CN102924550B - 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 PDFInfo
- Publication number
- CN102924550B CN102924550B CN201210385724.3A CN201210385724A CN102924550B CN 102924550 B CN102924550 B CN 102924550B CN 201210385724 A CN201210385724 A CN 201210385724A CN 102924550 B CN102924550 B CN 102924550B
- Authority
- CN
- China
- Prior art keywords
- decitabine
- carbobenzoxy
- cbz
- amino acid
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
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
Technical field
The invention belongs to medical art, relate to Decitabine (5-azepine-2-deoxycytidine) prodrug and preparation method thereof, be specifically related to a kind ofly treat 5 '-O-amino acid ester prodrugs of 5-azepine-2-deoxycytidine of myelodysplastic syndrome and preparation method thereof.
Background technology
Decitabine chemical name is 5-azepine-2-deoxycytidine.Decitabine is as special DNA methylation transferase inhibitor, and by deoxycytidine kinase phosphorylation, in the form of phosphate with DNA fusion, the methylation procedure of reversible DNA, inducing tumor cell is to normal cell differentiation or inducing apoptosis of tumour cell.Within 2006, in U.S.'s approval listing, commodity are called Dacogen to Decitabine.But Decitabine polarity is large, and small intestine membrane permeability is poor, causes its oral administration biaavailability to be only 3.9% ~ 14%.Therefore be necessary to find a kind of approach to improve the membrane permeability of Decitabine, and then improve its oral administration biaavailability.According to a large amount of bibliographical informations, if modified the free hydroxyl of nucleoside medicine, membrane permeability and the oral administration biaavailability of this kind of medicine may be improved.
Summary of the invention
The object of the present invention is to provide 5 '-O-amino acid ester prodrugs of a kind of 5-azepine-2-deoxycytidine, namely the 5 '-O-amino acid esters prodrug and preparation method thereof of Decitabine.
5 '-O-amino acid esters pro-drugs general formula of described Decitabine 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:
. 5 '-O-L-valyl Decitabine (
), structure is as follows:
. 5 '-O-D-valyl Decitabine (
)
. 5 '-O-L-isoleucyl-Decitabine (
)
. 5 '-O-L-phenylalanyl Decitabine (
)
. 5 '-O-L-tryptophyl Decitabine (
)
Decitabine 5 '-O-amino acid esters prodrug of the present invention is prepared by the following method: the amino acid of Decitabine and protection is at dicyclohexylcarbodiimide and N; under the dimethylaminopyridine catalysed condition of N-4-; carry out esterification; then carry out catalytic hydrogenation and slough protecting group formation Decitabine 5 '-O-amino acid ester prodrugs, reaction formula is as follows:
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 '-O-amino acid ester of Decitabine is carried out according to following general routes outlined:
The first step:
Under 0 ° of C condition, by the acid of 50mmol N-benzyloxycarbonyl amino and the mixing of 50mmol dicyclohexylcarbodiimide, stir 1h, 11.8g (50mmol) Decitabine and 5mmol N is dripped gradually with dropping funnel, DMF (250ml) solution of N-4-dimethyl aminopyridine, after dropwising, slowly be warmed up to room temperature, continue reaction 12 hours.Reaction terminate after, suction filtration, the DMF in pressure reducing and steaming filtrate, residue with ethyl acetate dissolve, then use successively distilled water,
Saturated sodium bicarbonate, saturated common salt is washed, and collects ethyl acetate layer, the dry post of Sodium Persulfate, filtrate and silica gel mixed sample, evaporate to dryness, and solid is separated through silicagel column, ethyl acetate and sherwood oil gradient elution, obtain compound (
), structure is as follows:
Wherein X is N-carbobenzoxy-(Cbz)--amino-acid residue.The acid of N-benzyloxycarbonyl-amino is preferably 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:
(III) of 10mmol is joined in 100ml ethyl acetate solution, add appropriate 5% palladium carbon (W/W) under agitation condition and make catalyzer, catalytic hydrogenation is carried out under hydrogen atmosphere, thin layer plate monitoring reaction process 40 ° of C react 6 hours, after question response is complete, filter, filtrate decompression evaporate to dryness obtain compound (
-
).
