CN101580529A - Didanosine pro-medicament and preparation method thereof - Google Patents

Didanosine pro-medicament and preparation method thereof Download PDF

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CN101580529A
CN101580529A CNA2009100117495A CN200910011749A CN101580529A CN 101580529 A CN101580529 A CN 101580529A CN A2009100117495 A CNA2009100117495 A CN A2009100117495A CN 200910011749 A CN200910011749 A CN 200910011749A CN 101580529 A CN101580529 A CN 101580529A
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didanosine
pro
medicament
amino acid
carbobenzoxy
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何仲贵
孙进
许佑君
闫中天
施世良
付强
林琳
常燕南
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Shenyang Pharmaceutical University
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Priority to PCT/CN2010/070253 priority patent/WO2010135918A1/en
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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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61P31/18—Antivirals for RNA viruses for HIV

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Abstract

The invention belongs to the technical field of medicaments, and discloses a substituted L-amino acid ester pro-medicament of an anti-AIDS medicament-didanosine and a preparation method thereof. The invention performs purposeful structural modification on the didanosine, ensures that the didanosine is combined with different amino acids, and designs and synthesizes a compound of a (I) structure, namely a didanosine pro-medicament. Compared with oral didanosine, the bioavailability of the compound is obviously improved and is equivalent to that of intravenously administrable didanosine. The pro-medicament and the preparation method are expected to develop a carrier pro-medicament with better therapeutic effect for treating AIDS. In the (I), R is L-type amino acid residue, and the L-type amino acid residue is preferably selected from L-valine, L-isoleucine, L-phenylalanine, L-proline and L-tryptophan.

Description

Didanosine pro-medicament and preparation method thereof
Technical field:
The invention belongs to medical technical field, relate to Didanosine pro-medicament and preparation method thereof, be specifically related to a kind of anti-medicine for treating AIDS 2 ', 3 '-dideoxyinosine (i.e. " didanosine ") 5 ' and replace L-amino acid ester prodrug and preparation method thereof.
Background technology:
Its chemical name of didanosine is 2 ', 3 '-dideoxy inosine.Didanosine is the nucleoside medicine of synthetic, compares with natural adenosine, and the latter's 3 '-hydroxyl becomes hydrogen.Didanosine be formed with after by the cell kinase phosphorylation active metabolite 5 '-the triphosphoric acid ddAdo.5 '-triphosphoric acid ddAdo suppresses hiv reverse transcriptase, and its mechanism comprises and the competition of natural substrate Deoxy-ATP, and is incorporated into viral DNA, the prolongation of termination DNA chain.Didanosine was listing in 1991.But didanosine decomposes under acidic conditions easily, and polarity is big, and the membrane permeability of small intestine is poor, causes its oral administration biaavailability to have only 20～40%.Therefore be necessary to seek the oral administration biaavailability that a kind of approach improves didanosine." natural according to the lot of documents report
Figure A20091001174900031
-amino acid can be realized active transport in vivo, it is linked to each other with the drug effect molecule as kinetophore, often can promote the absorption and the transhipment of pharmacophore, even can also improve the target of medicine, according to antiviral amino acid ester prodrugs such as valacyclovir that has gone on the market and valganciclovirs, this patent is intended didanosine 5 ' free hydroxyl is carried out in addition
Figure A20091001174900032
Amino acid modified, absorb bad shortcoming to overcome drug oral.
Summary of the invention:
The object of the present invention is to provide a kind of 5 '-O-L-amino acid ester of 2 ', 3 '-dideoxy inosine, just 5 ' of didanosine-O-L-amino acid ester and its preparation method.
Described didanosine 5 '-O-L-amino acid ester general structure is:
Figure A20091001174900033
Wherein R is the L amino-acid residue.
Described didanosine 5 '-O-L-amino acid ester comprises following compound:
A.5 '-and O-L-valyl didanosine (IV), structure is as follows:
Figure A20091001174900034
B.5 '-and O-L-isoleucyl-didanosine (V), structure is as follows:
Figure A20091001174900041
C.5 '-and O-L-phenylalanyl didanosine (VI), structure is as follows:
Figure A20091001174900042
D.5 '-and O-L-prolyl didanosine (VII), structure is as follows:
Figure A20091001174900043
E.5 '-and O-L-tryptophyl didanosine (VIII), structure is as follows:
Didanosine pro-medicament of the present invention prepares by the following method: the amino acid of didanosine and protection is at dicyclohexylcarbodiimide and N; under the dinethylformamide catalytic condition; be carried out to the ester reaction; and then catalytic hydrogenation sloughs protecting group and forms didanosine L-amino acid ester prodrug, and reaction formula is as follows:
Figure A20091001174900051
Wherein X is the amino acid of carbobenzoxy-(Cbz) protection, and Y is that carbobenzoxy-(Cbz) is protected amino acid whose residue, and R is the L-amino-acid residue.The preferred N-carbobenzoxy-(Cbz) of X-L-Xie Ansuan, N-carbobenzoxy-(Cbz)-L-Isoleucine, N-carbobenzoxy-(Cbz)-L-phenylalanine, N-carbobenzoxy-(Cbz)-L-proline(Pro) and N-carbobenzoxy-(Cbz)-L-tryptophane.
The concrete synthetic method of 5 ' of didanosine-O-L-amino acid ester is carried out according to following general routes outlined:
The first step: 50
Figure A20091001174900052
The acid of N-benzyloxycarbonyl amino and 50mmol dicyclohexylcarbodiimide and 5mmol N, the N-4-Dimethylamino pyridine is added to the N of 11.8g (50mmol) didanosine respectively, in dinethylformamide (250ml) solution, add the back and continue reaction 8 hours, temperature of reaction is a room temperature.After reaction finishes, suction filtration, the N in the pressure reducing and steaming filtrate, dinethylformamide, the resistates acetic acid ethyl dissolution is used distilled water, saturated sodium bicarbonate then successively, the saturated common salt washing, collect ethyl acetate layer, the dry post of Sodium Persulfate, filtrate evaporate to dryness, solid re-crystallizing in ethyl acetate, obtain compound (III), structure is as follows:
Figure A20091001174900053
Wherein Y is the amino acid whose residue of N-carbobenzoxy-(Cbz)-L-.N-carbobenzoxy-(Cbz)-L-amino acid is preferred following several: N-carbobenzoxy-(Cbz)-L-Xie Ansuan, N-carbobenzoxy-(Cbz)-L-Isoleucine, N-carbobenzoxy-(Cbz)-L-phenylalanine, N-carbobenzoxy-(Cbz)-L-proline(Pro) and N-carbobenzoxy-(Cbz)-L-tryptophane.
Second step: 10mmol (III) joined in the 250ml anhydrous ethyl acetate, agitation condition adds an amount of 5% palladium carbon (W/W) down and makes catalyzer, carries out catalytic hydrogenation under the hydrogen condition, and 60 ℃ were reacted 5 hours, filter, the filtrate decompression evaporate to dryness obtains compound (IV)-(VIII).
Advantage of the present invention: the present invention has synthesized serial didanosine 5 '-O-L-amino acid ester for the first time, and the preparation method is simple, easily row.Wherein after the oral administration of compound (IV), didanosine is suitable with tail vein injection at the intravital absolute bioavailability of rat, is expected to develop the prodrug of the better anti-HIV of oral administration biaavailability.
Description of drawings:
Fig. 1 be in the rat body didanosine through the time Plasma Concentration figure
Embodiment:
According to above-mentioned general synthetic route, make the compound (seeing Table 2) of embodiment 1-5 respectively.
Embodiment 1:
