CN108484706A - Didanosine intends meat poisoning bases prodrug and preparation method thereof - Google Patents
Didanosine intends meat poisoning bases prodrug and preparation method thereof Download PDFInfo
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- CN108484706A CN108484706A CN201810377395.5A CN201810377395A CN108484706A CN 108484706 A CN108484706 A CN 108484706A CN 201810377395 A CN201810377395 A CN 201810377395A CN 108484706 A CN108484706 A CN 108484706A
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- didanosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of quasi- meat poisoning bases prodrug of Didanosine, i.e. 5 ' the O L carnitine ester prodrugs and its preparation method and application of Didanosine.The general structure I that the Didanosine intends meat poisoning bases prodrug is as follows：Wherein, R is saturation binary of fatty acids residue.The Didanosine, which intends meat poisoning bases prodrug, can significantly improve membrane permeability and oral administration biaavailability, have broad application prospects.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of quasi- meat poisoning bases prodrug of Didanosine, i.e. Didanosine
5 '-O-L- carnitine ester prodrugs and its preparation method and application.
Background technology
The chemical name of Didanosine is 2 ', 3 '-dideoxy inosines, is a kind of artificial synthesized ucleosides medicine
Object is to be developed by Bristol-Myers Squibb companies of the U.S., and a kind of HIV-1 listed for the first time in the U.S. in 1991 is inverse
Transcripting enzyme inhibitor.
Didanosine is converted to the compound double deoxidation atriphos of antiviral activity by cell enzyme effect, interference
Reverse transcriptase and then the duplication for preventing virus, make the CD of AIDS patient4Cell number increases, when existence to extend patient
Between and reduce pathogenic infection incidence.It is invalid or asymptomatic that clinic has been used for not being resistant to Zidovudine, Zidovudine treatment
The AIDS patient of HIV infection.But it is easily decomposed under the strongly hydrophilic and acid condition due to Didanosine, is not easy to cross over liposoluble
Property cell membrane enter the duplication that cell interior inhibits virus, oral administration biaavailability is only 20%~40%, and blood plasma eliminates half
The phase decline for 1~2h, seriously affects the performance of its drug effect.
Therefore, it is necessary to find a kind of approach to improve the membrane permeability of Didanosine, and then improve its oral bio profit
Expenditure.According to a large amount of document report, if the free hydroxyl to nucleoside medicine is modified, this kind of drug may be improved
Membrane permeability and oral administration biaavailability.
Invention content
The purpose of the present invention is to provide a kind of Didanosines to intend meat poisoning bases prodrug, i.e. 2 ', 3 '-dideoxy hypoxanthine
5 '-O-L- carnitine esters of nucleosides, that is, Didanosine 5 '-O-L- carnitine esters and preparation method thereof, the Didanosine
Quasi- meat poisoning bases prodrug can significantly improve membrane permeability and oral administration biaavailability, have broad application prospects.
To achieve the goals above, the present invention adopts the following technical scheme that：
A kind of quasi- meat poisoning bases prodrug of Didanosine, i.e. 5 '-O-L- carnitine esters of Didanosine, general structure I are as follows：
Wherein R is saturation binary of fatty acids residue, that is, the standby esterification of carboxyl at binary of fatty acids both ends is saturated, without free
Carboxyl.
The Didanosine intends 3 ' the position hydroxyl quilts that meat poisoning bases prodrug is 5 ' the position hydroxyls and L-BETAIN by Didanosine
Obtained by the carboxyl esterification for being saturated binary of fatty acids both ends.
R is succinic acid, pimelic acid or azelaic acid residue in the general structure of the quasi- meat poisoning bases prodrug of the Didanosine.
5 ' the preferably following compound of-O-L- carnitines ester of Didanosine：
A.5 '-O-L- carnitines acyl-succinyl Didanosine (III), structure is as follows：
B.5 '-O-L- carnitines acyl-heptanedioyl Didanosine (IV), structure is as follows：
C.5 '-O-L- carnitines acyl-nonanedioyl Didanosine (V), structure is as follows：
The Didanosine of the present invention is intended meat poisoning bases prodrug and is prepared via a method which：L-BETAIN and saturation binary
Fatty acid anhydride carries out the first step and is reacted at ester under 4-dimethylaminopyridine catalytic condition, is then added and goes at ambient temperature
Hydroxyl inosine and catalyst dicyclohexylcarbodiimide carry out second step and are reacted at ester, form Didanosine L-BETAIN ester prodrugs,
Reaction equation is as follows：
Wherein, L is L-BETAIN, and X is saturation di-fatty acid anhydrides, and Y is the saturation binary of fatty acids containing 1 free carboxy
Residue and R for no free carboxy saturation binary of fatty acids residue residue.The preferred succinic anhydrides of X, pimelic acid acid anhydride or azelaic acid
Acid anhydride.
