effects, further improves the possibility of clinical cure, and has wide application prospect in the field of anti-tumor drugs.
The invention also provides a pharmaceutical composition for resisting bone tumor, which comprises an active ingredient and a biphosphate derivative shown in the formula (I).
Further, the dosage form of the pharmaceutical composition is an injection.
Further, the pharmaceutical composition further comprises at least one pharmaceutically acceptable auxiliary agent.
In preparing the anti-bone tumor medicament, the biphosphate derivative provided by the invention can be mixed with proper pharmacologically acceptable dispersing agents, diluents and the like to prepare injection.
Other common auxiliary materials in the field can be selected to prepare other pharmaceutical dosage forms, such as suspending agents, aerosols, oral liquids, syrups and the like according to the conventional preparation method in the field. The administration may be by injection, oral administration, or the like.
The invention also provides a liposome which comprises the biphosphate derivative, lecithin, cholesterol, phosphate buffer solution and other pharmaceutically acceptable auxiliary materials.
Further, the liposome also comprises an anti-bone tumor active ingredient.
Further, the mass ratio of the biphosphate derivative to the lecithin is 1:8-12.
The liposome comprises the following raw material components in parts by weight: paclitaxel 0.006 parts, lecithin 0.03 parts, cholesterol 0.01 parts, biphosphate derivatives 0.003 parts and phosphate buffer 50 parts.
Illustratively, the phosphate buffer has a ph=7.4.
Further, the preparation method of the liposome comprises the following steps:
adding the biphosphate derivative into phosphate buffer with pH=7.4, stirring and dissolving to obtain a water phase;
weighing docetaxel, soybean soft phosphorus and cholesterol according to a proportion, and adding into absolute ethyl alcohol for dissolution to obtain an oil phase;
slowly injecting the oil phase into the water phase, continuously stirring at 55deg.C, standing, cooling to room temperature, and filtering to obtain liposome.
Drawings
FIG. 1 shows ALE- (CH) prepared in example 1 2 ) 10 -CH 3 Is a infrared spectrogram of (2);
FIG. 2 shows ALE- (CH) prepared in example 2 2 ) 12 -CH 3 Is of (2)
FIG. 3 shows ALE- (CH) prepared in example 1 2 ) 14 -CH 3 Is of (2)
FIG. 4 shows ALE- (CH) prepared in example 1 2 ) 16 -CH 3 Is a infrared spectrogram of (2);
FIG. 5 is an embodiment1-appearance of the solution after self-assembly of the bisphosphate derivative prepared in example 4; wherein A: ALE- (CH) 2 ) 10 -CH 3 ，B：ALE-(CH 2 ) 12 -CH 3 ，C：ALE-(CH 2 ) 14 -CH 3 ，D：ALE-(CH 2 ) 16 -CH 3 )；
FIG. 6 is a graph showing the particle size distribution of the biphosphate derivatives prepared in examples 1 to 4 after self-assembly;
fig. 7 is an electron transmission microscope image after self-assembly of the biphosphate derivatives prepared in examples 1 to 4, wherein (a): ALE- (CH) 2 ) 10 -CH 3 ，(b)：ALE-(CH 2 ) 12 -CH 3 ，(c)：ALE-(CH 2 ) 14 -CH 3 ，(d)：ALE-(CH 2 ) 16 -CH 3 )；
Fig. 8 is a solution appearance of adding different volumes of calcium chloride solution to the solution prepared in example 1 after self-assembly of the biphosphate derivative, wherein (a): 1mL, (b): 2mL, (c): 3mL, (d): 0mL;
FIG. 9 is a 20-fold microscopic morphology of the floc of the biphosphate derivative of example 1 combined with calcium ions;
fig. 10 is a solution appearance diagram of a biphosphate derivative modified docetaxel liposome solution, wherein (a): DOC@ALE- (CH) 2 ) 10 -CH 3 -Lips，(b)：DOC@ALE-(CH 2 ) 12 -CH 3 -Lips，(c)：DOC@ALE-(CH 2 ) 14 -CH 3 -Lips，(d)：DOC@ALE-(CH 2 ) 16 -CH 3 -Lips；
