CN1298880A - Cyanoribofuranoside compound and its preparing process - Google Patents
Cyanoribofuranoside compound and its preparing process Download PDFInfo
- Publication number
- CN1298880A CN1298880A CN 00127905 CN00127905A CN1298880A CN 1298880 A CN1298880 A CN 1298880A CN 00127905 CN00127905 CN 00127905 CN 00127905 A CN00127905 A CN 00127905A CN 1298880 A CN1298880 A CN 1298880A
- Authority
- CN
- China
- Prior art keywords
- cyano group
- nucleoside
- ribofuranose
- benzoyl
- bromo
- 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.)
- Granted
Links
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an cyanofuran nucleotide compound and its preparation method. Said cyanofuran nucleotide compound and bionucleotide possess betler chemical similarity, the selected glycon and active base all naturally exist and can reduce toxic side effect. The in-vitro pharmacological activity experiments has shown that the invented cyanofuran nucleotide possesses very strong resistance to K562 blood cancer.
Description
The present invention relates to a kind of furan and feed nucleoside compound, and the preparation method of this compound.
Nucleoside compound has antitumor significantly, antivirus action.At present existing many documents and this compounds of patent disclosure, as:
Document New Engl, Med.1987,317,192 reports, 1987 by food and drug administration approval for be used for the treatment of immunodeficiency virus (HIV) be medicine one zidovudine that infects of HIV (human immunodeficiency virus) (Zidovudine, AZT), its structural formula is:
Be nucleoside compound.
But along with the life-time service of AZT in clinical, find it when prolonging life and improving symptom, exist the inhibition medullary cell, cause leukopenic side effect, and resistance occurs.
And for example document Drugs 1990,39, the nucleoside compound cytosine arabinoside (Ara-C) that is used for the treatment of acute leukemia and lymphatic cancer of 489 reports:
The remission rate that this compound can make acute leukemia brings up to 80% from original 20%, but exists easily in vivo by the defective of enzymolysis inactivation.
Therefore provide a kind of new nucleoside compound, will have crucial meaning.
One of purpose of the present invention is to disclose a kind of cyano group furans nucleoside compound, to overcome the existing existing defective of nucleoside compound, satisfies the needs of medicine industry.
Two of purpose of the present invention is to provide the preparation method of the disclosed compound of one of purpose.
Technical conceive of the present invention is such:
Late nineteen eighties the early 1990s, American-European countries has reported 2-at the ribofuranose parent for exploitation nucleosides new drug, 3-, the 4-position is that the furans nucleoside compound of cyano group has antiviral activity, as in the AZT structure-N
3Modification structure after quilt-CN replaces, even more effective, but these compounds or there is no biological activity than AZT, or toxicity is higher.The contriver thinks that its major cause is to make it be difficult to bring into play effect owing to lacking the enzyme that above-mentioned cyano group furans nucleosides is carried out triphosphoric acidization in the human body cell.Consider that the obstructed peroxophosphoric acidization of natural ketoside U-9586 (Psicofuranine) can bring into play biological effect,, have two active groups on the 1-position of furyl glycosyl simultaneously from its structure.Thus, contriver's imagination, feeding ribose with furan is parent (identical with naturally occurring structure), introduces active group-CN and activated base (as thymus pyrimidine in the human DNA and purine etc.) on the 1-position simultaneously, makes designed structure with important biological nucleosides better chemical similarity be arranged.And on the 1-position-CN is expected the active group as the natural U-9586 on the 1-position, can brings into play its biological effect without phosphorylation.
The said cyano group furan of the present invention is fed nucleoside compound, and its general structure is as follows:
Formula 1 or
Formula 2
The preparation of compound shown in the formula 1 comprises the steps:
(1) pyrimidine nucleoside is synthetic:
With parent 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in the solvent, adds molecular sieve and refluxes 0.5～1.5 hour, and cooling adds 2,4-two-(front three silica)-pyrimidine and Hg (CN) more then
2, under 60～80 ℃ condition, reacted 1～1.5 hour, from reactant, collect the white powder pyrimidine nucleoside then.Its reaction formula is:
Said solvent is CH
3NO
2, CH
3CN, CH
2Cl
2In a kind of, preferred CH
3NO
2
1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 2,4-two-(front three silica)-pyrimidine and Hg (CN)
2Molar ratio be:
1: (1.4～1.8): (1.0～1.8), preferred ratio is: 1: 1.6: 1.4.