The specific synthetic method of 5 '-O-L- carnitine esters of Didanosine is carried out according to following general routes outlined：
50mmol succinic anhydrides and 5 '-O-L- carnitines and 5mmol N, N-4- dimethylamino naphthyridines are added separately to N,
In dinethylformamide (250ml) solution, after room temperature reaction 12 hours, add 11.8g (50mmol) Didanosine and
50mmol dicyclohexylcarbodiimides mix, and after ice bath reacts 1 hour, reaction solution is warmed to room temperature to the reaction was continued 24 hours.Instead
It after answering, filters, decompression boils off the n,N dimethylformamide in filtrate, and residue is dissolved with ethyl acetate, then used successively
Ethyl acetate layer is collected in distilled water, saturated sodium bicarbonate, saturated common salt washing, and sodium peroxydisulfate dries column, and filtrate and silica gel are mixed
Sample is evaporated, and solid obtains compound (I), structure is as follows through silica gel post separation, ethyl acetate and petroleum ether gradient elution：
Wherein R is the saturation binary of fatty acids residue of no free carboxy.It is preferably following several to be saturated binary of fatty acids：Fourth two
Acid, pimelic acid, azelaic acid.
The Didanosine intends purposes of the meat poisoning bases prodrug in preparing inverase.
Compared with prior art, the Didanosine that prepared by the present invention, which intends meat poisoning bases prodrug, can preferably improve hydroxyl flesh
The membrane permeability and oral administration biaavailability of glycosides, have broad application prospects.
Description of the drawings
Fig. 1 be rat body in Didanosine through when blood concentration figure.
Specific implementation mode
Embodiment 1
Succinic anhydride is reacted with L-BETAIN, be added N, N-4- dimethylamino naphthyridines, reaction dissolvent be anhydrous tetrahydro furan,
Dichloromethane, hexamethylene or dimethylformamide, reaction temperature are 0 DEG C to solvent boiling point, preferably 20~60 DEG C, reaction time 12
After hour, adds Didanosine and dicyclohexylcarbodiimide and reaction solution is warmed to room temperature continuation after ice bath reacts 1 hour
Reaction 24 hours.After reaction, it filters, decompression boils off the n,N-Dimethylformamide in filtrate, residue ethyl acetate
Then dissolving uses distilled water, saturated sodium bicarbonate, saturated common salt washing to collect ethyl acetate layer, sodium peroxydisulfate drying successively
Column, filtrate and silica gel mixed sample, are evaporated, and solid obtains compound through silica gel post separation, ethyl acetate and petroleum ether gradient elution
(III), the mark of the chemical shift of each carbon atom is as follows：
Embodiment 2:
Pimelic acid acid anhydride is reacted with L-BETAIN, be added N, N-4- dimethylamino naphthyridines, reaction dissolvent be anhydrous tetrahydro furan,
Dichloromethane, hexamethylene or dimethylformamide, reaction temperature are 0 DEG C to solvent boiling point, preferably 20~60 DEG C, reaction time 12
After hour, adds Didanosine and dicyclohexylcarbodiimide and reaction solution is warmed to room temperature continuation after ice bath reacts 1 hour
Reaction 24 hours.After reaction, it filters, decompression boils off the n,N-Dimethylformamide in filtrate, residue ethyl acetate
Then dissolving uses distilled water, saturated sodium bicarbonate, saturated common salt washing to collect ethyl acetate layer, sodium peroxydisulfate drying successively
Column, filtrate and silica gel mixed sample, are evaporated, and solid is through silica gel post separation, and ethyl acetate and petroleum ether gradient elution are to get (IV).Often
The mark of the chemical shift of a carbon atom is as follows：
Embodiment 3:
Azelaic acid acid anhydride is reacted with L-BETAIN, be added N, N-4- dimethylamino naphthyridines, reaction dissolvent be anhydrous tetrahydro furan,
Dichloromethane, hexamethylene or dimethylformamide, reaction temperature are 0 DEG C to solvent boiling point, preferably 20~60 DEG C, reaction time 12
After hour, adds Didanosine and dicyclohexylcarbodiimide and reaction solution is warmed to room temperature continuation after ice bath reacts 1 hour
Reaction 24 hours.After reaction, it filters, decompression boils off the n,N-Dimethylformamide in filtrate, residue ethyl acetate
Then dissolving uses distilled water, saturated sodium bicarbonate, saturated common salt washing to collect ethyl acetate layer, sodium peroxydisulfate drying successively
Column, filtrate and silica gel mixed sample, are evaporated, and solid is through silica gel post separation, and ethyl acetate and petroleum ether gradient elution are to get (V).Each
The mark of the chemical shift of carbon atom is as follows：
The physical and chemical index of the compound of detection embodiment 1-3 respectively, the results are shown in Table 2.