FIG. 11 is a graph of DOC@ALE- (CH) 2 ) 10 -CH 3 -electron transmission microscopy of the Lips liposome solution;
FIG. 12 is a docetaxel solution (DOC), docetaxel liposome solution (DOC-Lips), DOC@ALE- (CH) 2 ) 10 -CH 3 -in vitro release profile of lip liposome solution.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
This example provides a bisphosphonate derivative ALE- (CH) 2 ) 10 -CH 3 Is prepared by the following steps:
step one, synthesis of laurate
Lauric acid (5.00 g,24.96 mmol), N-hydroxysuccinimide (3.45 g,29.98 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (14.24 g,37.45 mmol) were added into a three-necked flask containing 50mL of N, N-dimethylformamide, and mixed uniformly, N, N-Diisopropylethylamine (DIEA) (12.90 g,99.81 mmol) was added dropwise under ice bath conditions at 2-8deg.C, after the dropwise addition was completed, TLC was monitored for reaction, and after 24 hours, crude laurate was precipitated, and washed 3-5 times with ethyl acetate to obtain white laurate, yield 75.4%;
step two, ALE- (CH) 2 ) 10 -CH 3 Is synthesized by (a)
Laurate (2.00 g,6.72 mmol) was added to 8mL tetrahydrofuran and sonicated at 25℃for 3min to give laurate solution;
sodium alendronate (1.75 g,5.38 mmol) was added to 20mL of a 5% strength by mass sodium hydroxide solution to give a sodium alendronate solution;
dropwise adding laurate solution into alendronate sodium solution at room temperature at a dropwise adding speed of 1mL/min, detecting reaction by TLC after dropwise adding, finishing reaction for 20h, removing tetrahydrofuran by rotary evaporation, adding dichloromethane to remove unreacted laurate, filtering, and oven drying to obtain white solid, namely ALE- (CH) 2 ) 10 -CH 3 The yield thereof was found to be 49.6%.
1 H-NMR(DMSO，400MHz)：0.88-0.90(d，3H，CH 3 )，1.27-1.33(m，16H，CH 2 CH 2 )，1.55-1.79(m，4H，CH 2 )，2.13-2.35(m，4H，CH 2 )，3.16-3.19(m，2H，CH 2 )，6.41-6.43(m，1H，NH)。
ALE- (CH) prepared in this example 2 ) 10 -CH 3 The infrared spectrum of (2) is shown in FIG. 1.
The specific reaction equation is as follows:
example 2
This example provides a bisphosphonate derivative ALE- (CH) 2 ) 12 -CH 3 Is prepared by the following steps:
step one, synthesis of laurate
Myristic acid (5.00 g,21.89 mmol), N-hydroxysuccinimide (3.02 g,26.24 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (12.49 g,32.85 mmol) were added to a three-necked flask containing 50mL of N, N-dimethylformamide, and mixed well, N, N-Diisopropylethylamine (DIEA) (11.32 g,87.58 mmol) was added dropwise under ice bath conditions at 2-8deg.C, after the dropwise addition was completed, TLC was monitored for reaction, and after 24h, crude myristate was precipitated, and washed 3-5 times with ethyl acetate to give white myristate in 65.6% yield;
step two, ALE- (CH) 2 ) 12 -CH 3 Is synthesized by (a)
Myristate (2.00 g,6.16 mmol) was added to 8mL tetrahydrofuran and sonicated at 25℃for 3min to give myristate solution;
sodium alendronate (1.60 g,4.92 mmol) was added to 20mL of a 5% strength by mass sodium hydroxide solution to give a sodium alendronate solution;
dropping myristate solution into alendronate sodium solution at room temperature at a dropping speed of 1.5mL/min, detecting reaction by TLC after dropping, removing tetrahydrofuran by rotary evaporation after 20h reaction, adding dichloromethane to remove unreacted myristate, filtering, and oven drying to obtain white solid, namely ALE- (CH) 2 ) 12 -CH 3 The yield thereof was found to be 41.4%.
1 H-NMR(DMSO，400MHz)：0.88-0.90(d，3H，CH 3 )，1.27-1.33(m，20H，CH 2 CH 2 )，1.55-1.79(m，4H，CH 2 )，2.13-2.35(m，4H，CH 2 )，3.16-3.19(m，2H，CH 2 )，6.41-6.43(m，1H，NH)。
ALE- (CH) prepared in this example 2 ) 12 -CH 3 The infrared spectrum of (2) is shown in figure 2.
