CN1324034C - Dioxazole pyrimidine nucleotide compounds with function of releasing NO and its use in pharmaceutics - Google Patents
Dioxazole pyrimidine nucleotide compounds with function of releasing NO and its use in pharmaceutics Download PDFInfo
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Abstract
The present invention relates to a dioxazole [3, 4-d] pyrimidine nucleoside derivative with an NO releasing function and applications thereof on pharmacology. The derivative has a chemical structure shown as general formula (VIII), and is capable of releasing NO in bodies and generating various uridine derivatives. The dioxazole [3, 4-d] pyrimidine nucleoside derivative can be used to prepare medicines for preventing and treating diseases with viral symptoms (such as viral hepatitis and HIV viruses), medicines for preventing and treating rejection reactions of variant organ and tissue transplantation and medicines for treating diseases caused by decreased NO in bodies. Thus, the dioxazole [3, 4-d] pyrimidine nucleoside derivative has extensive applications on pharmacology.
Description
Technical field
The present invention relates to a class and can discharge nitric oxide free radical (NO in vivo, write a Chinese character in simplified form NO) De oxadiazole also [3,4-d] pyrimidine glycoside derivative, especially after this glycosides compound discharges NO in vivo, the urea glycoside derivates that produces can be to the synthetic generation interference effect of DNA and RNA, have antiviral, antitumor economic benefits and social benefits activity, can be used for preparation treatment tumour, the medicine of viral and cardiovascular disease etc.
Background technology
Nitrogen protoxide (Nitric oxide, be abbreviated as NO) as a kind of gas of free radical character, common toxic ingredient for topsoil, but in human body, nitrogen protoxide is a lower molecular weight and the bioactive molecules with hydrophobic property, can pass freely through cytolemma, act on the target molecule in the born of the same parents, nitrogen protoxide can arrive any position in cell and the tissue in theory, can regulate and control the various kinds of cell function in vivo and produce biological effect widely, so nitric oxide donors and conditioning agent are having important use to be worth aspect the new drug research exploitation.
NO participates in various important physical effects in the body as a kind of biological effector molecule, keeps body cell and organizes normal vital movement.At cardiovascular systems, NO has vasodilation, and anticoagulant also adheres to the effect of blood vessel endothelium, plays an important role for keeping antiotasis, blood pressure and haemodynamics aspect.In immunity system, NO is the effector molecule of white corpuscle, lymphocyte, scavenger cell, also is their adjusting molecule.In common immunologic process, the microorganism that NO kills invasion as the cell toxicant molecule comprises pathogenic agent and tumour cells such as bacterium, fungi and parasite.In central nervous system, NO plays an important role as informational molecule, participates in study, the memory process of animal, the adjusting of adjusting, cerebral blood flow (CBF) and the pain sensation that the participation neurotransmitter discharges etc.In peripheral nervous system, NO may be the mediator or the medium of non-adrenergic, non-cholinergic nerve, participates in gastrointestinal function and regulates.NO also can regulate the volume of blood flow of stomach mucous membrane by expansion gastrointestinal mucosa blood vessel, promotes the secretion of gastric mucus and the reparation behind the mucosa injury and has the effect of protection mucous membrane.In endocrine system, the secretion of NO energy stimulating growth element, Regular Insulin etc.At respiratory system, NO can regulate basic lung antiotasis, to keeping air flue diastole, normal ventilation/blood flow ratio and mucous membrane secretion vital role is arranged.In addition, the enhancing of the diastole of human cavernous body and penile erectile function is also relevant with NO.
Endogenous NO plays an important role in the physiological function of keeping a plurality of systems of body, reduce yet many acute and chronic diseases can cause NO to generate, so supplemented with exogenous NO is very important for treatment of diseases.The important source of exogenous NO is the NO donor, and the NO donor is according to discharging different six classes that are divided into of atom (carbon, nitrogen, oxygen etc.) that the position links to each other with NO: C-NO donor, N-NO donor, O-NO donor, S-NO donor, heterocycle-NO donor and transition metal-NO mixture.Divide from chemical structure, nitric oxide donors mainly contains the S-nitroso-group, nitrate esters, types such as furazan class.
At present, one of important research direction of nitric oxide donors is: nitric oxide donors and known drug are carried out amalgamation, by discharging nitrogen protoxide in vivo, make known drug have the effects such as toxicity of better medicament activity or reduction medicine.