Embodiment 4:In body small intestine list perfusion experiment.
Using rat in body small intestine list Perfusion, choose the jejunum in rats of 10cm long, both ends be intubated by Didanosine with
Compound (III)-(V) is dissolved in Kreb-Ringer ' s nutrient solutions (pH=5.5) respectively, and concentration is 0.05mM, with 0.2mL/
Min perfusions by jejunum in rats, obtain Didanosine and compound (III)-(V) jejunum film Penetration ration.
The membranous permeation rate of 1 Didanosine of table and compound (III)-(V)
The result shows that the membrane permeability of the compound of the present invention (III)-(V) significantly improves.
Embodiment 5:Sprague-Dawley Rats pharmacokinetics are studied.
To experimental group and control group Sprague-Dawley rats difference gavage (II) i.e. Didanosine and compound (III)
That is 5 '-O-L- carnitines acyls-succinyl Didanosine (being 15mg/Kg in terms of Didanosine) measures in rat plasma and removes hydroxyl
The concentration of inosine.Simultaneously to Sprague-Dawley rat tail veins injection Didanosine physiological saline aqueous solution (5mg/Kg).
As a result as shown in Fig. 1 and table 2.
After table 2 takes orally (IV) and Didanosine respectively, the pharmacokinetic parameters of Didanosine are (in terms of Didanosine in rat body
30mg/Kg)
It can be obtained by table 2 and Fig. 1, compound III bioavilabilities compared with oral Didanosine are significantly improved, relatively
Bioavilability has reached desired design purpose up to 179%.
The relevant information of 3 Didanosine pro-medicament of table
Claims (6)
1. a kind of Didanosine intends meat poisoning bases prodrug, it is characterised in that：The structure that the Didanosine intends meat poisoning bases prodrug is logical
Formulas I is as follows：
Wherein, R is saturation binary of fatty acids residue.
2. the Didanosine according to claim intends meat poisoning bases prodrug, which is characterized in that the Didanosine intends carnitine
Class prodrug is the carboxyl ester that binary of fatty acids both ends are saturated by 5 ' position hydroxyls of Didanosine and 3 ' position hydroxyls of L-BETAIN
Change gained.
3. the Didanosine according to claim intends meat poisoning bases prodrug, which is characterized in that the Didanosine intends carnitine
R is succinic acid, pimelic acid or azelaic acid residue in the general structure of class prodrug.
4. a kind of Didanosine as described in claim 1 intends the preparation method of meat poisoning bases prodrug, it is characterised in that：The preparation
Method includes the following steps：
L-BETAIN under 4-dimethylaminopyridine catalytic condition, carries out the first step and is reacted at ester with saturation di-fatty acid anhydrides,
Then Didanosine and catalyst dicyclohexylcarbodiimide are added at ambient temperature, carry out second step at ester react to get.
5. Didanosine according to claim 4 intends the preparation method of meat poisoning bases prodrug, it is characterised in that：The saturation
Di-fatty acid anhydrides is succinic anhydride, pimelic acid acid anhydride or azelaic acid acid anhydride.
6. Didanosine described in claim 1 intends purposes of the meat poisoning bases prodrug in preparing inverase.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810377395.5A CN108484706A (en) | 2018-04-25 | 2018-04-25 | Didanosine intends meat poisoning bases prodrug and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810377395.5A CN108484706A (en) | 2018-04-25 | 2018-04-25 | Didanosine intends meat poisoning bases prodrug and preparation method thereof |
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| CN108484706A true CN108484706A (en) | 2018-09-04 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077925A1 (en) * | 2004-02-04 | 2005-08-25 | Bristol-Myers Squibb Company | Sulfonylpyrrolodine modulators of androgen receptor fuction and method |
| CN101580529A (en) * | 2009-05-27 | 2009-11-18 | 沈阳药科大学 | Didanosine pro-medicament and preparation method thereof |
| CN105753921A (en) * | 2016-03-31 | 2016-07-13 | 沈阳药科大学 | Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof |
-
2018
- 2018-04-25 CN CN201810377395.5A patent/CN108484706A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077925A1 (en) * | 2004-02-04 | 2005-08-25 | Bristol-Myers Squibb Company | Sulfonylpyrrolodine modulators of androgen receptor fuction and method |
| CN101580529A (en) * | 2009-05-27 | 2009-11-18 | 沈阳药科大学 | Didanosine pro-medicament and preparation method thereof |
| CN105753921A (en) * | 2016-03-31 | 2016-07-13 | 沈阳药科大学 | Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| MURIEL LALANNE ET AL.: "Synthesis and biological evaluation of two glycerolipidic prodrugs of didanosine for direct lymphatic delivery against HIV", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20180904 |