Said parent 1-bromo-1-cyano group-2,3, the synthetic of 5-three-O-benzoyl-β-D-ribofuranose can be adopted prior art, this compound synthetic at document Tetrahedron Letters, 1982,2,237 and Tetrahedron, 1993,49 (38), 8579 report; Said 2,4-two-(front three silica)-pyrimidine synthetic at document Nucleosides ﹠amp; Nucleotides reports in 1994,13 (5), 1201 and J.Org.Chem., 1985,50 (19), 3644, so the present invention all repeats no more.
(2) deprotection of pyrimidine nucleoside:
The pyrimidine nucleoside that step (1) is obtained places the reaction that is hydrolyzed of basic solution and alcohols material; can remove the blocking group on the pyrimidine nucleoside, finally obtain target product, be i.e. 1-cyano group-2; 3,5-three-hydroxyl-1-(1 '-uridylic)-β-furans nucleosides.Preferred alcohols material is CH
3OH, CH
3CH
2A kind of and composition thereof among the OH, said basic solution is the ammoniacal liquor or the NaOH aqueous solution, and its preferred concentration is 20%～30%, and reaction formula is as follows:
The processing condition of reaction are such:
Stirring at room 7～10 hours, the mol ratio of pyrimidine nucleoside and alcohols are (5～8): 1.The preparation of the compound shown in the formula 2 comprises the steps:
(1) purine nucleoside is synthetic:
With parent 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in CH
3NO
2In, adding molecular sieve and refluxed 0.5～1.5 hour, cooling adds 6-chloropurine and Hg (CN) more then
2, under 100～120 ℃ condition, reacted 2～3 hours, from reactant, collect the white powder purine nucleoside then.Its reaction formula is:
Said solvent is CH
3NO
2, CH
3CN, CH
2Cl
2In a kind of, preferred CH
3NO
2
1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 6-chloropurine and Hg (CN)
2Mol ratio be: 1: (2.4～3.0): (0.5～0.9), preferred ratio is: 1: 2.6: 0.7.
Said parent 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-furan are fed the synthetic of ribose can adopt prior art, this compound synthetic at document Tetrahedron Letters, 1982,2,237 and Tetrahedron, 1993,49 (38), 8579 report; Said 6-chloropurine is the commercial goods, so the present invention all repeats no more.
(2) deprotection of purine nucleoside
The purine nucleoside that step (1) is obtained places the reaction that is hydrolyzed of basic solution and alcohols material; can remove the blocking group on the purine nucleoside, finally obtain target product, be i.e. 1-cyano group-2; 3,5-three-hydroxyl-1-(1 '-adenine)-β-furans nucleosides.Preferred alcohols material is CH
3OH, CH
3CH
2A kind of and composition thereof among the OH, said basic solution is ammoniacal liquor, the NaOH aqueous solution, and its concentration is 20%～30%, and reaction formula is as follows:
The processing condition of reaction are such:
Stirring at room 1～2.5 hour, the mol ratio of pyrimidine nucleoside and alcohols are (5～8): 1.
The present invention's said cyano group furans nucleoside compound and biological nucleosides have the better chemical similarity, selected glycosyl and activated base are natural existence, can reduce toxic side effect, double-active group on the 1-position will be expected to increase its biological activity, and be expected to bring into play in vivo without triphosphoric acidization effect.Through external pharmacologically active test, confirm that cyano group furans nucleoside compound of the present invention has very strong anti-K562 leukemia effect, therefore, compound of the present invention will have very wide application prospect.
Below will relevant details of the present invention be further described by embodiment.