The furazan ring (Furoxane claims 1,2 again, 5 oxadiazoles-2-oxygen, and 1,2,5-Oxadiazole-2-oxide) as the important known nitric oxide donors of a class, this compounds mainly is divided into three groups:
A) simple furazan class (See Figure I) is included in the derivative that different substituents is arranged on the furazan ring;
B) benzo furazan class (See Figure II);
C) furazano pyrimidine [as 4H-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone-1-oxygen, 4H-[1,2,5] Oxadiazolo[3,4-d] pyrimidine-5,7-dione-1-oxide] class III
(I)Furoxane (II)Benzofuroxane (III)Furoxanopyrimidine
More than three kinds of furazan compounds the same with other NO donor, under physiological condition, discharge NO, can become vasodilator (Zhong Cisheng. Sun Anyang chief editor. nitric oxide production biomedicine. Shanghai: the .1997 of press of Shanghai Medical Univ, p46-59 etc.), be used to bring high blood pressure down, anticoagulant and sticking, keep the stable of vascular environment, also have the cytotoxicity of comprising, mutagenicity, suppress the immune response of organism, the diastole unstriated muscle, spasmolytic suppresses effect (Wang PG such as monoamine oxidase, Xian M, Tang XP, et al, Chem.Rev.2002,102,1091-1134).NO physiological action in vivo is extensive, and for many years, experiment is done with NO donor and DNA and RNA viruses laboratory system in many domestic and international laboratories, and the result thinks: virus is responsive to NO, and part virus can produce the tolerance to NO; The long and is: NO suppresses the commitment of virus replication, can reach the propagation in vivo of pre-anti-virus, promotes virus sweep, makes host's rehabilitation.The host is to virus infection, the initial innate immunity responsing reaction that takes place, produce cytokine, as Interferon, rabbit s (TFNs), tumor necrosis factor alpha (TNF-α) etc., these cytokines can promote iNOS (inducible nitric oxide synthase) to express, and intravital NO level is risen, produce above-mentioned effect (Reiss CH to virus, Koatsu T, JVirology, 1998:4547).Someone did the research of NO and hepatitis B virus (HBV) Infection Status relation, the result shows, duplicates increase in vivo with HBV, and NOS and NO level are on a declining curve, when HBV the infected on the cycle of recovery, then the serum NO level is close to healthy person, illustrates that NO has certain effect (Zhang Jicai, Hu Xiuxue in removing HBV, Lee sea equality, China's experiment and clinical virology magazine, 2002,16 (2): 131).Accurate mechanism about the NO antivirus action is still very unclear, most scholars think that NO acts on the intravital crucial metabolic enzyme of virus, make its inactivation and bring into play antivirus action (Clancy RM, Abramson SB.Proc Soc Exp Biol Med, 1995,210:93).Another mechanism of NO antivirus action be by with the oxyradical effect (Huang Honglan, Li Fan, medical science summary 1999,5 (7): 327), i.e. NO and superoxide anion (O
2 -) effect generation peroxidation nitrite anions negatively charged ion (ONOO
-), ONOO
-Again with H
+Effect generates peroxidation nitrous acid (ONOOH), and ONOOH can resolve into NO
2 +And hydroxy radical qiao (OH), ONOO
-Be strong oxidizer, OH is the strongest oxyradical of effect, causes sulfydryl albumen to destroy, lipid peroxidation, and OH can also cause the DNA splitting of chain with nucleic acid reaction.NO suppresses and kill virus by above direct and indirect action mechanism.
