CN101768157A - Amantadine pidotimod carboxylate and preparation method and application thereof - Google Patents
Amantadine pidotimod carboxylate and preparation method and application thereof Download PDFInfo
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- CN101768157A CN101768157A CN200910076459A CN200910076459A CN101768157A CN 101768157 A CN101768157 A CN 101768157A CN 200910076459 A CN200910076459 A CN 200910076459A CN 200910076459 A CN200910076459 A CN 200910076459A CN 101768157 A CN101768157 A CN 101768157A
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Abstract
The invention relates to a new compound called amantadine pidotimod carboxylate (C19H29N3O4S) and simultaneously relates to a preparation method of the mantadine pidotimod carboxylate as well as application to the preparation of anti-influenza medicaments and anti-tumor medicaments. The invention not only retains the original characteristics of amantadine and pidotimod as raw materials in pharmacology, but also achieves the synthetic action of the two raw materials and has high bioavailability and good synthetic effect. In addition, the pH value of amantadine pidotimod carboxylate is neutral, thereby realizing the possibility of injection type application.
Description
Technical field
The present invention relates to a kind of carboxylate compounds, three ring [3.3.1.1
3.7] certain herbaceous plants with big flowers alkane-1-amine (R)-3-[(S)-(5-oxo-2-pyrrolidyl) carbonyl]-tetrahydro-thiazoles-4-carboxylic acid's salt, be called amantadine pidotimod carboxylate, and its production and application.
Background technology
Flu is the previous very general communicable disease of China's order, it mainly is due to the virus infection, virus is one of pathogenic agent of harm humans, and the structure of virus is different from bacterium, and it does not have cell walls, the center of virus is a nucleic acid, and be the molecule that shell is formed with protein, it colonizes in the host (animal, plant or microorganism), by the nucleic acid and the protein of the synthetic virus of the enzyme system of host cell self, then form virom crosome, seriously affect the healthy of people.
At present except Chinese medicine and, anti-common cold virus medicine is amine phenol alkanamine class compound preparation, it is the trade(brand)name difference, the effective ingredient of the anti-common cold virus of such preparation is an amantadine, amantadine can stop virus to enter host cell, clinical Ya Zhoujia-grippal prevention of II type and the early treatment that be used for, the history of existing three more than ten years.But along with the variation of viral production process, amantadine itself selectivity clinically in addition, amantadine has been subjected to bigger restriction on the result of treatment of anti-common cold virus.
How not the product developed by Italian Poli chemical industrial company of later stage eighties moral are a kind of immunopotentiating agents, and its chemical structure is similar to dipeptides.As respiratory tract that suppresses virus and growth of tumour cell and outbreak repeatedly and urinary tract infection etc.Clinical respiratory tract infection, chronic bronchitis, the urinary system infection that shows effect repeatedly and the adjuvant therapy of malignant tumor etc. that are used to prevent and treat children's outbreak have all played gratifying result, and its better tolerance does not almost have untoward reaction to produce.
Treat viral cold in the recent period clinically and begin amino phenol alkyl amine class preparation and pidotimod are joined the tax use jointly, played better therapeutic effect.But because the acidity strong excessively (pH value 2.0-3.0) of pidotimod, the sense that very easily makes the patient produce gastrointestinal discomfort influences appetite even can cause gastroenteropathy, and side effect is bigger; Simultaneously simple uses both compatibilities, and its bioavailability is lower, and synergy is bad; And the pH value of amantadine is 7.0-8.0, and the pH value of pidotimod is 2.0-3.0, has limited these two kinds of medicines and all can't make the injection formulation, has limited applying of medicine.
In view of this, the inventor is based on synthetic experience of abundant for many years medical chemistry and expertise, and in conjunction with the utilization of studying the science, the continuous research experiment of process has synthesized carboxylate compounds of the present invention finally.
Summary of the invention
The purpose of this invention is to provide a kind of new new compound with pharmaceutical use--amantadine pidotimod carboxylate and preparation method thereof and application.