Embodiment 1
Synthesizing of compound shown in the formula 1:
With 270mg1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in 8mlCH
3NO
2, add 4A molecular sieve 160mg, be heated to 120 ℃, refluxed 0.5 hour, solution is cooled to 60 ℃ again, add 200mg2,4-two-(front three silica)-pyrimidine and 175mg Hg (CN)
2, 60 ℃ of reaction 95min, cooled and filtered, the filtrate evaporation concentration is removed CH
3NO
2, enriched material separates (normal hexane: diethyl ether solution=1: 1), promptly obtain white powder intermediate pyrimidine nucleoside 245mg (yield 86%) with the chromatography column method;
Get the pyrimidine nucleoside 340mg that obtains by above-mentioned experiment, add 4ml methyl alcohol, 6ml25% ammoniacal liquor stirred 10.0 hours under the room temperature, and original suspension becomes clarification.Solution concentration is removed and is desolvated, and adds an amount of ethanol coevaporation, adds the 3.5ml frozen water then, and the white depositions that forms is filtered.After filtrate was freezing, moisture was removed in the low pressure evaporation.Residue separates (chloroform/15% methyl alcohol) with column chromatography, and the white crystals that obtains is the compound shown in the formula 1 (yield 66%).
R
f(0.18 chloroform/15% methyl alcohol)
m.p.120～121℃[α]
D 19=-21.28(C0.00059667,CH
3OH)
UV(95％EtOH):257nm
IR(KBr)νcm
-1:3431,1687,1452,1296,1095,1041,939,818
1H?NMR(d
6-DMSO):
δ11.62(S,1H,NH),8.08(d,1H,J
6,5=8.5Hz,H-6),6.75(d,1H,J
2’,OH
=5.9Hz,OH-2’),5.64(d,1H,H-5),5.26(t,2H,OH-5’,OH-3’),
4.37(d,1H,J
2,3’=4.1Hz,H-2’),4.13(m,1H,H-4’),3.82～3.91
(m, 2H, H-3 ' and H-5 ' a), 3.56 (d, 1H, J
5 ' b, 5 ' a=12.9Hz, H-5 ' b).
MS (FAB): 270 (MH
+), 243 (MH
+-HCN),
Ultimate analysis: C
10H
11N
3O
6
C H N
Calculated value 44.61 4.12 15.61
Measured value 44.39 4.17 15.52
This compound is 10
-1During μ M, be 14.9% to the inhibiting rate of tumour cell SGC-7901.
Embodiment 2
Synthesizing of compound shown in the formula 2:
With 350mg1-bromo-1-cyano group-2,3,5-three-oxygen-benzoyl base-β-D-ribofuranose is dissolved in 10mlCHN
3O
2, add 4A molecular sieve 250mg.In 115 ℃ of backflows 0.5 hour, in solution, add 150mg6-chloropurine and 225mgHg (CN) again under the Ar gas shiled
2, 115 ℃ were reacted 1 hour down.Cooled and filtered, filtrate concentrate to remove and desolvate, and residue separates (normal hexane: anhydrous diethyl ether=1: 3～1: 1), can obtain the intermediate purine nucleoside 310mg (yield 78%) of white powder with column chromatography.
Get the purine nucleoside 340mg that obtains by above-mentioned experiment, add 4ml methyl alcohol, 6ml25% ammoniacal liquor stirred 1.0 hours under the room temperature, and original suspension becomes clarification.Solution concentration is removed and is desolvated, and adds an amount of ethanol coevaporation, adds the 3.5ml frozen water then, and the white depositions that forms is filtered.After filtrate was freezing, moisture was removed in the low pressure evaporation.Residue separates (chloroform/15% methyl alcohol) with column chromatography, can obtain the compound shown in the formula 2 (yield 55%).