In addition, NO has dual function to tumour, and this depends on the growing amount of NO: on the one hand, the NO that continues suitable concn (pmol or fmol level) produces, and helps growth of tumor, mainly shows aspects such as promoting tumor-blood-vessel growth; On the other hand, the NO of high density (nmol level) mainly plays cytotoxicity, suppresses and killing tumor cell, promotes apoptosis of tumor cells (Thomsen LL, Miles DW, et al, Br J Cancer, 1995,72 (1): 41; JenkinsDC, Charles IG, Thomson LL, Natl Acad Sci USA, 1995,92 (10) 4392).NO it be unclear that the direct acting precise mechanism of tumour cell, sees mainly containing of report: 1, the superoxide anion (O that produces in NO and the cell
2 -) interacting forms peroxynitrite root (ONOO
-), resolve into NO rapidly after protonated
2With hydroxy radical qiao OH), the activity of OH is very high, can combine with the molecule of kinds of tumor cells, can cause the many-sided infringement of tumour cell in vivo, as lipid peroxidation, protein, amino acid whose crosslinked and with DNA, RNA covalent attachment [Edmiston KH, Shoji Y, Mizoi T, et al Cancer Res, 1998; 58 (7): 1524-1531; Okada M, Sagawa T, Tominage A, et al Immunology, 1996,89 (1): 158-164], produce antitumor action; 2, NO can combine with the reactive site Fe-S of tumour cell metabolism key enzyme base, forms iron-nitrosyl radical mixture, causes in the enzyme that iron must lose and destroy its activity, and then cause cytotoxicity [Parkins CS, Dennis MF, StratfordM, et al Cancer Res, 1995; 55 (24): 6026-6029]; 3, NO can also directly act on the Yeast Nucleic Acid reductase enzyme in the DNA building-up process, and this enzyme is the rate-limiting enzyme in the DNA building-up process, and then influences the dna replication dna of tumour cell, suppresses the propagation of tumour cell.NO also can make the DNA nitration simultaneously, causes nucleic acid replication transcription and translation obstacle, even causes fracture [Roy B, Lepoivre M, Henry Y, et al Biochemistry, 1995 of nucleic acid molecule; 34 (16): 5411-5418].
In sum, NO has bigger effect at antiviral, anti-tumor aspect, makes up effective molecule or the group with release NO if will have drug molecule antiviral, antitumor action, then can improve and improve curative effect antiviral, antitumor drug.
Discharging nitric oxide production condition from the furazan ring, must be to have sulfhydryl compound, forms nitroso-group mercapto alcohol, discharges nitrogen protoxide again.(Sorba G, Medana C, Fruttero R, Cena C; J.Med.Chem.1997,40,463-469). oxadiazole also [3,4-d] pyridine derivatives is as a kind of furazan lopps nitric oxide donors, and it discharges NO will have sulfhydryl compound to exist, as the N-acetylcysteamine, aminothiopropionic acid, gsh (Sako M, Oda S, OharaS, et al, J.Org.Chem.1998,63,6947).In figure below; mercaptan (being N-ethanoyl cysteamine in figure below) is 3 '-and 7 '-position of attack furazano pyrimidine at first; thereby the furazan ring is opened; again under another molecule mercaptan attack; form important intermediate nitrosothiols RSNO with the nitroso-group effect of pyrimidine 5-position, latter's cracking again discharges NO, and produces multiple urea pyrimidine derivant V; VI, VII.Obviously these several uracil uracil that all is non-natural; if at oxadiazole also [3,4-d] connect a glycan molecule Xing Cheng oxadiazole also [3 on the 4-position N atom of pyrimidine derivatives in advance, 4-d] the pyrimidine glycoside derivates, then can promptly form non-natural urea glycoside derivates after discharging NO, such glycoside can be brought into play further antiviral, antitumor action.
In fact the oxadiazole also [3,4-d] pyrimidine derivatives, itself had the purine constitutional features of uracil of holding concurrently, and be the non-natural purine uracil analogue of holding concurrently, connect carbohydrate and become glycosides, help cell to absorb, even do not discharge NO, also has antiviral, antitumor action, so Xuan Ze oxadiazole also [3,4-d] pyrimidine derivatives carries out glycosylation reaction, the compound of gained may produce economic benefits and social benefits: discharge NO, the urea glycoside derivates of generation can be hindered and damaged the synthetic generation of DNA and RNA, becomes characteristics of the present invention and purpose.Because nitrogen protoxide has in vivo and physiological action widely, and non-natural nucleoside the effect in antitumor, antiviral field (Zhang Li and, with nucleic acid is the drug research of effect target, Beijing: Science Press, 1997, p.198-220), so ， oxadiazole also [3,4-d] pyrimidine glycosylase derivative can have good pharmacological action in vivo, antitumor except being used for, antiviral, the disease that body internal cause NO minimizing is mediated has therapeutic value.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of nucleoside derivate of new base, and it can discharge NO in vivo and form the non-natural nucleoside derivative, bring into play antitumor, effect such as antiviral grade.
Technical scheme of the present invention is as follows:
1. the compound that has following general formula (VIII) expression
R wherein
1Represent hydrogen; The C of hydroxyl replacement or unsubstituted
1-C
8The alkyl of straight or branched; C
1-C
8The alkoxyl group of straight or branched; C
3-C
8Cycloalkyl; C
1-C
5The aryl R of the alkyl of straight or branched or alkoxyl group replacement or unsubstituted
2Represent furanose, pyranose, or ring-opened saccharides is like thing
Above-mentioned furanose has the structure of following general formula I X:
In the formula:
X represents O, N, S, CH
2Y represents CH, S, O;
When Y is CH, R
3, R
4, R
5Identical or different, independently represent group separately.And R
4, R
5α position or β position at the sugar ring
R
3Representation hydroxy, halogen and acyloxy.R
3Representation hydroxy more preferably; Fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
R
4, R
5Represent hydrogen respectively; Hydroxyl; Amino; Azido-; Halogen and acyloxy.R
4, R
5More preferably represent hydrogen; Hydroxyl; Amino; Azido-; Fluorine, chlorine, bromine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
When Y is O, S, then there is not R
4, and R
3, R
5Represent aforesaid situation.
Furanose also has the structure of following general formula X
X represents O, N, S, CH
2
B is also [3,4-d] pyrimidine derivatives of IX Zhong De oxadiazole;
R
3Representation hydroxy, halogen and acyloxy.R
3Representation hydroxy more preferably, fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
Pyranose has following general formula X I
B is also [3,4-d] pyrimidine derivatives of IX Zhong De oxadiazole;
R
3, R
7, R
8, R
9Identical or different, independently represent group separately.And R
7, R
8, R
9α position or β position at the sugar ring
R
3Representation hydroxy, halogen and acyloxy.R
3Representation hydroxy more preferably; Fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
R
7, R
8, R
9Represent hydrogen respectively; Hydroxyl; Amino; Azido-; Halogen and acyloxy.R
7, R
8, R
9More preferably represent hydrogen; Hydroxyl; Amino; Azido-; Fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy
Ring-opened saccharides has following general formula X II like thing
B is also [3,4-d] pyrimidine derivatives of IX Zhong De oxadiazole;
X represents O; N; S; CH
2
R
3Representation hydroxy, halogen and acyloxy.R
3Representation hydroxy more preferably, fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
Ring-opened saccharides also has following general formula X III like thing
B is also [3,4-d] pyrimidine derivatives of IX Zhong De oxadiazole;
X represents O; N; S; CH
2
R
3, R
10Representation hydroxy, halogen and acyloxy.R
3Representation hydroxy more preferably, fluorine, chlorine; Acetoxyl group, propionyloxy, butyryl acyloxy, benzoyloxy, p-nitrophenyl methanoyl, the ortho-nitrophenyl methanoyl, to toluyl oxygen, o-methyl-benzene methanoyl, benzyloxy, to the nitro benzyloxy, adjacent nitro benzyloxy, to the methyl benzyloxy, adjacent methyl benzyloxy.
The non-natural nucleoside compound of described general formula (VIII) expression, or its pharmacy acceptable salt has the application that can discharge in the nitrogen protoxide medicine in preparation is the preparation prevention and treat viral symptom disease medicament, as viral hepatitis, and HIV virus; It is the rejection medicine of preparation prevention and treatment allosome organ and tissue transplantation; It is the preparation anti-tumor drug; And the medicine that can be used as the disease for preparing the NO minimizing of treatment body internal cause and mediate.
The compound that the used general formula VIII of the present invention represents can their neutral form, when it has alkalescence, also can add and be shaped as corresponding salt and use with mineral acid or organic acid, in the medicine can with acid include: hydrochloric acid, hydrogen bromide, naphthalene disulfonic acid (1,5), phosphoric acid, nitric acid, sulfuric acid, oxalic acid, tartrate, lactic acid, Whitfield's ointment, phenylformic acid, formic acid, acetate, propionic acid, valeric acid, diethylacetic acid, propanedioic acid, succsinic acid, fumaric acid, Succinic Acid, pimelic acid, hexanodioic acid, toxilic acid, oxysuccinic acid, thionamic acid, phenylpropionic acid, glyconic acid, xitix, Yi Yansuan, methylsulfonic acid, tosic acid, citric acid, and amino acid etc.The compound that general formula VIII represents can add with many moles acid and is shaped as salt, these acid of many moles can be singlely also can make up, the situation of this main corresponding solvent as required or dilution decides, and the salt of these additions can transfer neutral form to by methods such as anionresins.