Decitabine 5 '-O-amino acid esters prodrug prepared by the present invention can improve membrane permeability and the oral administration biaavailability of Decitabine preferably.
Accompanying drawing explanation
Fig. 1 be in rat body Decitabine and 5 '-O-amino acid esters prodrug thereof through time Plasma Concentration figure.
Embodiment
According to above-mentioned general synthetic routes, the compound (see table 2) of the embodiment 1-5 made respectively.
Embodiment 1:
N-benzyloxy-oxo-L-valine and dicyclohexylcarbodiimide are reacted, and reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, N-4-dimethyl formamide, and temperature of reaction is 0 DEG C to 80 DEG C, preferably 0 DEG C-50 DEG C, and the reaction times is 1 hour; This reaction solution is slowly added drop-wise in the mixed solution of Decitabine and N, N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 DEG C-40 DEG C, preferred 10-30 DEG C; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, residue with ethyl acetate or dichloromethane extraction, and successively with the washing of distilled water, saturated sodium bicarbonate and saturated common salt, collected organic layer, the dry post of Sodium Persulfate, after filtrate evaporate to dryness, under ethyl acetate, methylene dichloride or Virahol make solvent, add Pd/C and make catalyzer, under hydrogen atmosphere, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, obtain compound (
).
Embodiment 2:
N-carbobenzoxy-(Cbz)-D-Val and dicyclohexylcarbodiimide are reacted, and reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, N-4-dimethyl formamide, and temperature of reaction is 0 DEG C to 80 DEG C, preferably 0 DEG C-50 DEG C, and the reaction times is 1 hour; This reaction solution is slowly added drop-wise in the mixed solution of Decitabine and N, N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 DEG C-40 DEG C, preferred 10-30 DEG C; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, residue with ethyl acetate or dichloromethane extraction, and successively with the washing of distilled water, saturated sodium bicarbonate and saturated common salt, collected organic layer, the dry post of Sodium Persulfate, after filtrate evaporate to dryness, under ethyl acetate, methylene dichloride or Virahol make solvent, add Pd/C and make catalyzer, under hydrogen atmosphere, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, obtain compound (
).
Embodiment 3:
N-carbobenzoxy-(Cbz)-ILE and dicyclohexylcarbodiimide are reacted, and reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, N-4-dimethyl formamide, and temperature of reaction is 0 DEG C to 80 DEG C, preferably 0 DEG C-50 DEG C, and the reaction times is 1 hour; This reaction solution is slowly added drop-wise in the mixed solution of Decitabine and N, N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 DEG C-40 DEG C, preferred 10-30 DEG C; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, residue with ethyl acetate or dichloromethane extraction, and successively with the washing of distilled water, saturated sodium bicarbonate and saturated common salt, collected organic layer, the dry post of Sodium Persulfate, after filtrate evaporate to dryness, under ethyl acetate, methylene dichloride or Virahol make solvent, add Pd/C and make catalyzer, under hydrogen atmosphere, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, obtain compound (
).
Embodiment 4:
N-carbobenzoxy-(Cbz)-L-Phe and dicyclohexylcarbodiimide are reacted, and reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, N-4-dimethyl formamide, and temperature of reaction is 0 DEG C to 80 DEG C, preferably 0 DEG C-50 DEG C, and the reaction times is 1 hour; This reaction solution is slowly added drop-wise in the mixed solution of Decitabine and N, N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 DEG C-40 DEG C, preferred 10-30 DEG C; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, residue with ethyl acetate or dichloromethane extraction, and successively with the washing of distilled water, saturated sodium bicarbonate and saturated common salt, collected organic layer, the dry post of Sodium Persulfate, after filtrate evaporate to dryness, under ethyl acetate, methylene dichloride or Virahol make solvent, add Pd/C and make catalyzer, under hydrogen atmosphere, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, obtain compound (
).