R
f(0.42 chloroform/15% methyl alcohol)
m.p.124～125℃[α]
D 19=-117.31(C0.00052,CH
3OH)
UV(95％EtOH):262.5nm
IR(KBr)v?cm
-1:3415,1672,1593,1560,1095,947,910
1HNMR(d
6-DMSO):
δ8.80(s,1H,H-2),8.67(s,1H,H-8),8.35(s,2H,NH
2-6),6.04
(d,1H,J
2’,OH=5.6Hz,OH-2’),5.68(dd,1H,J
2,3=3.5Hz,H-2’),
5.22(d,1H,OH-5’),4?68(t,1H,OH-3’),4.07～4.18(m,3H,H-4’,
H-3’,H-5’a),3.63(m,1H,H-5’b)。
13C?NMR(d
6-DMSO)：
165.36(C-6),151.30(C-2),150.87(C-4),149?25(C-5),145.45(C-8),
131.16(C≡N),95.33(C-1’),84.69(C-4’),72.07(C-2’),66?93(C-3’),
59.22(C-5’)
MS(FAB):294(M+2H
+)
Ultimate analysis: C
11H
12N
6O
4
C H N
Calculated value 45.20 4.14 28.76
Measured value 45.02 4.24 28.56
This compound is 10
-1During μ M, be 100% to the inhibiting rate of human leukemia K562.
Claims (6)
1. cyano group furans nucleoside compound is characterized in that structural formula is as follows:
2. cyano group furans nucleoside compound is characterized in that structural formula is as follows:
3. the preparation method of compound as claimed in claim 1 is characterized in that in turn including the following steps: (1) pyrimidine nucleoside synthetic:
With 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in the solvent, adds 2 again, 4-two-(front three silica)-pyrimidine and Hg (CN)
2, under 60～80 ℃ condition, reacted 1～1.5 hour, from reactant, collect the white powder pyrimidine nucleoside then;
Said solvent is CH
3NO
2, CH
3CN or CH
2Cl
2In a kind of;
1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 2,4-two-(front three silica)-pyrimidine and Hg (CN)
2Mol ratio be: 1: (1.4～1.8): (1.0～1.8);
(2) deprotection of pyrimidine nucleoside:
The pyrimidine nucleoside that step (1) is obtained places the reaction that is hydrolyzed of basic solution and alcohols material, obtains target product, i.e. 1-cyano group-2,3, and 5-three-hydroxyl-1-(1 '-uridylic)-β-furans nucleosides, the processing condition of reaction:
Stirring at room 7～10 hours, the mol ratio of pyrimidine nucleoside and alcohols are (5～8): 1.
4. preparation method as claimed in claim 3 is characterized in that, with parent 1-bromo-1-cyano group-2; 3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in the solvent, adds molecular sieve and refluxes 0.5～1.5 hour; building-up reactions is being carried out in the cooling back, and solvent is CH
3NO
2Alcohols material is CH
3OH or CH
3CH
2OH and composition thereof, said basic solution are the ammoniacal liquor or the NaOH aqueous solution; 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 2,4-two-(front three silica)-pyrimidine and Hg (CN)
2Mol ratio be: 1: 1.6: 1.4.
5. the preparation method of the described compound of claim 2 is characterized in that in turn including the following steps:
(1) purine nucleoside is synthetic:
With 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in the solvent, adds 6-chloropurine and Hg (CN) again
2, under 100～120 ℃ condition, reacted 2～3 hours, from reactant, collect the white powder purine nucleoside then.
Said solvent is CH
3NO
2, CH
3CN or CH
2Cl
2In a kind of;
1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 6-chloropurine and Hg (CN)
2Mol ratio be: 1: (2.4～3.0): (0.5～.09);
(2) deprotection of purine nucleoside:
The purine nucleoside that step (1) is obtained places the reaction that is hydrolyzed of basic solution and alcohols material, obtains target product, i.e. 1-cyano group-2,3,5-three-hydroxyl-1-(1 '-adenine)-β-furans nucleosides;
The processing condition of reaction:
Stirring at room 1～2.5 hour, the mol ratio of pyrimidine nucleoside and alcohols are (5～8): 1.