Compound-amantadine pidotimod carboxylate of the present invention is down shown in the array structure:
The preparation method of amantadine pidotimod carboxylate of the present invention comprises following steps:
(1) in the aqueous sodium carbonate with mol ratios such as amantadine hydrochloride addings, stirring reaction 40-60 minute, suction filtration washing back 70-80 ℃ dry 1-2 hour down, amantadine;
(2) will be dissolved in the pidotimod of the identical mole number of amantadine hydrochloride in the ethanolic soln;
(3) add the amantadine of gained in the step (1) in the solution of step (2), stirring and refluxing 1 hour to reaction solution is clarified;
(4) with gained solution cooling bath under agitation in the step (3), the white cotton-shaped crystallization of separating out places refrigerator and cooled to hide, and leaves standstill 2-12 hour;
(5) gained crystallization suction filtration, alcohol in the step (4) washed, promptly got amantadine pidotimod carboxylate after the drying.
In aforesaid method, reacting by heating thing during stirring reaction in the step (1), Heating temperature is 40-50 ℃; Washing described in the step (1) is twice of pure water rinsing; Ethanolic soln described in the step (2) is dehydrated alcohol or 95% above ethanolic soln.Alcohol described in the step (5) is washed to washing secondary with dehydrated alcohol, and described drying is following dry 2 hours at 80 ℃.
Amantadine pidotimod carboxylate of the present invention can be used for preparing anti-flu and anti-tumor drug.
Amantadine pidotimod carboxylate of the present invention, fusing point are 204.6-209.3 ℃, specific rotation for-99 ° to-101 °, pH value are 6-6.5, the mouth mildly bitter flavor.From whole molecular structure, it comprises bridge three rings, pyrrolidine ring, and 4 pharmacophores of thiazolidine ring and dipeptides do not have two identical or different electric charges to exist in the structure, meet the feature of pharmacophore in the marketed drug.Amantadine and pidotimod effectively combine with 1: 1 ratio as can be seen from its structure, the active drug group that has possessed the two simultaneously, the script characteristic that has not only kept amantadine and two kinds of raw materials of pidotimod from pharmacology, even reached the synergy of original two kinds of raw materials, the bioavailability height, synergy is good.And its pH value is neutral, thereby has realized the possibility that its injection type uses.
Amantadine pidotimod carboxylate of the present invention, the carbonyl in its structure, carboxyl are good hydrophilic radical, have good water-solubility.Water-soluble is the prerequisite that drug oral absorbs, and is the prerequisite of medicine penetration cell.Oral pharmaceutical need be the dispersion state of height through gastrointestinal tract mucous absorption, and water miscible significance is to make the sub-dispersion state of pharmaceutical cpd.Because biomembranous lipid in nature requires drug molecule that certain lipotropy (being to contain lipophilic group in the middle of the drug molecular structure) is arranged again, pass through cytolemma simultaneously with guarantee.So the ideal medicine is answered possess hydrophilic property and lipophilic matched well.And amantadine pidotimod carboxylate of the present invention not only has good hydrophilic radical, and the bridge in its structure three ring is good lipophilic group, also has good fat-soluble; Thereby it is water-soluble and fat-soluble all very good, reaches moderate state, more utilizes the effective absorption and the utilization of medicine.
Wenlock etc. have systematically analyzed the medicine of researching and developing between the 1985-2000 in clinical and clinical termination, and carried out retrospective analysis with 594 oral pharmaceutical that gone on the market, think that the medicine of relative molecular mass between 200-450 was more conducive to film and absorbs.And the molecular mass of amantadine pidotimod carboxylate of the present invention is 395.51, helps penetrating fenestra in drug metabolism processes.
Through clinical verification, the present invention has good therapeutic action, and data are as follows:
In pet clinic 10 routine pets (dog) are carried out the experiment of viral infection symptom, respectively with 0.32g/ time, every day secondary, the dosage of 0.64g/ day is supported by the arm food and is taken, finding after 3 days has obvious effects, and all the other 8 example recoveries from illness were arranged the obvious curative effects except that 2 examples after 5 days.
Due to illness the similar flu of disease, symptom of toxinfection is with 0.32g/ time to the people, and every day, second-dose was taken, and 10 routine patients all have obvious curative effects after taking medicine three, 9 example recoveries from illness after five days, 1 example because of physique a little less than week back recovery from illness.Period in a medicine does not have obvious negative interaction and produces.Obvious effective rate reaches 100%, and curative ratio reaches more than 90%.
Patients with gastric cancer 2 example checkings have been carried out: serve on 6 months after the example operation, recovery from illness at last, a routine invalid death (age is excessive).Curative ratio 50%.
Pet (doggie) clinical experiment statistics
Patient (people) clinical verification statistics
Description of drawings
Fig. 1 is the structural formula of amantadine pidotimod carboxylate of the present invention;
Fig. 2 is preparation technology's schema of amantadine pidotimod carboxylate of the present invention.
Embodiment
Reach technique means and the effect that predetermined purpose is adopted for further setting forth the present invention, below the preparation method of amantadine pidotimod carboxylate of the present invention is described in detail.
In following examples, the starting material and the proportioning of employing are as shown in the table:
| Material name | Specification | Charging capacity | Molecular weight | Mole number | Mole ratio | Weight ratio |
| Amantadine hydrochloride | Pharmaceutical grade | ??5.0g | ??187.71 | ??0.02664 | ??1.000 | ??1.000 |
| Pidotimod | Pharmaceutical grade | ??7.53g | ??244.26 | ??0.03083 | ??1.157 | ??1.506 |
| Anhydrous sodium bicarbonate | Reagent | ??2.83g | ??106 | ??0.02670 | ??1.002 | ??0.566 |
| 95% ethanol | Reagent | ??80ml | ??46 |
| Material name | Specification | Charging capacity | Molecular weight | Mole number | Mole ratio | Weight ratio |
| Dehydrated alcohol | Reagent | ??80ml | ??46 |
Wherein: the hydrochloric acid diamantane is the antivirus raw material medicine trade(brand)name, and its chemistry is by name: three ring [3.3.1.1
3.7] certain herbaceous plants with big flowers alkane-1-amine hydrochlorate.Pidotimod is the immunostimulant trade(brand)name, and its chemistry is by name: (R)-3-[(S)-(5-oxo-2-pyrrolidyl) carbonyl]-tetrahydro-thiazoles-4-carboxylic acid.
Reaction formula is:
Embodiment 1
With the 2.83g anhydrous Na
2CO
3Put in the 150ml there-necked flask, add the 50ml pure water again.Heated and stirred is to molten entirely, after being 40 ℃-50 ℃, Heating temperature under agitation drops into the 5g amantadine hydrochloride, stirring heating reaction 60 minutes, Heating temperature is 40 ℃-50 ℃, suction filtration behind the cooling bath cool to room temperature, wash secondary with pure water, drain the back in 80 ℃ of dryings 2 hours, amantadine 4.0g (yield: 99%).
The 7.53g pidotimod is put in the 150ml there-necked flask, drop into 80ml 95% ethanol, be stirred and heated to moltenly entirely, Heating temperature is 40 ℃-50 ℃, afterwards the above-mentioned amantadine that obtains is dropped in the reaction flask, reflux and clarified to reaction solution in 1 hour, behind the reaction terminating reaction solution is poured in the 200ml beaker, stirs cooling bath down, separate out the cotton-shaped crystallization of a large amount of whites, refrigerator cold-storage (0-5 ℃) is put in crystallization, left standstill 12 hours.
Behind the crystallization suction filtration, with 30ml dehydrated alcohol flushing secondary, after draining, drying is 2 hours under 80 ℃, gets amantadine pidotimod carboxylate, constant weight 9.12g (yield 79%) respectively.After testing, fusing point is 208.8 ℃; Specific optical rotation is-99.12 °; PH value is 6.1.