Embodiment 5:
N-carbobenzoxy-(Cbz)-L-Trp and dicyclohexylcarbodiimide are reacted, and reaction solvent is anhydrous tetrahydro furan, methylene dichloride or N, N-4-dimethyl formamide, and temperature of reaction is 0 DEG C to 80 DEG C, preferably 0 DEG C-50 DEG C, and the reaction times is 1 hour; This reaction solution is slowly added drop-wise in the mixed solution of Decitabine and N, N-4-dimethyl aminopyridine.Finish, continue reaction 12 hours, temperature is 0 DEG C-40 DEG C, preferred 10-30 DEG C; Reaction solution is cooled to room temperature, pressure reducing and steaming solvent, residue with ethyl acetate
Or dichloromethane extraction, and successively with the washing of distilled water, saturated sodium bicarbonate and saturated common salt, collected organic layer, the dry post of Sodium Persulfate, after filtrate evaporate to dryness, under ethyl acetate, methylene dichloride or Virahol make solvent, add Pd/C and make catalyzer, under hydrogen atmosphere, carry out catalytic hydrogenation, reaction times is 6 hours, suction filtration, pressure reducing and steaming filtrate, obtain compound (
).
Example 6:
Utilize rat at body small intestine list Perfusion, choose the jejunum in rats that 10cm is long, two ends intubate. by Decitabine and compound (
)-(
) be dissolved in Kreb-Ringer ' s nutritive medium (pH=5.5) respectively, concentration is 0.05mM, with 0.2mL/min perfusion by jejunum in rats, obtain Decitabine and compound (
)-(
) at the film Penetration ration of jejunum.
Decitabine and compound (
)-(
) film Penetration ration
Embodiment 7:
Sprague-Dawley Rats pharmacokinetics is studied
To experimental group and control group Sprague-Dawley rat respectively gavage (
) namely Decitabine, compound (
) namely 5 '-O-L-valyl Decitabine and compound (
) i.e. 5 '-O-L-phenylalanyl Decitabine (being 15mg/Kg in Decitabine), measure the concentration of Decitabine in rat plasma.Give the Sprague-Dawley rat tail vein injection Decitabine physiological saline aqueous solution (15mg/Kg) simultaneously.Can be drawn by table 1 and Fig. 1, compound
and compound
bioavailability is significantly improved compared with oral Decitabine, reaches desired design object.
Table 1 respectively oral (
) (
) and Decitabine after, the pharmacokinetic parameters (in Decitabine 15mg/Kg) of Decitabine in rat body
Claims (3)
1. Decitabine 5 '-O-amino acid esters prodrug, is characterized in that: 5 ' position hydroxyl of Decitabine is by amino acid esterification, and its general structure is as follows:
Wherein R is amino-acid residue, and described prodrug is that Decitabine and amino acid are formed by connecting by ester bond, and wherein R is Valine, D-Val, ILE, L-Phe or L-Trp.
2. the preparation method of Decitabine 5 '-O-amino acid esters prodrug as claimed in claim 1; it is characterized in that: the amino acid Y of Decitabine (II) and carbobenzoxy-(Cbz) protection is at dicyclohexylcarbodiimide and N; under the dimethylaminopyridine catalysed condition of N-4-; carry out into ester reaction; then slough protecting group through catalytic hydrogenation and form Decitabine 5 '-O-amino acid esters prodrug (I), reaction formula is as follows:
Wherein Y is 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, X is N-benzyloxycarbonyl-amino acid residue, described N-benzyloxycarbonyl-amino acid residue is: 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, R is amino-acid residue, described amino-acid residue is: Valine, D-Val, ILE, L-Phe or L-Trp.