6. method as claimed in claim 5 is characterized in that, with 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose is dissolved in the solvent, adds molecular sieve and refluxes 0.5～1.5 hour, carries out building-up reactions after the cooling again, and solvent is CH
3NO
2, 1-bromo-1-cyano group-2,3,5-three-O-benzoyl-β-D-ribofuranose, 6-chloropurine and Hg (CN)
2Mol ratio be: 1: 2.6: 0.7, alcohols material was CH
3OH or CH
3CH
2OH and composition thereof, basic solution are the ammoniacal liquor or the NaOH aqueous solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB00127905XA CN1137132C (en) | 2000-12-14 | 2000-12-14 | Cyanoribofuranoside compound and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB00127905XA CN1137132C (en) | 2000-12-14 | 2000-12-14 | Cyanoribofuranoside compound and its preparing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1298880A true CN1298880A (en) | 2001-06-13 |
| CN1137132C CN1137132C (en) | 2004-02-04 |
Family
ID=4592815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB00127905XA Expired - Fee Related CN1137132C (en) | 2000-12-14 | 2000-12-14 | Cyanoribofuranoside compound and its preparing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1137132C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2697241B1 (en) * | 2011-04-13 | 2019-06-12 | Gilead Sciences, Inc. | 1'-substituted pyrimidine n-nucleoside analogs for antiviral treatment |
-
2000
- 2000-12-14 CN CNB00127905XA patent/CN1137132C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2697241B1 (en) * | 2011-04-13 | 2019-06-12 | Gilead Sciences, Inc. | 1'-substituted pyrimidine n-nucleoside analogs for antiviral treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1137132C (en) | 2004-02-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0980377B1 (en) | Anti-viral pyrimidine nucleoside analogues | |
| CN1076021C (en) | L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents | |
| DE69829760T3 (en) | BI- AND TRI-CYCLIC-NUCLEOSIDE, NUCLEOTIDE AND OLIGONUCLEOTIDE ANALOG | |
| PL188359B1 (en) | Compounds and method serving to treat carcinoma | |
| CN110776512A (en) | Preparation method of nucleoside analogue | |
| CN1115320A (en) | Nucleosides and oligonucleotides having 2'-ether groups | |
| CN102971335A (en) | Reagents for reversibly terminating primer extension | |
| JPH10507772A (en) | L-ribofuranosyl nucleoside | |
| HU211132A9 (en) | Nucleoside derivatives useful in treating retroviral infections | |
| AU5494501A (en) | Anti-viral pyrimidine nucleoside analogues | |
| CA2288146A1 (en) | A pulping apparatus | |
| RU2361875C2 (en) | SYNTHESIS OF β-L-2'-DESOXYNUCLEOSIDES | |
| Calvo-Mateo et al. | 3′-C-Cyano-3′-deoxythymidine | |
| CN1137132C (en) | Cyanoribofuranoside compound and its preparing process | |
| Pedersen et al. | Stabilisation of nucleic acid secondary structures by oligonucleotides with an additional nucleobase; synthesis and incorporation of 2′-deoxy-2′-C-(2-(thymine-1-yl) ethyl) uridine | |
| CN1255420C (en) | Process for preparation of L-ribavirin | |
| CN100475831C (en) | Synthesis of beta-l-2'-deoxy nucleosides | |
| CN102241721A (en) | Method for preparing capecitabine and hydroxyl derivative intermediate thereof | |
| Kiritsis et al. | Synthesis and Biological Evaluation of 3'-C-Ethynyl and 3'-C-(1, 4-disubstituted-1, 2, 3-triazolo) Double-Headed Pyranonucleosides | |
| EP2253640B1 (en) | Photoresponsive nucleic acid manufacturing method | |
| CN1771253A (en) | Nucleotide lipid ester derivatives | |
| CN1324034C (en) | Dioxazole pyrimidine nucleotide compounds with function of releasing NO and its use in pharmaceutics | |
| CN1366530A (en) | Process for preparation of trifluorothymidine derivatives | |
| CN114456169B (en) | 3' -deoxy-3 ',4' -didehydroribonucleoside analogues and preparation method thereof | |
| CN1274703C (en) | Unsaturated pyranocarbonoside compounds and preparing process thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |