CN105777601A - Alprostadil derivative and pharmaceutical preparation thereof - Google Patents

Alprostadil derivative and pharmaceutical preparation thereof Download PDF

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Publication number
CN105777601A
CN105777601A CN201410853661.9A CN201410853661A CN105777601A CN 105777601 A CN105777601 A CN 105777601A CN 201410853661 A CN201410853661 A CN 201410853661A CN 105777601 A CN105777601 A CN 105777601A
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alprostadil
injection
derivative
pharmaceutical preparation
derivant
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陈建明
余侬
张元声
吴婵
高保安
姚建忠
刘文丽
陈丽娜
邓莉
马娟娟
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Second Military Medical University SMMU
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Second Military Medical University SMMU
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Abstract

本发明涉及医药技术领域，本发明涉及一种前列地尔的衍生物及其药物制剂，本发明的化合物具有式(I)所示的结构。式中R1为氢原子、甲基，式中R2为氢原子、甲基、乙基、正丙基、异丙基、环己基、叔丁基、正丁基。本发明还提供了该化合物的药物制剂，该药物制剂具有包封率高、性质稳定、用于临床治疗安全性高等特点。 The present invention relates to the technical field of medicine. The present invention relates to a derivative of alprostadil and a pharmaceutical preparation thereof. The compound of the present invention has a structure shown in formula (I). In the formula, R1 is a hydrogen atom, a methyl group, and in the formula , R2 is a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, cyclohexyl group, tert-butyl group, n-butyl group. The invention also provides the pharmaceutical preparation of the compound, which has the characteristics of high encapsulation rate, stable property, high safety for clinical treatment and the like.

Description

A kind of Alprostadil derivant and pharmaceutical preparation thereof
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of Alprostadil derivant and synthetic method thereof, and the pharmaceutical preparation of this Alprostadil derivant and preparation method thereof.
Background technology
Alprostadil, also known as PGE1 (PGE1), its chemical name is: (1R, 2R, 3R)-3-hydroxyl 2-[(E)-(3S)-3-hydroxyl-1-octenyl]-5-oxo-cyclopentane enanthic acid, has the effect suppressing platelet aggregation, thromboxane A2 generation, atherosclerosis, Lipid Plaque formation and immune complex.Expanding peripheral blood vessel and coronary vasodilator, reduce Peripheral resistance and blood pressure, have protection ischemic myocardial, reducing myocardial infarction area etc. acts on.Also have and arrange sodium, diuresis and liver, kidney, lung, gastropathy are all had treatment, protective effect; application (Wang Xuegong is all had clinically in cardiovascular disease, respiratory system disease, cerebrovascular disease, diabetic complication, pulmonary hypertension, nephropathy, male sterility disease, liver, kidney syndrome (HRS) etc. are many; Xiao Minghui; Tang Xiaobo etc. the dosage form of Alprostadil and New research progress [J]. Heilungkiang medicine; 2008,21 (6): 37-40.).
Owing to the pharmacological action of Alprostadil is extensive, some pharmaceutical factories, home and abroad and scientific research institution carry out the research of the synthesis about Alprostadil and preparation one after another.But Alprostadil poor chemical stability, in gastrointestinal tract, easily it is metabolized inactivation, unsuitable oral administration, generally adopt the mode of intravenous drip to be administered.Listing mainly has Alprostadil freeze-dried powder pin, Alprostadil liposome microsphere injection, Alprostadil freeze-dried breast etc. at present.
After the lyophilized injectable powder administration of Alprostadil, the Alprostadil of 60%-90% inactivates at pulmonary metabolism, and the half-life only has a few minutes.In order to maintain effective blood drug level, administration administration must be maintained by heavy dose of long-time (more than 5h) continuous intravenous infusion, thus bring a series of such as side effect (Wang Xuegong such as phlebitis, dizziness, Nausea and vomiting, Xiao Minghui, Tang Xiaobo etc. the dosage form of Alprostadil and New research progress [J]. Heilungkiang medicine, 2008,21 (6): 37-40.).
In order to solve Alprostadil freeze-dried powder Problems existing, often by row ground, you prepare into lipid microsphere injection (trade name " time triumphant ") at present, there is the affinity of height at vascular inflammation position by said preparation, Alprostadil is made to be gathered in lesion, considerably reduce Alprostadil to the stimulation of blood vessel and inflammatory reaction, and reduce and inactivate at pulmonary metabolism, dosage is 1/10th of tradition Alprostadil injectable powder, thus reduce toxic and side effects (Yu Cuiqin. the preparation characteristic [J] time triumphant. Journal of Chinese Hospital Pharmacy .2002, 22, (11): 691-692.).
Lipid microsphere injection is as the ideal medicine carrying mode of current Alprostadil, however it remains some not yet solve the technical problem that.Due to the physicochemical property that Alprostadil self is special, the dissolubility in aqueous phase and oil phase is all poor, therefore has substantial amounts of Alprostadil not to be wrapped in Alprostadil liposome microsphere, thus can cause great blood vessel irritation.And Alprostadil chemical stability extreme difference, at water and higher than under normal temperature condition, especially easy degraded generates PGA1, therefore the storage and transportation conditions of Alprostadil liposome microsphere injection is harsh, must store and transport under the environment of 0 DEG C to 5 DEG C, and effect duration is also only one year.
Chinese patent CN201010168597.2 discloses a kind of Alprostadil freeze-dried emulsion for injection and preparation method thereof, this patent is in order to avoid the storage and transportation conditions of Alprostadil liposome microsphere harshness, and the shortcoming such as catabolite level is high, having invented injection Alprostadil dry emulsion, this product only needs in the cool (less than 20 DEG C) to preserve and gets final product (publication number is CN101843594A).This patent is in order to reduce the level of free Alprostadil in Alprostadil freeze-dried emulsion for injection, make up Alprostadil emulsions and cause the shortcoming that product stability is poor, blood vessel irritation is big because of the existence of free drug, its each embodiment all adds different cyclodextrin derivative, such as alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-β-CD etc..