N-carbobenzoxy-(Cbz)-L-Xie Ansuan and didanosine reaction, add dicyclohexylcarbodiimide and N, the N-4-Dimethylamino pyridine, reaction solvent is anhydrous tetrahydro furan, methylene dichloride, hexanaphthene or dimethyl formamide, temperature of reaction be 0 ℃ to solvent boiling point, preferred 20～60 ℃, 8 hours reaction times; Reaction solution is cooled to room temperature, the pressure reducing and steaming solvent, resistates is with ethyl acetate or dichloromethane extraction, and successively with distilled water, saturated sodium bicarbonate and saturated common salt washing, collected organic layer, the dry post of Sodium Persulfate, behind the filtrate evaporate to dryness, with ethyl acetate or methylene dichloride recrystallization, recrystallized product, do under the solvent in ethyl acetate or methylene dichloride, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 5 hours reaction times, suction filtration, pressure reducing and steaming filtrate promptly gets (IV.)
Embodiment 2:
N-carbobenzoxy-(Cbz)-L-Isoleucine and didanosine reaction, add dicyclohexylcarbodiimide and N, the N-4-Dimethylamino pyridine, reaction solvent is anhydrous tetrahydro furan, methylene dichloride, hexanaphthene or dimethyl formamide, temperature of reaction be 0 ℃ to solvent boiling point, preferred 20～60 ℃, 8 hours reaction times; Reaction solution is cooled to room temperature, the pressure reducing and steaming solvent, resistates is with ethyl acetate or dichloromethane extraction, and successively with distilled water, saturated sodium bicarbonate and saturated common salt washing, collected organic layer, the dry post of Sodium Persulfate, behind the filtrate evaporate to dryness, with ethyl acetate or methylene dichloride recrystallization, recrystallized product, do under the solvent in ethyl acetate or methylene dichloride, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 5 hours reaction times, suction filtration, pressure reducing and steaming filtrate promptly gets (V.)
Embodiment 3:
N-carbobenzoxy-(Cbz)-L-phenylalanine and didanosine reaction, add dicyclohexylcarbodiimide and N, the N-4-Dimethylamino pyridine, reaction solvent is anhydrous tetrahydro furan, methylene dichloride, hexanaphthene or dimethyl formamide, temperature of reaction be 0 ℃ to solvent boiling point, preferred 20～60 ℃, 8 hours reaction times; Reaction solution is cooled to room temperature, the pressure reducing and steaming solvent, resistates is with ethyl acetate or dichloromethane extraction, and successively with distilled water, saturated sodium bicarbonate and saturated common salt washing, collected organic layer, the dry post of Sodium Persulfate, behind the filtrate evaporate to dryness, with ethyl acetate or methylene dichloride recrystallization, recrystallized product, do under the solvent in ethyl acetate or methylene dichloride, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 5 hours reaction times, suction filtration, pressure reducing and steaming filtrate promptly gets (VI.)
Embodiment 4:
N-carbobenzoxy-(Cbz)-L-proline(Pro) and didanosine reaction, add dicyclohexylcarbodiimide and N, the N-4-Dimethylamino pyridine, reaction solvent is anhydrous tetrahydro furan, methylene dichloride, hexanaphthene or dimethyl formamide, temperature of reaction be 0 ℃ to solvent boiling point, preferred 20～60 ℃, 8 hours reaction times; Reaction solution is cooled to room temperature, the pressure reducing and steaming solvent, resistates is with ethyl acetate or dichloromethane extraction, and successively with distilled water, saturated sodium bicarbonate and saturated common salt washing, collected organic layer, the dry post of Sodium Persulfate, behind the filtrate evaporate to dryness, with ethyl acetate or methylene dichloride recrystallization, recrystallized product, do under the solvent in ethyl acetate or methylene dichloride, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 5 hours reaction times, suction filtration, pressure reducing and steaming filtrate promptly gets (VII.)
Embodiment 5:
N-carbobenzoxy-(Cbz)-L-tryptophane and didanosine reaction, add dicyclohexylcarbodiimide and N, the N-4-Dimethylamino pyridine, reaction solvent is anhydrous tetrahydro furan, methylene dichloride, hexanaphthene or dimethyl formamide, temperature of reaction be 0 ℃ to solvent boiling point, preferred 20～60 ℃, 8 hours reaction times; Reaction solution is cooled to room temperature, the pressure reducing and steaming solvent, resistates is with ethyl acetate or dichloromethane extraction, and successively with distilled water, saturated sodium bicarbonate and saturated common salt washing, collected organic layer, the dry post of Sodium Persulfate, behind the filtrate evaporate to dryness, with ethyl acetate or methylene dichloride recrystallization, recrystallized product, do under the solvent in ethyl acetate or methylene dichloride, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 5 hours reaction times, suction filtration, pressure reducing and steaming filtrate promptly gets (VIII.)
The research of embodiment 6:Sprague-Dawley rat interior medicine dynamics
Irritating stomach (II) respectively for experimental group and control group Sprague-Dawley rat is didanosine and compound (IV.) i.e. 5 '-O-L-valyl didanosine (being 30mg/Kg in didanosine), the concentration of didanosine in the mensuration rat plasma.Give the Sprague-Dawley rat tail vein injection didanosine physiological saline aqueous solution (5mg/Kg) simultaneously.Can be drawn by table 1 and Fig. 1, compound IV is compared bioavailability with oral didanosine and is significantly improved, and suitable with intravenously administrable didanosine bioavailability, has reached the desired design purpose.
Behind table 1 difference oral (IV) and the didanosine, the pharmacokinetic parameters (in didanosine 30mg/Kg) of didanosine in the rat body
Figure A20091001174900071
Figure A20091001174900081