Embodiment 2
The 2.83g anhydrous Na2CO3 is put in the 150ml there-necked flask, added the 50ml pure water again.Be stirred to moltenly entirely, under agitation drop into the 5g amantadine hydrochloride afterwards, stirring heating reaction 40 minutes, suction filtration behind the cooling bath cool to room temperature is washed secondary with cold pure water, drains the back in 80 ℃ of dryings 2 hours, must amantadine 4.0g (yield: 96%).
The 7.53g pidotimod is put in the 150ml there-necked flask, dropped into the 80ml dehydrated alcohol, be stirred to molten entirely, afterwards the above-mentioned amantadine that obtains is dropped in the reaction flask, be warming up to 75-80 ℃ for making to be dissolved fast to stir by molten thing, refluxed 1 hour, reaction solution is clarified.Be poured into behind the reaction terminating in the 200ml beaker, stir cooling bath down, separate out the cotton-shaped crystallization of a large amount of whites, put into refrigerator cold-storage (0-5 ℃), left standstill 2.5 hours.
Suction filtration, with 30ml dehydrated alcohol flushing secondary, after draining, drying is 2 hours under 80 ℃, constant weight 9.12g (yield 76%) respectively.After testing, fusing point is 205.6 ℃; Specific optical rotation is-100.29 °; PH value is 6.4.
Claims (8)
1. the described compound of following structural, name is called amantadine pidotimod carboxylate, C
19H
29N
3O
4S:
2. the preparation method of the described amantadine pidotimod carboxylate of claim 1 comprises following steps:
(1) in the aqueous sodium carbonate with mol ratios such as amantadine hydrochloride addings, stirring reaction 40-60 minute, suction filtration washing back 70-80 ℃ dry 1-2 hour down, amantadine;
(2) will be dissolved in the pidotimod of the identical mole number of amantadine hydrochloride in the ethanolic soln;
(3) add the amantadine of gained in the step (1) in the solution of step (2), stirring and refluxing 1 hour to reaction solution is clarified;
(4) with gained solution cooling bath under agitation in the step (3), the white cotton-shaped crystallization of separating out places refrigerator and cooled to hide, and leaves standstill 2-12 hour;
(5) gained crystallization suction filtration, alcohol in the step (4) washed, promptly got amantadine pidotimod carboxylate after the drying.
3. the preparation method of amantadine pidotimod carboxylate according to claim 2 is characterized in that:
Reacting by heating thing during stirring reaction in the step (1), Heating temperature is 40-50 ℃.
4. according to the preparation method of claim 2 or 3 described amantadine pidotimod carboxylates, it is characterized in that:
Ethanolic soln described in the step (2) is dehydrated alcohol or 95% above ethanolic soln.
5. the preparation method of amantadine pidotimod carboxylate according to claim 4 is characterized in that:
Washing described in the step (1) is for twice of pure water rinsing; Alcohol described in the step (5) is washed to washing secondary with dehydrated alcohol, and described drying is following dry 2 hours at 80 ℃.
6. according to the preparation method of claim 2 or 3 described amantadine pidotimod carboxylates, it is characterized in that:
Washing described in the step (1) is for twice of pure water rinsing; Alcohol described in the step (5) is washed to washing secondary with dehydrated alcohol, and described drying is following dry 2 hours at 80 ℃.
7. the described amantadine pidotimod carboxylate of claim 1 is used to prepare anti-cold medicine.
8. the described amantadine pidotimod carboxylate of claim 1 is used to prepare antitumor drug.
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|---|---|---|---|
| CN200910076459A CN101768157A (en) | 2009-01-05 | 2009-01-05 | Amantadine pidotimod carboxylate and preparation method and application thereof |
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| CN200910076459A CN101768157A (en) | 2009-01-05 | 2009-01-05 | Amantadine pidotimod carboxylate and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN108354904A (en) * | 2018-05-21 | 2018-08-03 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing amantadine hydrochloride |
-
2009
- 2009-01-05 CN CN200910076459A patent/CN101768157A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN108354904A (en) * | 2018-05-21 | 2018-08-03 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing amantadine hydrochloride |
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Application publication date: 20100707 |