Cyclodextrin still has certain risk as injection supplementary material, especially during beta-schardinger dextrin-drug administration by injection, nephrotoxicity is bigger, kidney damage can be caused, cause haemolysis and injection site necrosis, in preparation safety, bury unknown hidden danger (Wang Xuegong, Xiao Minghui, Tang Xiaobo etc. the dosage form of Alprostadil and New research progress [J]. Heilungkiang medicine, 2008,21 (6): 37-40).Owing to Alprostadil is fat-soluble not high, although increasing the parcel to medicine to a certain extent by the addition of cyclodextrin, but still can't resolve the risk that the seepage of medicine is brought, the symptom such as vasculitis and vascular pain (see excellent Supreme Being that package insert, Chongqing Yaoyou Pharmaceutical Co., Ltd.) occurs during use.
Due to the problem that the pharmaceutical dosage form physicochemical properties that still unresolved Alprostadil is special of above-mentioned Alprostadil are brought, some pharmaceutical factories and scientific research institution solve current Alprostadil preparation Problems existing by Alprostadil chemical modification both at home and abroad.Such as Chinese patent CN200910093400.0 has invented at 11,15 Alprostadil derivants being connected with glycosyl, owing to protecting two hydroxyls, has reached stable purpose.Meanwhile, prepared compound water soluble is substantially improved, it is not necessary to adds cosolvent and can form the aqueous solution (publication number is CN101671377A) of clarification.But its aqueous solution injection does not possess vascular inflammation position targeting compared with lipoid microsphere, easily rapid deactivation, internal safety and effectiveness are not so good as Alprostadil liposome microsphere injection to medicine in vivo.And for example Chinese patent application CN200980145796.7 discloses a kind of Novel prostate element E1 derivant and encloses the nanoparticle of this prostaglandin E 1 derivatives, it is synthesized PGE1 phosphate derivative by PGE1, its object is to increase the persistence of effect, slow-releasing (publication number is CN102216310A) in medicine body.Although added the water solublity of medicine by the known phosphate ester of this patent application, therefore yet suffer from the problem that vascular inflammation targeting is low, blood vessel irritation is big existing for water soluble drug.
Current this area is devoted to find novel Alprostadil derivant by Alprostadil is chemically modified always, to solve Alprostadil preparation--the problems such as the product stability that particularly injection exists is poor, envelop rate is low, clinical practice safety is low.
Summary of the invention
It is an object of the invention to provide a kind of novel Alprostadil derivant, another object of the present invention is to provide the pharmaceutical preparation of the stability of this Alprostadil derivant
For solving the problems referred to above, the carboxyl in Alprostadil structure is chemically modified by the present invention, it is provided that the esterification derivative of a kind of novel Alprostadil, and have developed a kind of injection containing this novel Alprostadil derivant as active component.
Technical scheme is as follows:
A first aspect of the present invention, it is provided that a kind of Alprostadil derivant, shown in described its chemical constitution of Alprostadil derivant such as formula (I):
In formula (I),
R1For hydrogen atom, methyl；
R2For hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, cyclohexyl, the tert-butyl group, normal-butyl.
Preferred compounds of the invention, has the compound as shown in formula (II), formula (III), it is preferred that shown in its chemical constitution of Alprostadil derivant such as formula (II), wherein R1For methyl；R2For methyl:
Shown in preferred its chemical constitution of Alprostadil derivant such as formula (III), wherein R1For hydrogen atom；R2For n-pro-pyl:
A second aspect of the present invention, it is provided that the synthetic method of above-mentioned Alprostadil derivant, reaction process is as follows:
This synthetic method comprises the following steps:
A) Alprostadil and catalyst are dissolved in organic solvent, stir 0.5 to 2 hour under condition of ice bath；
The organic acid esters b) will with compound (IV) structure dissolves in organic solvent, is slowly added dropwise to the solution of step a), stirring reaction 10～40 hours under room temperature condition；
C) after completion of the reaction, reactant liquor adds appropriate extraction into ethyl acetate, organic facies is proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, washing 1-3 time with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality again；
D) dividing and take organic layer, anhydrous sodium sulfate dries, and filters, and concentration obtains target compound.
The synthetic method of Alprostadil derivant of the present invention, organic acid esters is compound shown in structural formula (IV), and substituent R 1 therein, R2 are consistent with target compound；X is halogen.
In formula (IV), R1For hydrogen atom, methyl；R2For hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, cyclohexyl, the tert-butyl group, normal-butyl；X is iodine, chlorine, bromine atoms.
During preparation formula (II) compound, the structure of organic acid esters is as follows:
During preparation formula (III) compound, the structure of organic acid esters is as follows:
The synthetic method of Alprostadil derivant of the present invention, reaction dissolvent is the one in ethanol, acetonitrile, Isosorbide-5-Nitrae-dioxane, oxolane, acetone.
The synthetic method of Alprostadil derivant of the present invention, catalyst is the one in sodium bicarbonate, triethylamine, 1,8-diazabicylo 11 carbon-7-alkene (DBU), sodium carbonate, potassium carbonate.
A third aspect of the present invention, it is provided that the pharmaceutical preparation of a kind of Alprostadil derivant, described pharmaceutical preparation is with Alprostadil derivant of the present invention for active ingredient.
Preferably, the present invention provides a kind of injection containing this Alprostadil derivant, following prescription volume ratio by weight prepare:
Oil for injection of the present invention, selected from soybean oil, medium chain triglyceride, Oleum Camelliae, olive oil, Oleum Ricini, Semen Maydis oil one or both.
Emulsifying agent of the present invention, one or more in soybean phospholipid, egg yolk lecithin, hydrogenated soya phosphatide, hydrogenation egg yolk lecithin, Polyethylene Glycol-distearoyl phosphatidylcholine, Polyethylene Glycol 12-hydroxy stearic acid ester.
Co-emulsifier of the present invention, any one or more in oleic acid, Palmic acid, stearic acid, linoleic acid plus linolenic acid.
Freeze drying protectant of the present invention, one or more in glucose, lactose, galactose, fructose, mannitol, sorbitol, xylitol, sucrose, trehalose.
Isoosmotic adjusting agent of the present invention, one or more in glycerol, mannitol, sorbitol, glucose and sodium chloride.
PH value regulator of the present invention, one or more in maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, citric acid, triethanolamine.
A fourth aspect of the present invention, it is provided that the preparation method of above-mentioned Alprostadil derivant injection, the method comprises the following steps:
G. Alprostadil derivant is dissolved in oil for injection, as oil phase；
H. isoosmotic adjusting agent and freeze drying protectant are dissolved in appropriate water for injection, as aqueous phase；
I. emulsifying agent is scattered in aqueous phase or is dissolved in oil phase；
J. co-emulsifier is dissolved in oil phase；
K. oil phase is added in aqueous phase when stirring, or aqueous phase adds in oil phase when stirring, emulsifying at the beginning of when the water bath with thermostatic control of 20-90 DEG C, obtains colostrum；
L. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to full dose with water for injection, add pH adjusting agent and regulate pH 4～9, obtain feed liquid；By this feed liquid, filter, degerming, subpackage, lyophilizing, sealing, obtain Alprostadil derivant lyophilized injectable powder；Also this feed liquid can be filtered, degerming, subpackage, sealing, obtain Alprostadil derivative injection；This injection carries out sterilizing also by the mode of terminal sterilization.
In the preparation method of injection of the present invention, described terminal sterilization refers to employing: high pressure steam sterilization, and temperature is 100～121 DEG C, and the time is 15～45 minutes.
The present invention provides Alprostadil derivant lyophilized injectable powder, and before lyophilizing, the percentage composition of its various formula is w/v, for instance grams per milliliter, kg/liter etc..
Alprostadil derivant injection of the present invention can also be a kind of Liposomal formulation.
The preparation method of described Liposomal formulation may refer to textbook (Cui Fude. pharmaceutics: the 7th edition [M]. Beijing: People's Health Publisher, 2011).
Alprostadil derivant injection prepared by the present invention has the following characteristics that compared with existing commercially available alprostadil injection fat milk
1. owing to defining ester structure, and being wrapped in lipoid microsphere, medicine at lesion slow releasing, can extend drug treating time.
2. the fat-soluble relatively Alprostadil of Alprostadil derivant of the present invention significantly improves, and Alprostadil derivant major part can be made to be wrapped in lipoid microsphere, thus improve the envelop rate of this injection.The raising of envelop rate can reach: 1. reduces the level of free drug, thus reducing blood vessel irritation；2. the medicine overwhelming majority is present in lipoid microsphere, adds the chemical stability of medicine；3. due to medicine not easy to leak, medicine with lipoid microsphere intravasation inflammation part, can improve the targeted therapy effect of medicine.
3. this process for preparation of injection is simple, can meet the requirement of industrialized great production；Various adjuvant good biocompatibilities used, safety is high；This preparation does not need harsh storage and transportation conditions requirement, it is possible to greatly reduce producing and circulation cost；Therapeutic effect is significantly better than existing commercialized product, is well positioned to meet the demand of clinical treatment, has wide market prospect.
Accompanying drawing explanation
Fig. 1 is Alprostadil derivant (II) injection group vascular stimulation test tissue slice figure.
Fig. 2 is Alprostadil derivant (III) injection group vascular stimulation test tissue slice figure.
Fig. 3 is normal saline group vascular stimulation test tissue slice figure.
Detailed description of the invention
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.Agents useful for same of the present invention and raw material all commercially maybe can be prepared by literature method.
Alprostadil raw material of the present invention is purchased from Jilin Yinglian Biopharmaceutical Co., Ltd..
The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, or according to manufacturer it is proposed that condition.
Embodiment 1: the compounds of this invention prepares example
Adding in 10ml acetone by 25mg Alprostadil and 21 μ l triethylamines, condition of ice bath stirs 2 hours.Dissolve acetic acid-1-bromine ethyl ester 35 μ l by proper amount of acetone, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Divide and take organic layer, anhydrous sodium sulfate dries, filter, concentration, obtaining yellow oily liquid is Alprostadil derivant (II), and chemistry is by name: 1-Acetoxyethyl-7-(1R, 2R, 3R)-3-hydroxyl-2 (E)-3 (S)-3-hydroxyl-1-octenyl-5-oxo-cyclopentane heptanoate is 84.8% relative to raw material Alprostadil yield.
1HNMR ((CD3) 2CO-d6,300MHz) δ: 6.67 (1H, q), 5.50-5.49 (2H, m), 4.00-3.89 (2H, m), and 1.98-1.91 (5H, m), 1.89 (3H, s), and 1.30-1.16 (19H, m), 0.76-0.74 (6H, m).
Embodiment 2: the compounds of this invention prepares example
Adding in 40ml acetonitrile by 200mg Alprostadil and 168 μ l triethylamines, condition of ice bath stirs half an hour, dissolves acetic acid-1-bromine ethyl ester 280 μ l with appropriate acetonitrile, is slowly added dropwise to above-mentioned reactant liquor, continues stirring reaction 20h at ambient temperature.Adding 200ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Dividing and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, and obtaining yellow oily liquid is Alprostadil derivant (II), is 84.5% relative to raw material Alprostadil yield.
Embodiment 3: the compounds of this invention prepares example
Adding in 30ml acetonitrile by 100mg Alprostadil and 88 μ lDBU, condition of ice bath stirs half an hour.Dissolve acetic acid-1-bromine ethyl ester 140 μ l with appropriate acetonitrile, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Dividing and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, and obtaining yellow oily liquid is Alprostadil derivant (II), is 84.2% relative to raw material Alprostadil yield.
Embodiment 4: the compounds of this invention prepares example
Adding in 20ml acetonitrile by 50mg Alprostadil and 44 μ lDBU, condition of ice bath stirs half an hour.Dissolve acetic acid-1-bromine ethyl ester 70 μ l with appropriate acetonitrile, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 3 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Dividing and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, and obtaining yellow oily liquid is Alprostadil derivant (II), is 86.7% relative to raw material Alprostadil yield.
Embodiment 5: the compounds of this invention prepares example
Adding in 10ml ethanol by 25mg Alprostadil and 21 μ l triethylamines, condition of ice bath stirs half an hour.Dissolve butanoic acid chloromethyl ester 21 μ l by ethanol in proper amount, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 10h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 1 time with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Divide and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, obtaining yellow oily liquid is Alprostadil derivant (III), chemistry is by name: butyroxymethyl-7-(1R, 2R, 3R)-3-hydroxyl-2 (E)-3 (S)-3-hydroxyl-1-octenyl-5-oxo-cyclopentane heptanoate is 89.5% relative to raw material Alprostadil yield.
1HNMR ((CD3) 2CO-d6,300MHz) δ: 6.72 (2H, s), 5.50-5.49 (2H, m), and 4.00-3.89 (2H, m), 1.95-1.90 (7H, m), and 1.28-1.15 (21H, m), 0.87-0.85 (6H, m).
Embodiment 6: the compounds of this invention prepares example
Adding in 40ml acetone by 200mg Alprostadil and 178 μ lDBU, condition of ice bath stirs half an hour.Dissolve butanoic acid chloromethyl ester 240 μ l by proper amount of acetone, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 300ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Dividing and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, and obtaining yellow oily liquid is Alprostadil derivant (III), is 84.7% relative to raw material Alprostadil yield.
Embodiment 7: the compounds of this invention prepares example
Adding in 20ml1,4-dioxane by 100mg Alprostadil and 10mg sodium bicarbonate, condition of ice bath stirs half an hour.Dissolve butanoic acid chloromethyl ester 84 μ l with appropriate Isosorbide-5-Nitrae-dioxane, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 100ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Dividing and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, and obtaining yellow oily liquid is Alprostadil derivant (III), is 87.5% relative to raw material Alprostadil yield.
Embodiment 8: the compounds of this invention prepares example
Adding in 10ml oxolane by 25mg Alprostadil and 21 μ l triethylamines, condition of ice bath stirs half an hour.Dissolve isopropylformic acid. chloromethyl ester 21 μ l with appropriate oxolane, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 40h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Divide and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, obtaining yellow oily liquid is Alprostadil derivant (V), chemistry is by name: isobutyryloxymethyl-7-(1R, 2R, 3R)-3-hydroxyl-2 (E)-3 (S)-3-hydroxyl-1-octenyl-5-oxo-cyclopentane heptanoate is 83.7% relative to raw material Alprostadil yield.
1HNMR ((CD3) 2CO-d6,300MHz) δ: 6.72 (2H, s), 5.50-5.49 (2H, m), 4.00-3.89 (2H, m), and 1.95-1.90 (6H, m), 1.32-1.19 (19H, m), 1.10 (6H, d), 0.87 (3H, t).
Embodiment 9: the compounds of this invention prepares example
Adding in 30ml acetone by 100mg Alprostadil and 15mg potassium carbonate, condition of ice bath stirs half an hour.Dissolve iodometyl pivalate 220 μ l by proper amount of acetone, be slowly added dropwise to above-mentioned reactant liquor, be slowly added dropwise to above-mentioned reactant liquor, continue stirring reaction 20h at ambient temperature.Adding 200ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Divide and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, obtaining yellow oily liquid is Alprostadil derivant (VI), chemistry is by name: tert-butyl group methanoyl methyl-7-(1R, 2R, 3R)-3-hydroxyl-2 (E)-3 (S)-3-hydroxyl-1-octenyl-5-oxo-cyclopentane heptanoate is 78.7% relative to raw material Alprostadil yield.
1HNMR ((CD3) 2CO-d6,300MHz) δ: 6.72 (2H, s), 5.50-5.49 (2H, m), 4.00-3.89 (2H, m), and 1.95-1.90 (5H, m), 1.28-1.19 (19H, m), 1.07 (9H, s), 0.87 (3H, t).
Embodiment 10: the compounds of this invention prepares example
Adding in 10ml acetone by 20mg Alprostadil and 22 μ lDBU, condition of ice bath stirs 1 hour, dissolves the bromo-ethyl ester 29 μ l of propanoic acid 1-by proper amount of acetone, is slowly added dropwise to above-mentioned reactant liquor, continues stirring reaction 20h at ambient temperature.Adding 50ml extraction into ethyl acetate in reactant liquor, organic facies proceeded in separatory funnel, with the aqueous citric acid solution washing that concentration is 3% to slightly acidity, then wash 2 times with saturated sodium bicarbonate aqueous solution, saturated common salt is washed to neutrality.Divide and take organic layer, anhydrous sodium sulfate dries, filters, concentrates, obtaining yellow oily liquid is Alprostadil derivant (VII), chemistry is by name: the third acyloxymethyl-7-(1R, 2R, 3R)-3-hydroxyl-2 (E)-3 (S)-3-hydroxyl-1-octenyl-5-oxo-cyclopentane heptanoate is 76.4% relative to raw material Alprostadil yield.
1HNMR ((CD3) 2CO-d6,300MHz) δ: 6.67 (2H, s), 5.50-5.49 (2H, m), and 4.00-3.89 (2H, m), 1.98-1.91 (7H, m), and 1.30-1.13 (22H, m), 0.87 (3H, t).
Embodiment 11: pharmaceutical preparation example of the present invention
1. 1mg Alprostadil derivant (II) is dissolved in 5g injection soybean oil as oil phase；
2. 20g sucrose and 50g lactose are dissolved in appropriate water for injection as aqueous phase；
3. 1g soybean phospholipid and 0.1g oleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with Malaysia acid for adjusting pH to 4, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 12: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (II) is dissolved in 30g injection soybean oil as oil phase；
2. 20g mannitol and 300g galactose are dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 0.1g Palmic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 60 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, regulate pH to 7 with sodium hydroxide, and carry out aseptic filtration, subpackage, lyophilizing through filter, seal to obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 13: pharmaceutical preparation example of the present invention
1. 25mg Alprostadil derivant (II) is dissolved in the mixture of 30g injection soybean oil and 30g medium chain triglyceride as oil phase；
2. 20g sorbitol and 200g fructose are dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 0.1g stearic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 70 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, regulate pH to 7 with sodium hydroxide, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 14: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (II) is dissolved in 80g injection soybean oil as oil phase；
2. 50g trehalose and 12g egg yolk lecithin are dissolved in appropriate water for injection as aqueous phase；
3. 0.1g stearic acid and 0.1g Palmic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 90 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with winestone acid for adjusting pH to 4, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 15: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (II) is dissolved in the mixture of 20g injection soybean oil and 20g medium chain triglyceride as oil phase；
2. 20g sorbitol and 30g xylitol are dissolved in appropriate water for injection as aqueous phase；
3. 12g hydrogenated soya phosphatide and 0.1g oleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 80 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with citric acid pH to 5, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 16: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (II) is dissolved in 80g injection soybean oil as oil phase；
2. 20g glucose and 40g sucrose are dissolved in appropriate water for injection as aqueous phase；
3. 12g is hydrogenated egg yolk lecithin and 0.1g oleic acid is dissolved in oil phase；
4. aqueous phase is added in oil phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 70 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 6.5, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 17: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (II) is dissolved in 50g injection soybean oil and 50g medium chain triglyceride as oil phase；
2. 100g sorbitol and 200g trehalose are dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 5g oleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 50 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with winestone acid for adjusting pH to 5, and carry out aseptic filtration, subpackage, lyophilizing, sealing through filter, obtain Alprostadil derivant lyophilized injectable powder.
Embodiment 18: pharmaceutical preparation example of the present invention
1. 100mg Alprostadil derivant (II) is dissolved in 300g Oleum Ricini as oil phase；
6. 80g sorbitol is dissolved in appropriate water for injection as aqueous phase；
7. 60g Polyethylene Glycol-distearoyl phosphatidylcholine and 10g oleic acid are dissolved in oil phase；
2. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 60 DEG C in high-speed stirred, obtain colostrum；
3., by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, Fructus Citri Limoniae acid for adjusting pH is to 5.5, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 121 DEG C, 15 minutes time, obtains Alprostadil derivative injection.
Embodiment 19: pharmaceutical preparation example of the present invention
1. 5mg Alprostadil derivant (III) is dissolved in 100g Semen Maydis oil as oil phase；
2. 70g sodium chloride is dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 5g Polyethylene Glycol-distearoyl phosphatidylcholine are soluble in the aqueous phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 40 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 6, and carry out aseptic filtration, subpackage, sealing through filter, obtain Alprostadil derivative injection.
Embodiment 20: pharmaceutical preparation example of the present invention
1. 50mg Alprostadil derivant (III) is dissolved in 110g olive oil as oil phase；
2. 50g glucose is dissolved in appropriate water for injection as aqueous phase；
3. 100g Polyethylene Glycol 12-hydroxy stearic acid ester and 10g linolenic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 30 DEG C in high-speed stirred, obtain colostrum；
5., by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with sodium hydroxide regulate pH to 8, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 121 DEG C, 15 minutes time, obtains Alprostadil derivative injection.
Embodiment 21: pharmaceutical preparation example of the present invention
1. 25mg Alprostadil derivant (II) is dissolved in 100g injection soybean oil as oil phase；
2. 40g sorbitol is dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 6g linoleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, obtain colostrum；
5., by colostrum by homogenizer homogenizing, obtain uniform emulsion, be then settled to 1000ml with water for injection, with sodium hydroxide regulate pH to 9, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 121 DEG C, 15 minutes time, obtains Alprostadil derivative injection.
Embodiment 22: pharmaceutical preparation example of the present invention
1. 25mg Alprostadil derivant (II) is dissolved in 70g Oleum Camelliae as oil phase；
2. 20g glycerol is dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 1g linoleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, then it is settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 7, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 121 DEG C, 15 minutes time, obtain Alprostadil derivative injection.
Embodiment 23: pharmaceutical preparation example of the present invention
1. 25mg Alprostadil derivant (II) is dissolved in 90g injection soybean oil as oil phase；
2. 20g sorbitol is dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 0.1g linoleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, then it is settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 7, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 100 DEG C, 45 minutes time, obtain Alprostadil derivative injection.
Embodiment 24: pharmaceutical preparation example of the present invention
1. 25mg Alprostadil derivant (II) is dissolved in 100g injection soybean oil as oil phase；
2. 20g mannitol is dissolved in appropriate water for injection as aqueous phase；
3. 12g egg yolk lecithin and 10g linoleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, with sodium hydroxide and winestone acid for adjusting pH to 7, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, then it is settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 7, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 121 DEG C, 15 minutes time, obtain Alprostadil derivative injection.
Embodiment 25: pharmaceutical preparation example of the present invention
1. 100mg Alprostadil derivant (III) is dissolved in 300g injection soybean oil as oil phase；
2. 50g sorbitol is dissolved in appropriate water for injection as aqueous phase；
3. 100g Polyethylene Glycol-distearoyl phosphatidylcholine and 0.1g linoleic acid are dissolved in oil phase；
4. oil phase is added in aqueous phase when stirring, make its just emulsifying the water bath with thermostatic control conditions of 20 DEG C in high-speed stirred, obtain colostrum；
5. by colostrum by homogenizer homogenizing, obtain uniform emulsion, then it is settled to 1000ml with water for injection, with sodium hydroxide and winestone acid for adjusting pH to 7, and be filtered through filter, subpackage, sealing, high pressure steam sterilization, temperature is 105 DEG C, 45 minutes time, obtain Alprostadil derivative injection.
Experimental example 26: the mensuration of Alprostadil derivant and PGE1 Determination of oil-water partition coefficient
Experimental technique
Take 5 kinds of Alprostadil derivants respectively appropriate with PGE1, be dissolved in water saturated n-octyl alcohol, make into saturation, after standing centrifugal (3000d/min, 10min).Accurate Aspirate supernatant 0.5ml is in 10ml tool plug test tube, add the phosphate buffered solution 5ml of pH7.4, jolting 24h in 25 DEG C of Air oscillators, upper oil phase and lower floor's aqueous phase, centrifugal (14000r/min, 15min) is drawn after standing, sample introduction respectively, record peak area, detects the concentration of Alprostadil derivant by external standard method with peak area, calculates Determination of oil-water partition coefficient according to formula.Computing formula is as follows:
LogP value=log (C oil/C water)
(logP value is Determination of oil-water partition coefficient；C oil records the concentration taking Alprostadil derivant in n-octyl alcohol when being partition equilibrium, C water records the concentration taking Alprostadil derivant in aqueous phase when being partition equilibrium.) experimental result
The mensuration of table 1 Alprostadil derivant and PGE1 Determination of oil-water partition coefficient
Sample Outward appearance LogP value
PGE1 White solid 0.72
Alprostadil derivant (II) Yellow oily 4.19
Alprostadil derivant (III) Yellow oily 4.87
Alprostadil derivant (V) Yellow oily 4.94
Alprostadil derivant (VI) Yellow oily 5.63
Alprostadil derivant (VII) Yellow oily 4.57
Interpretation of result
Five kinds of Alprostadil derivant Determination of oil-water partition coefficients are all higher than Alprostadil, and lipotropy is significantly increased.
Experimental example 27: Alprostadil derivant injection and envelop rate contrast test under related preparations condition of different pH
Sample source
1. the Alprostadil derivant injection of the present invention
Choose embodiment 17,18,19.
2. commercially available alprostadil injection (Emulsion)
Beijing Tide Pharmaceutical Co., Ltd., specification 1ml:5 μ g, commodity are called " time triumphant ".
3. the Alprostadil freeze-dried breast of injection
Lyophilizing breast according to the preparation of Chinese patent CN201010168597.2 (publication number is CN101843594A) embodiment 1, called after " lyophilizing example ", as a comparison case, redissolves it with water for injection during experiment.Experimental program
Precision pipettes five kinds of samples of 1mL in processed good bag filter respectively, put into after the clamping of two ends equipped with in beaker containing the buffer of 5% tween of 100mLpH=3,4,5,6,7,8,9, it is placed in magnetic agitation under room temperature and stirs, timing takes dialysis solution high effective liquid chromatography for measuring medicament contg therein, bag filter is taken out when medicament contg in dialysis solution is constant, liquid in bag filter is transferred in 10mL measuring bottle completely, with isopropanol breakdown of emulsion constant volume, measures medicament contg W.Computational envelope rate, the computing formula of envelop rate is w/wtotal× 100% (wtotalFor recording sample drug content before dialysis), result is in Table 2.Experimental result
Table 2 Alprostadil derivant injection and envelop rate contrast test under related preparations condition of different pH
Sample PH=3 PH=4 PH=5 PH=6 PH=7 PH=8 PH=9
Embodiment 17 99.21% 99.12% 98.98% 98.89% 98.83% 98.87% 98.64%
Embodiment 18 99.61% 99.52% 99.34% 99.25% 99.23% 99.12% 98.75%
Embodiment 19 99.31% 99.13% 99.03% 98.87% 98.78% 98.27% 98.21%
Time triumphant 98.12% 98.02% 96.33% 86.64% 61.32% 51.54% 50.21%
Lyophilizing example 98.23% 98.14% 96.13% 87.64% 67.23% 60.31% 56.12%
Interpretation of result
From result it can be seen that five samples under the condition of pH=3～5, envelop rate is without significant change, along with pH value increases, decline substantially with lyophilizing example sample envelop rate time triumphant, Alprostadil derivant injection is slightly decreased.The normal ph of blood of human body is 7.35 7.45, under the condition of pH=7～8, time triumphant and lyophilizing example sample envelop rate decline about 40～50%, explanation has high amount of drug to leak out from emulsion droplet, and Alprostadil derivant injection envelop rate under the condition of pH=7～8 is substantially unchanged, it can thus be appreciated that drug leakage greatly reduces after Alprostadil derivant injection enters human body compared with commercially available two kinds of Alprostadil injection products, thus significantly reducing blood vessel irritation, improve medication effect, clinical practice is safer.
Experimental example 28: the stability contrast test of Alprostadil derivant injection and related preparations
Sample source
1. the Alprostadil derivant injection of the present invention
Selected embodiment 11,12,13 is freeze-dried powder, and selected embodiment 22,23,24 is injection.
2. commercially available alprostadil injection (Emulsion)
Purchased from Beijing Tide Pharmaceutical Co., Ltd., specification 1ml:5 μ g, commodity are run after fame " triumphant time ".
3. the Alprostadil freeze-dried breast of injection
Lyophilizing breast according to the preparation of Chinese patent CN201010168597.2 (publication number is CN101843594A) embodiment 1, called after " lyophilizing example ", as a comparison case.
Experimental program
Adopt thermostatic accelerated experiment method, accelerated test at 40 DEG C and 60 DEG C, mensuration Alprostadil derivant injection and two kinds of Alprostadil injection stability under acceleration conditions.Measuring sample drug content respectively at the 0th day, the 5th day, the 10th day, with the 0th day medicament contg for 100%, the percentage composition of sample when calculating the 5th day, the 10th day, result is in Table 3, table 4.
Experimental result
The stability contrast test of Alprostadil derivant injection and related preparations under 340 DEG C of conditions of table
The stability contrast test of Alprostadil derivant injection and related preparations under 460 DEG C of conditions of table
Interpretation of result
In 40 DEG C of accelerated tests, Alprostadil derivative injection and lyophilizing example sample drug content are slightly decreased, and Alprostadil derivant freeze-dried powder injecta medicine content is basically unchanged, and kai-shi injection sample drug content declines substantially.
It is accelerated in test Alprostadil derivative injection and lyophilizing example sample drug content at 60 DEG C slightly to decline, kai-shi injection sample drug content declines to a great extent, Alprostadil derivant freeze-dried powder injecta medicine content slightly reduces compared with 40 DEG C, but still less than other three kinds of samples.Alprostadil derivant freeze-dried powder and Alprostadil derivative injection are stably all significantly higher than relevant similar preparation in summary.
Experimental example 29: Alprostadil derivant injection vascular stimulation tests
Sample source
Example 14 Alprostadil derivant (II) injection and embodiment 19 Alprostadil derivant (III) injection are as experimental preparation.
Experimental program
Rabbit 6, body weight 2.0～3.0kg, it is randomly divided into two groups, medicine normal saline suitably dilutes, dosage is 0.5 μ g/kg (in Alprostadil), by the rabbit right auricular vein rate of administration with about 1.0mL/min, being administered 1 time, left ear gives isopyknic normal saline as comparison simultaneously.After being administered front and administration, animal and injection site are carried out perusal by 24h, and observing ear local vascular stimulates situation.Observation puts to death rabbit after terminating, and takes the injection site nearly body a bit of tissue of end, puts in 10% formalin fixing, paraffin embedding, and section, HE dyes, and carries out histopathological examination under light microscopic.