Non-natural nucleoside compounds involved in the present invention and their corresponding salt can (comprise corresponding vehicle of pharmaceutically permitting application with suitable dressing, tackiness agent, sustained release dosage, stablizer, spices, seasonings, pigment etc.) make tablet or capsule oral, also can make corresponding injection or freeze-dried powder and be used for clinical.
The represented compound of general formula of the present invention (VIII) is that this invents new synthetic compound, and new synthetic compound has all carried out the structure evaluation through various physical methods, comprises
1H-NMR, MS and ultimate analysis.All compounds all be according to or synthesize with reference to the method delivered.
(XIV) is as follows for key intermediate of the present invention:
In the formula: R
1Represent hydrogen; The C of hydroxyl replacement or unsubstituted
1-C
8The alkyl of straight or branched; C
1-C
8The alkoxyl group of straight or branched; C
3-C
8Cycloalkyl; C
1-C
5The aryl of the alkyl of straight or branched or alkoxyl group replacement or unsubstituted.
General formula X IV compound synthetic has following steps:
At first single substituted ureas is reacted with diethyl malonate, generate 1-and replace barbituric acid (2), generate 6-chloro-3-substituted pyrimidines-2 through chlorination, 4-diketone (3), obtain 6-chloro-5-nitro-3-substituted pyrimidines-2 through nitration reaction, 4-diketone (4), then in tetrahydrofuran solution with NaN
3Reaction obtains 6-nitrine-5-nitro-3-substituted pyrimidines-2,4-diketone (5), and final reaction generates intermediate X IV
2. the synthesis step of purpose compound that has general formula VIII is as follows:
The intermediate X IV of corresponding replacement is having a large amount of corresponding replacements in the presence of the sugar, and available scorification or Silyl-method in the presence of the different catalyzer or under the catalyst-free condition, are prepared target compound VIII.
Prepared by intermediate X IV in the process of compound VIII, available scorification or Silyl-method are being carried out in the presence of the different catalyzer or under the catalyst-free condition.More excellent preparation method is the Silyl-method; Catalyzer can be selected Lewis acid, mineral acid, organic acid, heteropolyacid, iodine, salt compounded of iodine etc. for use.Better suited catalyzer has SnCl
4, ZnCl
2, TiCl
4, FeCl
3, TMSOTf; H
2SO
4, P
2O
5The Phosphorus heteropolyacid of tungsten; I
2, KI, NaI etc.More excellent catalyzer has SnCl
4, TiCl
4, TMSOTf, P
2O
5, the Phosphorus heteropolyacid of tungsten, I
2, KI.
Embodiment
1. the preparation of compound
[1,2,5] oxadiazoles [3,4-d] pyrimidines-5 (4H), 7 (6H)-diketone 1-oxide compounds are synthetic for intermediate
6-chloro-2 with 2.0g, 4-dihydroxyl-4-nitro-pyrimidine is dissolved in the 100mL tetrahydrofuran (THF), yellow transparent liquid, add the 1.0g sodiumazide again, stirred at ambient temperature then 3 hours, produce a large amount of white solids, filter then, filter cake washs with less water, get white solid, this solid is placed 25mL HCl (1mol/L), and stirring at room 3 hours is evaporated to dried then, use tetrahydrofuran (THF)-sherwood oil recrystallization then, get solid, use the Vanadium Pentoxide in FLAKES drying then, get 500mg faint yellow solid ESI-MS:169.0[M-H]
-, C
4H
2N
4O
4(Mr=170.01); UV (EtOH, ε) λ
Max263nm (1.55 * 10
4).
Intermediate 6-methyl-[1,2,5] oxadiazoles [3,4-d] pyrimidines-5 (4H), 7 (6H)-diketone 1-oxide compounds are synthetic
In the 100mL reaction flask, add 6-chloro-2-hydroxy-3-methyl-5-nitro-4 (3H)-pyrimidine dione 1g and 50mL tetrahydrofuran (THF), with the 0.5g sodiumazide, refluxed then 5 hours, placement is spent the night, filter, filter cake is used tetrahydrofuran (THF) successively, water washing, and filter cake is a faint yellow solid, filter cake placed 12mL HCl (1mol/L) stirring at room 1 hour, be evaporated to then dried, the off-white color solid, vacuum P
2O
5Get yellow solid, ESI-MS:183.0[M-H after the drying]
-, C
5H
4N
4O
4(Mr=184.02); UV (EtOH, ε) λ
Max264nm (1.25 * 104).