The specific reaction equation is as follows:
example 3
This example provides a bisphosphonate derivative ALE- (CH) 2 ) 14 -CH 3 Is prepared by the following steps:
step one, synthesis of palmitate
Palmitic acid (5.00 g,19.50 mmol), N-hydroxysuccinimide (2.69 g,23.37 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (11.12 g,29.25 mmol) were added into a three-necked flask containing 50mL of N, N-dimethylformamide, mixed well, and N, N-Diisopropylethylamine (DIEA) (10.08 g,77.99 mmol) was added dropwise under ice bath conditions at 2-8deg.C, after the dropwise addition was completed, TLC was monitored for reaction, and after 24 hours, crude palmitate was precipitated by adding, suction filtration and washing 3-5 times with ethyl acetate to obtain white palmitate in 55.8% yield;
step two, ALE- (CH) 2 ) 14 -CH 3 Is synthesized by (a)
Palmitate (2.00 g,5.67 mmol) was added to 8mL tetrahydrofuran and sonicated at 25℃for 3min to give a palmitate solution;
sodium alendronate (1.47 g,4.52 mmol) was added to 20mL of a 5% strength by mass sodium hydroxide solution to give a sodium alendronate solution;
dropwise adding the palmitate solution into the alendronate sodium solution at room temperature at the dropwise adding speed of 1mL/min, detecting the reaction by TLC after the dropwise adding is finished, finishing the reaction for 20 hours, removing tetrahydrofuran by rotary evaporation, and adding dichloromethaneRemoving unreacted palmitate, vacuum filtering, and oven drying to obtain white solid, namely ALE- (CH) 2 ) 14 -CH 3 The yield thereof was found to be 39.8%.
1 H-NMR(DMSO，400MHz)：0.88-0.90(d，3H，CH 3 )，1.27-1.33(m，24H，CH 2 CH 2 )，1.55-1.79(m，4H，CH 2 )，2.13-2.35(m，4H，CH 2 )，3.16-3.19(m，2H，CH 2 )，6.41-6.43(m，1H，NH)。
ALE- (CH) prepared in this example 2 ) 14 -CH 3 The infrared spectrum of (2) is shown in FIG. 3.
The specific reaction equation is as follows:
example 4
This example provides a bisphosphonate derivative ALE- (CH) 2 ) 16 -CH 3 Is prepared by the following steps:
step one, synthesis of stearate
Stearic acid (5.00 g,17.58 mmol), N-hydroxysuccinimide (2.43 g,21.11 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (10.02 g,26.35 mmol) were added to a three-necked flask containing 50mL of N, N-dimethylformamide, mixed well, N, N-Diisopropylethylamine (DIEA) (9.07 g,70.17 mmol) was added dropwise under ice bath conditions at 2-8deg.C, after the dropwise addition was completed, TLC was monitored for reaction, after 24h reaction was completed, crude stearate was added, and washing with ethyl acetate was performed 3-5 times to obtain white stearate in 54.4% yield;
step two, ALE- (CH) 2 ) 16 -CH 3 Is synthesized by (a)
Stearate (2.00 g,5.25 mmol) was added to 8mL tetrahydrofuran and sonicated at 25℃for 3min to give a stearate solution;
sodium alendronate (1.36 g,4.18 mmol) was added to 20mL of a 5% strength by mass sodium hydroxide solution to give a sodium alendronate solution;
dropwise adding the stearate solution into the alendronate sodium solution at room temperature at the dropwise adding speed of 1.5mL/min, detecting the reaction by TLC after the dropwise adding is finished, removing tetrahydrofuran by rotary evaporation, adding dichloromethane to remove unreacted stearate, filtering, and drying to obtain white solid, namely ALE- (CH) 2 ) 16 -CH 3 The yield thereof was found to be 27.6%.
1 H-NMR(DMSO，400MHz)：0.88-0.90(d，3H，CH 3 )，1.27-1.33(m，28H，CH 2 CH 2 )，1.55-1.79(m，4H，CH 2 )，2.13-2.35(m，4H，CH 2 )，3.16-3.19(m，2H，CH 2 )，6.41-6.43(m，1H，NH)。
ALE- (CH) prepared in this example 2 ) 16 -CH 3 The infrared spectrum of (2) is shown in FIG. 4.
The specific reaction equation is as follows:
example 5-example 7
The procedure of the preparation method of stearate provided in this example is the same as that of example 4, except that the ratio of stearic acid to N-hydroxysuccinimide is different, and the other conditions are exactly the same, and specific reaction conditions are shown in Table 1.
TABLE 1 yield and purity of stearate
As a result, it was found that when the molar ratio of stearic acid to N-hydroxysuccinimide was 1:1.2 or greater than 1:1.2, the yield of stearate was kept at about 55%, and the molar ratio of stearic acid to N-hydroxysuccinimide was 1:1.2 in view of cost.
Example 8-example 10
The procedure of the preparation method of stearate provided in this example is the same as that of example 4, except that the addition amount of 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) is different, and the other conditions are exactly the same as those of example 4, and specific reaction conditions are shown in Table 2.
TABLE 2 yield and purity of stearate
Numbering device Stearic acid: HATU Yield (%) Purity (%)
Example 4 1:1.5 54.4 65.3
Example 8 1:0 9.1 7.8
Example 9 1:1.0 41.7 26.2
Example 10 1:2.0 57.3 33.9
As a result, it was found that HATU had a great influence on the yield of stearate, and that the addition of HATU significantly improved the yield of stearate, but in view of cost, the molar ratio of stearic acid to HATU was selected to be 1:1.5.
Example 11-example 13
The procedure of the preparation method of stearate provided in this example is the same as that of example 4, except that the addition amount of N, N-Diisopropylethylamine (DIEA) is different, and the other conditions are exactly the same as those of example 4, and the specific reaction conditions are shown in Table 3.
TABLE 3 yield and purity of stearate
As a result, it was found that the yield of stearate was significantly improved when the amount of DIEA added was 4 times that of stearic acid, but the yield was lowered when the amount of DIEA was 5 times that of stearic acid, and the molar ratio of stearic acid to DIEA was 1:4 was comprehensively considered.
Example 14-example 15
The procedure of the preparation method of stearate provided in this example is the same as that of example 4, except that the solvent for washing the crude stearate is different, and the other conditions are exactly the same as those of example 4, and the specific reaction conditions are shown in table 4.
TABLE 4 yield and purity of stearate
Numbering device Post-treatment solvent Yield (%) Purity (%)
Example 4 Acetic acid ethyl ester 54.4 65.3
Example 14 Dichloromethane (dichloromethane) 27.7 60.5
Example 15 Petroleum ether 35.2 40.3
The crude stearate is yellow, colored impurities are required to be removed by washing with an organic solvent, and finally ethyl acetate is selected as a detergent through experimental comparison.
Example 16-example 18
ALE- (CH) provided in this embodiment 2 ) 16 -CH 3 The procedure of example 4 was followed except that the volume ratio of tetrahydrofuran to sodium hydroxide solution was changed, and the other conditions were exactly the same as in example 4, and the specific reaction conditions are shown in Table 5.
TABLE 5 ALE- (CH) 2 ) 16 -CH 3 Yield and purity of (C)
As a result, it was found that the amount of tetrahydrofuran and sodium hydroxide solution greatly affected the amount of the objective product, and that when the addition ratio of one solvent was too large, the collision probability of stearate and alendronate sodium in the reaction system was reduced, and the reaction could not be performed well. When the volume ratio of tetrahydrofuran to sodium hydroxide solution is 5:2, the yield of the target product reaches the maximum.
Self-assembly property test
1. Preparation of self-assembled vesicles
100mg of ALE- (CH) prepared in example 1-example 4 was taken 2 ) 10 -CH 3 、ALE-(CH 2 ) 12 -CH 3 、ALE-(CH 2 ) 14 -CH 3 And ALE- (CH) 2 ) 16 -CH 3 Respectively, in 100mL of water to obtain 1g/L of sample solution. After each sample solution was vortexed for 10min, it was found that all four solutions self-assembled into vesicles with obvious blue light phenomenon, and the results are shown in fig. 5.
From the figure, the solution of the four biphosphate derivatives after self-assembly is light blue, no obvious precipitation is visible, and the state is good.
2. Self-assembled particle size testing
The particle size (n=3) of the self-assembled solution was measured by a malvern particle sizer, and the particle size distribution diagram is shown in fig. 6.
As can be seen from the figure, ALE- (CH) prepared in example 1 2 ) 10 -CH 3 The average grain diameter after self-assembly is 147.2nm, and the PDI value is 0.180; ALE- (CH) prepared in example 2 2 ) 12 -CH 3 The average particle diameter after self-assembly is 152.1nm, and the PDI value is 0.152; ALE- (CH) prepared in example 3 2 ) 14 -CH 3 The average grain diameter after self-assembly is 133.2nm, and the PDI value is 0.178; ALE- (CH) prepared in example 4 2 ) 16 -CH 3 The average particle diameter after self-assembly is 143.5nm, the PDI value is 0.196, and the particle diameter is uniform.
3. Form of electron microscope
Diluting the self-assembled solution to 0.1mg/mL, dripping the diluted self-assembled solution to a copper mesh, dyeing for 3min with 1% phosphomolybdic acid dye solution, irradiating with infrared, drying the water, and observing by a transmission electron microscope, wherein the result is shown in figure 7.
As can be seen from the figure, the four biphosphate derivatives prepared in examples 1 to 4 are in a sphere shape after self-assembly, and have a good morphology.
4. Binding test with calcium ion after self-assembly
100mg of ALE- (CH) prepared in example 1 were taken 2 ) 10 -CH 3 The compound was added to 100mL of water to give a self-assembled solution. 100mg of calcium chloride was dissolved in 10mL of water to obtain a calcium chloride solution.
10mL of ALE- (CH) 2 ) 10 -CH 3 The self-assembled solution of the compound is placed in a clean and transparent penicillin bottle, and the prepared calcium chloride solution is dripped into the penicillin bottle according to the amount of 1mL each time, and the solution state is observed. ALE- (CH) 2 ) 10 -CH 3 The floc of the compound after the self-assembled solution and calcium ions are combined is placed under a microscope to observe the morphology.
When the calcium chloride solution is added into the penicillin bottle according to the amount of 1mL each time, the self-assembled solution is obviously changed when the 1mL of the calcium chloride solution is added, a small layer of colorless, clear and transparent phenomenon appears on the lower layer, when the 2mL of the calcium chloride solution is added in an accumulated manner, half of the whole self-assembled solution appears clear and transparent phenomenon, when the 3mL of the calcium chloride solution is added in an accumulated manner, only a small part of the upper layer of the whole self-assembled solution is still in a suspension state, the other parts are all changed into a clear and transparent state, and when the calcium chloride is continuously added to 4mL or more in a dropwise manner, the solution is not obviously changed any more, as shown in figure 8, the ALE- (CH) is proved 2 ) 10 -CH 3 The compound is completely combined with calcium ions.
FIG. 9 shows ALE- (CH) under a microscope 2 ) 10 -CH 3 The form of floc after the compound was combined with calcium ions was seen to form crystals.
In vitro targeting assay
The most viable approach to bone targeted therapy is to develop bone targeted carriers by affinity to hydroxyapatite. The bone matrix has the highest inorganic salt content in human body, accounting for 65% -70% of bone, and its main component is Hydroxyapatite (HAP). It is estimated that the calcium content in bone may account for 99% of the total calcium in the human body. Thus, based on this property of bone, molecules capable of specifically binding to hydroxyapatite can be used for bone targeting vectors, thereby selectively delivering drugs to bone tissue.
The adsorption test was performed using HAP, a major component of bone mineral salts, as an adsorbent. An amount of HAP was added to a sample solution of a certain concentration, adsorption test was performed under the same conditions, and its adsorption rate was measured by measuring its absorbance value to verify bone targeting.
10mg of lauric acid was precisely weighed and dissolved in 10mL of methanol, and the absorbance value of the solution was measured. 10mg of ALE- (CH) prepared in examples 1-4 was precisely weighed 2 ) 10 -CH 3 、ALE-(CH 2 ) 12 -CH 3 、ALE-(CH 2 ) 14 -CH 3 And ALE- (CH) 2 ) 16 -CH 3 The solutions were dissolved in 100mL of water, and absorbance values of the solutions were measured.
20mL of the lauric acid solution prepared above and four aqueous solutions of the bisphosphate derivatives were taken respectively, 100mg of HAP was added to each solution, stirring was performed, sampling was performed at 60min, the samples were centrifuged at 5000rpm for 10min in a centrifuge, the supernatants were taken to measure absorbance values respectively, and the adsorption rate was calculated. The results are shown in Table 6.
Adsorption rate= (a Before measurement -A After measurement )/A Before measurement ×100％
Wherein A is Before measurement For absorbance values without HAP solution, A After measurement Absorbance values for 60min for HAP addition.