Interpretation of result
According to administration during and administration after to rabbit ear medicine-feeding part blood vessel perusal, Alprostadil derivant (II) and (III) injection group medicine-feeding part and surrounding tissue stimulate phenomenon to occur without redness, hyperemia, variable color etc., and compare rabbit ear no significant difference；Angiological pathology checks that result is shown in Fig. 1～3, according to pathological section, Alprostadil derivant (II) injection group and Alprostadil derivant (III) injection group auricular vein tube wall are complete, blood vessel is without obvious extension, tube wall and official's week are without obvious inflammatory cell infiltration, having no the pathological changes such as thrombosis in tube chamber and compare the rabbit ear without significant difference, when illustrative experiment, blood vessel is had no significantly damage and stimulates by Alprostadil derivant injection.
Below the preferred embodiment of the invention has been illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all equivalent modification or replacement, these equivalent modification or replacement under the premise without prejudice to the invention spirit and be all contained in the application claim limited range.

Claims (15)

1.一种前列地尔衍生物，所述的前列地尔衍生物其化学结构如式(I)所示：1. a kind of alprostadil derivative, its chemical structure of described alprostadil derivative is as shown in formula (I): 式(I)中，In formula (I), R1为氢原子、甲基；R 1 is a hydrogen atom, a methyl group; R2为氢原子、甲基、乙基、正丙基、异丙基、环己基、叔丁基、正丁基。R 2 is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclohexyl, tert-butyl, n-butyl. 2.根据权利要求1所述的一种前列地尔衍生物，其特征在于，式(I)中，2. a kind of alprostadil derivative according to claim 1, is characterized in that, in formula (I), R1为甲基、R2为甲基；或者R 1 is methyl, R 2 is methyl; or R1为氢原子、R2为正丙基。R 1 is a hydrogen atom, and R 2 is an n-propyl group. 3.如权利要求1所述的一种前列地尔衍生物的合成方法，其特征在于，该合成方法包括以下步骤：3. the synthetic method of a kind of alprostadil derivative as claimed in claim 1, is characterized in that, this synthetic method comprises the following steps: a)将前列地尔和催化剂溶于有机溶剂中，在冰浴条件下搅拌0.5至2小时；b)将有机酸酯溶解在有机溶剂中，缓慢滴加至步骤a)的溶液中，室温条件下搅拌反应10～40小时；a) Dissolve alprostadil and the catalyst in an organic solvent, and stir for 0.5 to 2 hours under ice-bath conditions; b) dissolve the organic acid ester in an organic solvent, and slowly add it dropwise to the solution of step a), at room temperature Stir and react for 10 to 40 hours; c)反应完毕后，在反应液中加入适量的乙酸乙酯萃取，将有机相转入分液漏斗中，用浓度为3％的柠檬酸水溶液洗涤至略酸性，再用饱和碳酸氢钠水溶液洗涤1-3次，饱和食盐水洗至中性；c) After the reaction is completed, add an appropriate amount of ethyl acetate to the reaction solution for extraction, transfer the organic phase to a separatory funnel, wash with a 3% aqueous solution of citric acid until slightly acidic, and then wash with a saturated aqueous solution of sodium bicarbonate 1-3 times, washed with saturated saline until neutral; d)分取有机层，无水硫酸钠干燥，过滤，浓缩，得目标化合物；d) Separate the organic layer, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the target compound; 所述的有机酸酯的结构如式(IV)所示：The structure of described organic acid ester is shown in formula (IV): 式(IV)中，R1、R2与目标化合物一致；X为卤素。In formula (IV), R 1 and R 2 are consistent with the target compound; X is halogen. 4.根据权利要求3所述的一种前列地尔衍生物的合成方法，其特征在于，所述的反应溶剂为乙醇、乙腈、1,4-二氧六环、四氢呋喃、丙酮中的一种。4. the synthetic method of a kind of alprostadil derivative according to claim 3 is characterized in that, described reaction solvent is the one in ethanol, acetonitrile, 1,4-dioxane, THF, acetone . 5.根据权利要求3或4所述的一种前列地尔衍生物的合成方法，其特征在于，所述的催化剂为碳酸氢钠、三乙胺、1,8-二氮杂二环十一碳-7-烯(DBU)、碳酸钠、碳酸钾中的一种。5. according to the synthetic method of a kind of alprostadil derivative described in claim 3 or 4, it is characterized in that, described catalyzer is sodium bicarbonate, triethylamine, 1,8-diazabicyclound One of carbon-7-ene (DBU), sodium carbonate, and potassium carbonate. 6.如权利要求1或2所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的药物制剂以前列地尔衍生物为活性成份，该药物制剂为注射剂，所述的注射剂由下列处方按重量体积比制备：6. the pharmaceutical preparation of a kind of alprostadil derivative as claimed in claim 1 or 2, is characterized in that, described pharmaceutical preparation is active ingredient with prostadil derivative, and this pharmaceutical preparation is injection, described Injections are prepared from the following prescriptions in weight-to-volume ratio: 7.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的注射用油选自大豆油、中链甘油三酯、茶油、橄榄油、蓖麻油、玉米油一种或两种。7. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6 is characterized in that, described oil for injection is selected from soybean oil, medium chain triglyceride, tea oil, olive oil, castor oil, One or two corn oils. 8.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的乳化剂选自大豆磷脂、蛋黄磷脂、氢化大豆磷脂、氢化蛋黄磷脂、聚乙二醇-二硬脂酰磷脂酰胆碱、聚乙二醇12-羟基硬脂酸酯中的一种或两种以上。8. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, described emulsifying agent is selected from soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, polyethylene glycol- One or more of distearoylphosphatidylcholine and polyethylene glycol 12-hydroxystearate. 9.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述助乳化剂选自油酸、棕榈酸、硬脂酸、亚油酸和亚麻酸中的任一种或两种以上。9. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, described co-emulsifier is selected from any in oleic acid, palmitic acid, stearic acid, linoleic acid and linolenic acid One or more than two. 10.