3. the application of Decitabine 5 '-O-amino acid esters prodrug according to claim 1 in preparation treatment myelodysplastic syndrome medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210385724.3A CN102924550B (en) | 2012-10-12 | 2012-10-12 | Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210385724.3A CN102924550B (en) | 2012-10-12 | 2012-10-12 | Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102924550A CN102924550A (en) | 2013-02-13 |
| CN102924550B true CN102924550B (en) | 2015-02-04 |
Family
ID=47639500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210385724.3A Active CN102924550B (en) | 2012-10-12 | 2012-10-12 | Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102924550B (en) |
Families Citing this family (3)
| 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 |
| 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 |
| CN116178292A (en) * | 2022-05-20 | 2023-05-30 | 吴卫东 | Fluoroalkyl and aza group substituted nucleoside analogue precursor, its synthesis method and medical use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840538A (en) * | 2005-04-01 | 2006-10-04 | 李伟章 | 1-(2'-deoxy-2'-fluoro-3'-O-amino acid ester-beta-L-furyl arabinosyl)-5-methyl uracil and its application |
| US20060241017A1 (en) * | 2003-07-29 | 2006-10-26 | Chandran V R | Novel compounds with high therapeutic index |
| CN101812105A (en) * | 2009-02-25 | 2010-08-25 | 沈阳药科大学 | Cytarabine 5'-O-amino-acid ester, salts thereof and preparation method thereof |
-
2012
- 2012-10-12 CN CN201210385724.3A patent/CN102924550B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060241017A1 (en) * | 2003-07-29 | 2006-10-26 | Chandran V R | Novel compounds with high therapeutic index |
| CN1840538A (en) * | 2005-04-01 | 2006-10-04 | 李伟章 | 1-(2'-deoxy-2'-fluoro-3'-O-amino acid ester-beta-L-furyl arabinosyl)-5-methyl uracil and its application |
| CN101812105A (en) * | 2009-02-25 | 2010-08-25 | 沈阳药科大学 | Cytarabine 5'-O-amino-acid ester, salts thereof and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Xueqin Song,等.Amino Acid Ester Prodrugs of the Anticancer Agent Gemcitabine: Synthesis, Bioconversion, Metabolic Bioevasion, and hPEPT1-Mediated Transport.《MOLECULAR PHARMACEUTICS》.2005,第2卷(第2期),第157-167页. * |
| 谭昀杜熙,等.治疗骨髓增生异常综合征新药-地西他滨.《中国新药杂志》.2010,第19卷(第2期),第91-94页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102924550A (en) | 2013-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3582784B1 (en) | Processes for the preparation of benzodiazepine derivatives | |
| KR20200086696A (en) | Separation method of benzodiazepin-2-one and benzoazepin-2-one derivatives | |
| KR20140053330A (en) | Process and intermediates for preparing macrolactams | |
| CN113563414B (en) | Tissue-targeted protein targeted degradation compound and application thereof | |
| CN101812105A (en) | Cytarabine 5'-O-amino-acid ester, salts thereof and preparation method thereof | |
| CN102924550B (en) | Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof | |
| CN105503739A (en) | Preparation method of high-purity olaparib | |
| CN104292158B (en) | Preparation method, detecting method and application of moxifloxacin hydrochloride impurity | |
| CN101250209B (en) | Alexan 5'-O-amino acid ester hydrochloride and preparation method thereof | |
| WO2016184361A1 (en) | Anti-hepatitis c virus nucleoside compound and use thereof | |
| Meltzer et al. | Synthesis and structure–activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists | |
| CN106632335A (en) | Preparation method of valaciclovir hydrochloride | |
| CN103864885B (en) | The application of 1-hydroxyl-1,2,3-phentriazine-4 (3H)-one in Peptide systhesis | |
| CN104774161B (en) | Polypeptide, protein PEG dressing agent synthetic methods | |
| CN106928217A (en) | A kind of Analogue of moxifloxacin and preparation method thereof, purposes | |
| CN105273023B (en) | A kind of preparation method of 5 '-O-L- valinate hydrochlorides of cytarabine | |
| CN110914243B (en) | As AT 2 Carboxylic acid derivatives of R receptor antagonists | |
| CN106905193A (en) | Aroyl guanidine radicals Oseltamivir carboxylic acid derivates and its preparation method and application | |
| CN109111386A (en) | The synthetic method of L- prolineamide | |
| CN103012233A (en) | Preparation method of N-(amino sulfo methyl)-5-oxo-1-propyl-2-pyrrolidine acetamide | |
| CN112209884B (en) | 1-H benzimidazole derivative, preparation method and application thereof | |
| CN101580529A (en) | Didanosine pro-medicament and preparation method thereof | |
| CN109280044A (en) | Raltitrexed impurity C and its preparation and application | |
| CN115368333B (en) | Ibuprofen-coumarin skeleton-containing compound and application thereof | |
| CN104447763B (en) | Biphenyl tetrazole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |