CN102924550A - Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof - Google Patents

Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof Download PDF

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CN102924550A
CN102924550A CN2012103857243A CN201210385724A CN102924550A CN 102924550 A CN102924550 A CN 102924550A CN 2012103857243 A CN2012103857243 A CN 2012103857243A CN 201210385724 A CN201210385724 A CN 201210385724A CN 102924550 A CN102924550 A CN 102924550A
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decitabine
amino acid
carbobenzoxy
cbz
amino
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CN102924550B (en
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孙进
何仲贵
张又夕
王永军
孙英华
刘晓红
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicine, and discloses a decitabine 5'-O-amino-acid ester prodrug for treating myelodysplastic syndrome and a preparation method thereof. The decitabine is subjected to purposeful structure modification, so that the decitabine is combined with different amino acids, thereby designing and synthesizing the compound decitabine 5'-O-amino-acid ester prodrug disclosed as (I). In (I), R is an amino acid, preferably L-valine, D-valine, L-isoleucine, L-phenylalanine or L-tryptophane. Compared with oral decitabine, the invention obviously enhances the bioavailability of the prodrug, and is hopeful to develop a carrier prodrug with more definite curative effect for treating myelodysplastic syndrome.

Description

Decitabine 5 '-O-amino acid esters prodrug and preparation method thereof
Technical field
The invention belongs to medical technical field, relate to Decitabine (5-azepine-2-deoxycytidine) prodrug and preparation method thereof, be specifically related to 5 '-O-amino acid ester prodrug of a kind of 5-azepine for the treatment of myelodysplastic syndrome-2-deoxycytidine and preparation method thereof.
Background technology
The Decitabine chemical name is 5-azepine-2-deoxycytidine.Decitabine is as special dna methylation transferase inhibitor, by the deoxycytidine kinase phosphorylation, and with phosphatic form and DNA fusion, the process that methylates of reversible DNA, inducing tumor cell is to normal cell differentiation or inducing apoptosis of tumour cell.Commodity were called Dacogen to Decitabine in U.S.'s approval listing in 2006.But Decitabine polarity is large, and the small intestine membrane permeability is poor, and causing its oral administration biaavailability only is 3.9% ~ 14%.Therefore be necessary to seek the membrane permeability that a kind of approach improves Decitabine, and then improve its oral administration biaavailability.According to a large amount of bibliographical informations, if the free hydroxyl of nucleoside medicine is modified, may improve membrane permeability and the oral administration biaavailability of this class medicine.
Summary of the invention
The object of the present invention is to provide 5 '-O-amino acid ester prodrug of a kind of 5-azepine-2-deoxycytidine, namely 5 ' of Decitabine-O-amino acid esters prodrug and preparation method thereof.
5 ' of described Decitabine-O-amino acid esters prodrug general structure is:
Wherein R is amino-acid residue, and described amino-acid residue is selected from Valine, D-Val, ILE, L-Phe or L-Trp.
Described Decitabine 5 '-O-amino acid ester comprises following compound:
Figure 262485DEST_PATH_IMAGE002
. 5 '-O-L-valyl Decitabine (
Figure 59540DEST_PATH_IMAGE003
), structure is as follows:
Figure 606059DEST_PATH_IMAGE004
Figure 779552DEST_PATH_IMAGE005
. 5 '-O-D-valyl Decitabine ( )
Figure 149668DEST_PATH_IMAGE007
Figure 245800DEST_PATH_IMAGE008
. 5 '-O-L-isoleucyl-Decitabine (
Figure 895087DEST_PATH_IMAGE009
)
Figure 836816DEST_PATH_IMAGE011
. 5 '-O-L-phenylalanyl Decitabine ( )
Figure 106178DEST_PATH_IMAGE013
Figure 29134DEST_PATH_IMAGE014
. 5 '-O-L-tryptophyl Decitabine (
Figure 276576DEST_PATH_IMAGE015
)
Figure 347300DEST_PATH_IMAGE016
Decitabine 5 ' of the present invention-O-amino acid esters prodrug prepares by the following method: the amino acid of Decitabine and protection is at dicyclohexylcarbodiimide and N; under the N-4-dimethyl aminopyridine catalytic condition; carry out esterification; then carry out catalytic hydrogenation and slough protecting group formation Decitabine 5 '-O-amino acid ester prodrug, reaction formula is as follows:
Figure 338390DEST_PATH_IMAGE017
Wherein Y is the amino acid of carbobenzoxy-(Cbz) protection, and X is the residue of carbobenzoxy-(Cbz) protected amino acid, and R is amino-acid residue.The preferred N-benzyloxy-oxo-L-valine of Y, N-carbobenzoxy-(Cbz)-D-Val, N-carbobenzoxy-(Cbz)-ILE, N-carbobenzoxy-(Cbz)-L-Phe or N-carbobenzoxy-(Cbz)-L-Trp.
The concrete synthetic method of 5 ' of Decitabine-O-amino acid ester is carried out according to following general routes outlined:
The first step:
Under 0 ° of C condition, the acid of 50mmol N-benzyloxycarbonyl amino and 50mmol dicyclohexylcarbodiimide are mixed, stir 1h, drip gradually 11.8g (50mmol) Decitabine and 5mmol N with dropping funnel, the DMF of N-4-dimethyl aminopyridine (250ml) solution is after dropwising, slowly be warmed up to room temperature, continue reaction 12 hours.After reaction finishes, suction filtration, the DMF in the pressure reducing and steaming filtrate, the resistates acetic acid ethyl dissolution, then use successively distilled water,
Saturated sodium bicarbonate, ethyl acetate layer is collected in saturated common salt washing, the dry post of Sodium Persulfate, filtrate and silica gel mixed sample, evaporate to dryness, solid separates through silicagel column, ethyl acetate and sherwood oil gradient elution, obtain compound (
Figure 178170DEST_PATH_IMAGE018
), structure is as follows:
Figure 95048DEST_PATH_IMAGE019
Wherein X is N-carbobenzoxy-(Cbz)--amino-acid residue.N-carbobenzoxy-(Cbz)-amino acid is preferred following several: N-benzyloxy-oxo-L-valine, N-carbobenzoxy-(Cbz)-D-Val, N-carbobenzoxy-(Cbz)-ILE, N-carbobenzoxy-(Cbz)-L-Phe or N-carbobenzoxy-(Cbz)-L-Trp.