TABLE 6 adsorption rate
Preparation and characterization of biphosphate derivative modified docetaxel liposome
1. Preparation of docetaxel liposome
50mL of phosphate buffer pH=7.4 was measured and placed in a 100mL beaker and placed in a 55℃water bath for preheating. Weighing paclitaxel 0.006g, soybean lecithin 0.03g and cholesterol 0.01g, placing into a small beaker, adding 2mL absolute ethanol, and dissolving by ultrasonic for 5min to obtain paclitaxel solution. Sucking paclitaxel solution by syringe, slowly injecting into preheated phosphate buffer solution at constant speed, stirring at 200r/min, continuously stirring for 2 hr to remove ethanol, and cooling to room temperature to obtain docetaxel liposome solution (DOC-LIPs).
2. Preparation of biphosphate derivative modified docetaxel liposome
3mg of ALE- (CH) prepared in example 1 to example 4 2 ) 10 -CH 3 、ALE-(CH 2 ) 12 -CH 3 、ALE-(CH 2 ) 14 -CH 3 And ALE- (CH) 2 ) 16 -CH 3 Respectively adding the mixture into 50mL of phosphate buffer solution with pH=7.4 preheated to 55 ℃ to obtain an aqueous phase.
Docetaxel 0.006g, soybean lecithin 0.03g and cholesterol 0.01g are weighed into a small beaker, and 2mL of absolute ethyl alcohol is added for ultrasonic dissolution for 5min, so that the docetaxel solution is obtained.
Sucking taxol solution with injector, slowly injecting into aqueous solution at constant speed, stirring at 200r/min, stirring at 55deg.C for 2 hr to remove ethanol, standing for 1 hr, cooling to room temperature, filtering the reaction solution with 0.22 μm, centrifuging to obtain bisphosphate derivative modified docetaxel liposome solution, respectively designated DOC@ALE- (CH) 2 ) 10 -CH 3 -Lips，DOC@ALE-(CH 2 ) 12 -CH 3 -Lips，DOC@ALE-(CH 2 ) 14 -CH 3 -Lips and DOC@ALE- (CH) 2 ) 16 -CH 3 -Lips。
3. Appearance form
The appearance of the prepared biphosphate derivative modified docetaxel liposome solution is shown in figure 10, and the biphosphate derivative modified docetaxel liposome solution is light blue in color of the liposome, no precipitation is visible, and the liposome state is good.
4. Particle size test
The prepared biphosphate derivative modified docetaxel liposome is subjected to high-pressure homogenization, and then the particle size of the docetaxel liposome is tested by a Markov particle size analyzer, and the high-pressure homogenization condition is 1000bar pressure, and the high-pressure homogenization is carried out twice.
As a result, DOC@ALE- (CH) 2 ) 10 -CH 3 The particle size of the Lips was 92.8nm, the PDI value was 0.204 and the particle size was uniform. Measured under the same conditions, DOC@ALE- (CH) 2 ) 12 -CH 3 The particle size of the-Lips is 102.9nm, DOC@ALE- (CH) 2 ) 14 -CH 3 The particle size of the-Lips is 93.9nm, DOC@ALE- (CH) 2 ) 16 -CH 3 The particle size of the Lips is 90.5nm.
5. Form of electron microscope
DOC@ALE-(CH 2 ) 10 -CH 3 Electron transmission microscopy of Lips is shown in FIG. 11, from which it can be seen that DOC@ALE- (CH) 2 ) 10 -CH 3 The morphology of Lips is spherical, with a better morphology.
Other DOC@ALE- (CH) 2 ) 12 -CH 3 -Lips，DOC@ALE-(CH 2 ) 14 -CH 3 -Lips and DOC@ALE- (CH) 2 ) 16 -CH 3 The morphology of Lips is also spherical, with a better morphology.
6. In vitro release
A commercially available 20. Mu.g/mL docetaxel solution (Shanghai Ala-dine) was used as a control, and a phosphate buffer pH7.4 containing 0.5% tween-80 was used as a release medium. Precision measuring docetaxel solution (DOC), docetaxel liposome solution (DOC-Lips), DOC@ALE- (CH) 2 ) 10 -CH 3 Placing 10mL of Lips liposome solution in dialysis bags (molecular weight cut-off 8000-14000 Da), placing the cut-off solution in 80mL of release medium, oscillating in constant temperature water bath at a speed of 100r/min, setting the temperature to 37 ℃, sampling with 0.22 μm filter membrane at time points of 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h and 48h respectively, subjecting the filtrate to HPLC sample injection analysis, determining peak area,the cumulative release rate is calculated. The results are shown in FIG. 12.