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的冻干保护剂选自葡萄糖、乳糖、半乳糖、果糖、甘露醇、山梨醇、木糖醇、蔗糖、海藻糖中的一种或两种以上。10. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, described lyoprotectant is selected from glucose, lactose, galactose, fructose, mannitol, sorbitol, xylose One or more of alcohol, sucrose, and trehalose. 11.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的等渗调节剂选自甘油、甘露醇、山梨醇、葡萄糖和氯化钠中的一种或两种以上。11. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, described isotonic regulator is selected from the one in glycerin, mannitol, sorbitol, glucose and sodium chloride or two or more. 12.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，所述的pH值调节剂，选自马来酸、盐酸、酒石酸、氢氧化钠、柠檬酸、三乙醇胺中的一种或两种以上。12. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, described pH regulator, is selected from maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, citric acid, three One or two or more of ethanolamines. 13.根据权利要求6所述的一种前列地尔衍生物的药物制剂，其特征在于，该药物制剂为脂质体。13. the pharmaceutical preparation of a kind of alprostadil derivative according to claim 6, is characterized in that, this pharmaceutical preparation is liposome. 14.如权利要求6所述的一种前列地尔衍生物的药物制剂的制备方法，其特征在于，该方法包括以下步骤：14. the preparation method of the pharmaceutical preparation of a kind of alprostadil derivative as claimed in claim 6, is characterized in that, the method comprises the following steps: A.将前列地尔衍生物溶解于注射用油中，作为油相；A. the alprostadil derivative is dissolved in the oil for injection, as the oil phase; B.将等渗调节剂和冻干保护剂溶于适量注射用水中，作为水相；B. Dissolving the isotonic regulator and the lyoprotectant in an appropriate amount of water for injection as the water phase; C.将乳化剂分散于水相或溶于油相；C. Disperse the emulsifier in the water phase or dissolve it in the oil phase; D.将助乳化剂溶于油相；D. Dissolving the co-emulsifier in the oil phase; E.将油相在搅拌的条件下加入水相中，或水相在搅拌的条件下加入油相中，在20-90℃的恒温水浴条件下初乳化，得到初乳；E. Add the oil phase to the water phase under stirring conditions, or add the water phase to the oil phase under stirring conditions, and colostrum in a constant temperature water bath at 20-90°C to obtain colostrum; F.将初乳通过均质机均质，得到均匀的乳状液，然后用注射用水定容至全量,加入pH调节剂调节pH在4～9，得料液；将该料液，过滤、除菌、分装、冻干、封口，得前列地尔衍生物冻干粉针剂；也可将该料液过滤、除菌、分装、封口，得前列地尔衍生物注射液；该注射液也可通过终端灭菌的方式进行灭菌。F. Homogenize the colostrum through a homogenizer to obtain a uniform emulsion, then dilute to the full volume with water for injection, add a pH regulator to adjust the pH to 4-9, and obtain a feed liquid; filter the feed liquid, remove sterilize, subpackage, freeze-dry, and seal to obtain alprostadil derivative freeze-dried powder injection; or filter the material liquid, sterilize, subpackage, and seal to obtain alprostadil derivative injection; Sterilization can be performed by terminal sterilization. 15.根据权利要求14所述的一种前列地尔衍生物的药物制剂的制备方法，其特征在于，所述的终端灭菌是指采用：高压蒸汽灭菌，温度为100～121℃，时间为15～45分钟。15. The preparation method of a pharmaceutical preparation of alprostadil derivatives according to claim 14, characterized in that, said terminal sterilization refers to the use of: high pressure steam sterilization at a temperature of 100-121°C for a time of 15 to 45 minutes.
CN201410853661.9A 2014-12-26 2014-12-26 Alprostadil derivative and pharmaceutical preparation thereof Pending CN105777601A (en)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59206349A (en) * 1983-05-10 1984-11-22 Green Cross Corp:The Prostaglandin e1 derivative
WO1995006471A1 (en) * 1993-09-01 1995-03-09 The Green Cross Corporation Blood triglyceride lowering agent
JPH08277222A (en) * 1995-04-05 1996-10-22 Green Cross Corp:The Prophylactic / therapeutic agent for neurological diseases
CN1522147A (en) * 2001-05-02 2004-08-18 ��������˹�����տ����� Compositions containing 15-keto-prostanoids for the treatment of drug-induced constipation
CN101627968A (en) * 2009-08-14 2010-01-20 北京中海康医药科技发展有限公司 Preparation method of alprostadil injection
CN102038639A (en) * 2010-12-24 2011-05-04 海南碧凯药业有限公司 Alprostadil injection preparation
CN102216310A (en) * 2008-11-18 2011-10-12 日本株式会社Ltt生物医药 Novel prostaglandin e1 derivative, and nanoparticle having same encapsulated therein
CN102526065A (en) * 2011-12-26 2012-07-04 西安力邦制药有限公司 Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof
CN103110579A (en) * 2013-02-20 2013-05-22 北京德立福瑞医药科技有限公司 Alprostadil injection

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59206349A (en) * 1983-05-10 1984-11-22 Green Cross Corp:The Prostaglandin e1 derivative
WO1995006471A1 (en) * 1993-09-01 1995-03-09 The Green Cross Corporation Blood triglyceride lowering agent
JPH08277222A (en) * 1995-04-05 1996-10-22 Green Cross Corp:The Prophylactic / therapeutic agent for neurological diseases
CN1522147A (en) * 2001-05-02 2004-08-18 ��������˹�����տ����� Compositions containing 15-keto-prostanoids for the treatment of drug-induced constipation
CN102216310A (en) * 2008-11-18 2011-10-12 日本株式会社Ltt生物医药 Novel prostaglandin e1 derivative, and nanoparticle having same encapsulated therein
CN101627968A (en) * 2009-08-14 2010-01-20 北京中海康医药科技发展有限公司 Preparation method of alprostadil injection
CN102038639A (en) * 2010-12-24 2011-05-04 海南碧凯药业有限公司 Alprostadil injection preparation
CN102526065A (en) * 2011-12-26 2012-07-04 西安力邦制药有限公司 Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof
CN103110579A (en) * 2013-02-20 2013-05-22 北京德立福瑞医药科技有限公司 Alprostadil injection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
杨明，李小芳: "《药剂学》", 1 August 2014 *

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