Second step:
10mmol (III) joined in the 100ml ethyl acetate solution, add an amount of 5% palladium carbon (W/W) under the agitation condition and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, 40 ° of C reactions of thin layer plate monitoring reaction process 6 hours, after question response is complete, filter, the filtrate decompression evaporate to dryness obtain compound (
Figure 325172DEST_PATH_IMAGE003
-
Figure 182270DEST_PATH_IMAGE015
).
The Decitabine 5 ' of the present invention's preparation-O-amino acid esters prodrug can improve membrane permeability and the oral administration biaavailability of Decitabine preferably.
Description of drawings
Fig. 1 be Decitabine and 5 ' in the rat body-O-amino acid esters prodrug through the time Plasma Concentration figure.
Embodiment
According to above-mentioned general synthetic route, the compound (seeing Table 2) of the embodiment 1-5 that makes respectively.
Embodiment 1:
N-benzyloxy-oxo-L-valine and dicyclohexylcarbodiimide reaction, reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, the N-4-dimethyl formamide, temperature of reaction is 0 ℃ to 80 ℃, preferred 0 ℃-50 ℃, the reaction times is 1 hour; This reaction solution slowly is added drop-wise to Decitabine and N, in the mixed solution of N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 ℃-40 ℃, preferred 10-30 ℃; 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, do under the solvent at ethyl acetate, methylene dichloride or Virahol, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, namely get compound (
Figure 814240DEST_PATH_IMAGE003
).
Embodiment 2:
N-carbobenzoxy-(Cbz)-D-Val and dicyclohexylcarbodiimide reaction, reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, the N-4-dimethyl formamide, temperature of reaction is 0 ℃ to 80 ℃, preferred 0 ℃-50 ℃, the reaction times is 1 hour; This reaction solution slowly is added drop-wise to Decitabine and N, in the mixed solution of N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 ℃-40 ℃, preferred 10-30 ℃; 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, do under the solvent at ethyl acetate, methylene dichloride or Virahol, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, namely get compound (
Figure 465801DEST_PATH_IMAGE006
).
Embodiment 3:
N-carbobenzoxy-(Cbz)-ILE and dicyclohexylcarbodiimide reaction, reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, the N-4-dimethyl formamide, temperature of reaction is 0 ℃ to 80 ℃, preferred 0 ℃-50 ℃, the reaction times is 1 hour; This reaction solution slowly is added drop-wise to Decitabine and N, in the mixed solution of N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 ℃-40 ℃, preferred 10-30 ℃; 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, do under the solvent at ethyl acetate, methylene dichloride or Virahol, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, namely get compound (
Figure 448800DEST_PATH_IMAGE009
).
Embodiment 4:
N-carbobenzoxy-(Cbz)-L-Phe and dicyclohexylcarbodiimide reaction, reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, the N-4-dimethyl formamide, temperature of reaction is 0 ℃ to 80 ℃, preferred 0 ℃-50 ℃, the reaction times is 1 hour; This reaction solution slowly is added drop-wise to Decitabine and N, in the mixed solution of N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 ℃-40 ℃, preferred 10-30 ℃; 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, do under the solvent at ethyl acetate, methylene dichloride or Virahol, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, namely get compound (
Figure 280228DEST_PATH_IMAGE012
).
Embodiment 5:
N-carbobenzoxy-(Cbz)-L-Trp and dicyclohexylcarbodiimide reaction, reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, the N-4-dimethyl formamide, temperature of reaction is 0 ℃ to 80 ℃, preferred 0 ℃-50 ℃, the reaction times is 1 hour; This reaction solution slowly is added drop-wise to Decitabine and N, in the mixed solution of N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 ℃-40 ℃, preferred 10-30 ℃; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, resistates 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, do under the solvent at ethyl acetate, methylene dichloride or Virahol, add Pd/C and make catalyzer, under the hydrogen condition, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, namely get compound (
Figure 829021DEST_PATH_IMAGE015
).
Example 6:
Utilize rat at body small intestine list Perfusion, choose the long jejunum in rats of 10cm, the two ends intubate. with Decitabine and compound (
Figure 854746DEST_PATH_IMAGE003
)-(
Figure 59462DEST_PATH_IMAGE015
) be dissolved in respectively Kreb-Ringer ' s nutritive medium (pH=5.5), concentration is 0.05mM, with the 0.2mL/min perfusion by jejunum in rats, obtain Decitabine and compound (
Figure 258362DEST_PATH_IMAGE003
)-(
Figure 599345DEST_PATH_IMAGE015
) in the penetrating rate of the film of jejunum.
Decitabine and compound ( )-(
Figure 54695DEST_PATH_IMAGE015
) the penetrating rate of film
Figure 729390DEST_PATH_IMAGE020
Embodiment 7:
The research of Sprague-Dawley Rats pharmacokinetics
Give experimental group and control group Sprague-Dawley rat respectively gavage (
Figure 252775DEST_PATH_IMAGE021
) be Decitabine, compound (
Figure 620303DEST_PATH_IMAGE003
) namely 5 '-O-L-valyl Decitabine and compound (
Figure 534032DEST_PATH_IMAGE012
) i.e. 5 '-O-L-phenylalanyl Decitabine (being 15mg/Kg in Decitabine), measure the concentration of Decitabine in the rat plasma.Give simultaneously the Sprague-Dawley rat tail vein injection Decitabine physiological saline aqueous solution (15mg/Kg).Can draw compound by table 1 and Fig. 1
Figure 74735DEST_PATH_IMAGE003
And compound
Figure 154424DEST_PATH_IMAGE012
Compare bioavailability with oral Decitabine and be significantly improved, reached the desired design purpose.
 
Table 1 respectively oral ( ) (
Figure 156195DEST_PATH_IMAGE012
) and Decitabine after, the pharmacokinetic parameters (in Decitabine 15mg/Kg) of Decitabine in the rat body
Figure 172693DEST_PATH_IMAGE022
Figure 670670DEST_PATH_IMAGE023
Figure 114421DEST_PATH_IMAGE024

Claims (5)

1. Decitabine 5 '-O-amino acid esters prodrug, it is characterized in that: 5 ' hydroxyl of Decitabine is by the amino acid esterification, and its general structure is as follows:
Wherein R is amino-acid residue.
2. according to Decitabine 5 ' claimed in claim 1-O-amino acid esters prodrug, it is characterized in that described prodrug is that Decitabine and amino acid are formed by connecting by ester bond, wherein the preferred Valine of R, D-Val, ILE, L-Phe or L-Trp.
3. preparation method such as claim 1 or 2 described Decitabine 5 '-O-amino acid esters prodrug; it is characterized in that: the amino acid Y of Decitabine (II) and carbobenzoxy-(Cbz) protection is at dicyclohexylcarbodiimide and N; under the N-4-dimethyl aminopyridine catalytic condition; become the ester reaction; then slough protecting group through catalytic hydrogenation and form Decitabine 5 '-O-amino acid esters prodrug (I), reaction formula is as follows:
Figure 409893DEST_PATH_IMAGE002
Wherein Y is the amino acid of carbobenzoxy-(Cbz) protection, and X is the amino-acid residue of carbobenzoxy-(Cbz) protection, and R is amino-acid residue.
4. according to preparation method claimed in claim 3, it is characterized in that: the preferred N-benzyloxy-oxo-L-valine of Y, N-carbobenzoxy-(Cbz)-D-Val N-carbobenzoxy-(Cbz)-ILE, N-carbobenzoxy-(Cbz)-L-Phe or N-carbobenzoxy-(Cbz)-L-Trp.
5. the application of claim 1 or 2 described Decitabine 5 '-O-amino acid esters prodrug in preparation treatment myelodysplastic syndrome medicine.
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CN110746476A (en) * 2019-01-11 2020-02-04 江苏豪森药业集团有限公司 5-azacytosine nucleoside compound and preparation method thereof
CN110845560A (en) * 2019-11-21 2020-02-28 广东中科药物研究有限公司 Phenylalanine amidated nucleotide derivative and preparation method and application thereof

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN110746476A (en) * 2019-01-11 2020-02-04 江苏豪森药业集团有限公司 5-azacytosine nucleoside compound and preparation method thereof
CN110845560A (en) * 2019-11-21 2020-02-28 广东中科药物研究有限公司 Phenylalanine amidated nucleotide derivative and preparation method and application thereof
CN110845560B (en) * 2019-11-21 2021-08-24 广东中科药物研究有限公司 Phenylalanine amidated nucleotide derivative and preparation method and application thereof

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