As can be seen from fig. 12, the release of docetaxel solution (DOC) tended to be smooth within 24 hours, and the cumulative release rate reached 100% within 48 hours; while docetaxel liposome solution (DOC-Lips) and DOC@ALE- (CH) 2 ) 10 -CH 3 The Lips Liposome solution group was then released for the first 12 hours and then released until the 48 hour cumulative release rate at the end of the test was 97.38% and 96.24%, respectively. Due to DOC-Lips and DOC@ALE- (CH) 2 ) 10 -CH 3 The lip solution group is a liposome formulation, releasing more slowly relative to the DOC solution group. The DOC@ALE- (CH 2) 16-CH3-Lips solution set allows for DOC@ALE- (CH) due to the presence of bone target molecules 2 ) 16 -CH 3 The lip solution group released slightly slower than the DOC-Lips solution group, but almost all over 48h release. Thus, comparing DOC-Lips solutions to DOC@ALE- (CH) 2 ) 10 -CH 3 The release of both groups of Lips solutions can prove that the sodium alendronate coupled fatty acid prepared in the examples of the invention has little effect on the release of docetaxel.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims (10)

1. A biphosphate derivative, which is characterized in that the structure is shown as a formula (I):
wherein n is 10-18.
2. The method for producing a bisphosphate derivative according to claim 1, comprising the steps of:
step a, in an inert solvent, carrying out esterification reaction on a fatty acid compound shown in a formula (II) and N-hydroxysuccinimide to obtain a fatty acid ester compound shown in a formula (III);
and b, carrying out amidation reaction on the fatty acid ester compound shown in the formula (III) and alendronate sodium in a polar solvent under alkaline conditions to obtain the compound shown in the formula (I).
3. The method for producing a bisphosphate derivative according to claim 2, wherein the method comprises the steps of:
step a, adding a fatty acid compound shown in a formula (II), N-hydroxysuccinimide and a catalyst into an inert solvent, reacting for 20-24 hours at the temperature of 2-8 ℃, adding water, filtering, washing and drying to obtain the fatty acid ester compound shown in the formula (III);
step b, dissolving a fatty acid ester compound shown in a formula (III) in a polar solvent to obtain a fatty acid ester compound solution; dissolving alendronate in an alkaline solution to obtain an alendronate solution;
slowly adding the fatty acid ester compound solution into the alendronate solution at 20-30 ℃ for reaction for 20-24 h, extracting, filtering and drying to obtain the compound shown in the formula (I).
4. A process for the preparation of a biphosphate derivative according to claim 3, wherein in step a, the inert solvent is at least one of N, N-dimethylformamide, dichloromethane or acetic acid; and/or
In the step a, the catalyst is at least one of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate, N, N ' -dicyclohexylcarbodiimide or N, N-diisopropylethylamine; and/or
In the step a, the washing agent adopted in the washing is ethyl acetate.
5. The method of preparing a bisphosphonate derivative according to claim 3 or 4, wherein in step a, the molar ratio of the fatty acid compound to N-hydroxysuccinimide is 1:1.2-1:2; and/or
In the step a, the molar ratio of the fatty acid compound to the catalyst is 1:5.5-1:7.
6. A process for the preparation of a biphosphate derivative according to claim 3, wherein in step b, the polar solvent tetrahydrofuran; and/or
In the step b, the alkaline solution is sodium hydroxide solution with the mass concentration of 3% -8%; and/or
In the step b, the alendronate is alendronate sodium.
7. A process for the preparation of a bisphosphonate derivative according to claim 3, characterized in that in step b the molar ratio of fatty acid active ester compound to alendronate is from 1:0.8 to 1:1; and/or
In the step b, the concentration of the fatty acid ester compound solution is 0.5mol/L to 1.0mol/L; and/or
In the step b, the volume ratio of the sodium hydroxide solution to the polar solvent is 5:1-5:2.
8. Use of the biphosphate derivative according to claim 1 in the preparation of an anti-bone tumor medicament.
9. A pharmaceutical composition for treating bone tumors comprising an active ingredient and the biphosphate derivative according to claim 1.
10. A liposome comprising the biphosphate derivative of claim 1, lecithin, cholesterol, phosphate buffer and other pharmaceutically acceptable excipients.
CN202311581173.2A 2023-11-24 2023-11-24 Biphosphate derivative and preparation method and application thereof Pending CN117603261A (en)

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