Claims (6)

1, Didanosine pro-medicament is characterized in that: 5 ' hydroxyl of didanosine is by the esterification of L-amino acid, and its general structure is as follows:
Figure A2009100117490002C1
Wherein R is the L amino-acid residue.
2, according to the described Didanosine pro-medicament of claim 1, it is characterized in that described prodrug is that didanosine and amino acid form by the ester bond link, wherein the preferred L-Xie Ansuan of R, L-Isoleucine, L-phenylalanine, L-proline(Pro) or L-tryptophane.
3, a kind of preparation method of Didanosine pro-medicament as claimed in claim 1 or 2; it is characterized in that: the amino acid of didanosine and protection is at dicyclohexylcarbodiimide and N; under the dinethylformamide catalytic condition; be carried out to the ester reaction; and then catalytic hydrogenation sloughs protecting group and forms didanosine L-amino acid ester prodrug, and reaction formula is as follows:
Figure A2009100117490002C2
4, according to the described preparation method of claim 3, it is characterized in that: wherein X is the amino acid of carbobenzoxy-(Cbz) protection, and Y is that carbobenzoxy-(Cbz) is protected amino acid whose residue, and R is the L-amino-acid residue.
5, according to the described preparation method of claim 4, it is characterized in that: the preferred N-carbobenzoxy-(Cbz) of X-L-Xie Ansuan, N-carbobenzoxy-(Cbz)-L-Isoleucine, N-carbobenzoxy-(Cbz)-L-phenylalanine, N-carbobenzoxy-(Cbz)-L-proline(Pro) and N-carbobenzoxy-(Cbz)-L-tryptophane.
6, the purposes of the described Didanosine pro-medicament of claim 1 in the preparation inverase.
CNA2009100117495A 2009-05-27 2009-05-27 Didanosine pro-medicament and preparation method thereof Pending CN101580529A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135918A1 (en) * 2009-05-27 2010-12-02 沈阳药科大学 Didanosine precursor drug and its preparation method
CN108484706A (en) * 2018-04-25 2018-09-04 中国医科大学附属第四医院 Didanosine intends meat poisoning bases prodrug and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4935394A (en) * 1972-07-31 1974-04-01
US20060241017A1 (en) * 2003-07-29 2006-10-26 Chandran V R Novel compounds with high therapeutic index

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101580529A (en) * 2009-05-27 2009-11-18 沈阳药科大学 Didanosine pro-medicament and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4935394A (en) * 1972-07-31 1974-04-01
US20060241017A1 (en) * 2003-07-29 2006-10-26 Chandran V R Novel compounds with high therapeutic index

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135918A1 (en) * 2009-05-27 2010-12-02 沈阳药科大学 Didanosine precursor drug and its preparation method
CN108484706A (en) * 2018-04-25 2018-09-04 中国医科大学附属第四医院 Didanosine intends meat poisoning bases prodrug and preparation method thereof

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Application publication date: 20091118