4-(2,3,5-three-oxy-acetyl-1-β-D-ribofuranosyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
a)
With 0.2g (1.18mmol) compound VI I (in the formula: R
1=H), 0.27mL (1.27mmol) hexamethyldisilane amine (Hexamethyldisilazane), 2mL1,2-ethylene dichloride and anhydrous on a small quantity (NH
4)
2SO
4Join in the 10mL round-bottomed flask, refluxed 12 hours, be evaporated to driedly then, add 0.3g tetrem acyl ribose then, add 2mL1 again, the 2-ethylene dichloride is chilled to below 0 ℃, adds 0.15mLSnCl
4And 1mL1, the solution that the 2-ethylene dichloride is formed finishes, and stirred overnight at room temperature adds cold NaHCO then
3Aqueous solution stopped reaction, with 1,2-ethylene dichloride extraction 2 times merges organic phase, and washes anhydrous Na SO with water 2 times
4Dry.Concentrate oily matter, column chromatographic isolation and purification (the eluent chloroform: methyl alcohol=50: 1), white solid 0.1g (
a) yield 20%; Mp83-85 ℃;
1H-NMR (BruckerAV-300, CDCl
3) δ: 8.36 (s, 1H, N-H), 6.21 (d, 1H, J=4.2Hz, 1 '-H), 5.87 (m, 1H, 3 '-H), 5.45 (t, 1H, 2 '-H), 4.52 (m, 1H, 4 '-H), 4.31,4.19 (m, 2H, 5 '-H), 2.11 (m, 9H, CH
3).ESI-MS：451.0[M+Na]
+，C
15H
16N
4O
11(Mr＝428.08)；UV(EtOH，ε)λ
max267nm(1.65×10
4)；Anal.Calcd for C
15H
16N
4O
11·0.5H
2O(437.30)：C41.20，H3.92，N12.80；Found：C41.66，H3.94，N12.16。
4-(β-D-ribofuranosyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
b)
0.2g (0.467mmol) compound a joins in 2mL methyl alcohol/ammonia, dissolving back stirred overnight at room temperature is separated out white solid, filter, white solid, mother liquor is separated out white solid after concentrating, combining solid use recrystallizing methanol, get white solid 0.1g (
b), yield 71%; Mp159-160 ℃;
1H-NMR (Brucker AV-300, D
6-DMSO) δ: 5.93 (d, 1H, J=5.4Hz, 1 '-H), 4.59 (t, 1H, 3 '-H), 3.95 (t, 1H, 2 '-H), 3.67 (m, 1H, 4 '-H), 3.51,3.37 (m, 2H, 5 '-H); .ESI-MS:325.0[M+Na]
+, C
9H
10N
4O
8(Mr=302.05); Anal.Calcd forC
9H
10N
4O
8NH
31/4H
2O (323.727): C33.39, H4.20, N21.63; Found:C32.92, H4.34, N21.56
4-(2-acetoxyethoxy methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
c)
With 0.2g (1.18mmol) compound VI I (in the formula: R
1=H), 0.27mL (1.27mmol) hexamethyldisilane amine (Hexamethyldisilazane), 2mL1,2-ethylene dichloride and anhydrous on a small quantity (NH
4)
2SO
4Join in the 10ml round-bottomed flask, refluxed 12 hours, be evaporated to driedly then, add 0.5g (2.84mmol) 2-oxa--1 then, 4-butyleneglycol diacetate esters adds 2mL1 again, and the 2-ethylene dichloride is chilled to below 0 ℃, adds 0.15mLTiCl
4And 1mL1, the 2-dichloroethane solution finishes, and stirred overnight at room temperature adds cold NaHCO then
3Aqueous solution stopped reaction, with 1,2-ethylene dichloride extraction 2 times merges organic phase, and washes anhydrous Na SO with water 2 times
4Dry.Concentrate oily matter, column chromatographic isolation and purification (the eluent chloroform: methyl alcohol=50: 1), white solid 0.04g (
c) yield 12%; Mp114-116 ℃;
1H-NMR (Brucker AV-300, CDCl
3) δ: 8.73 (s, 1H, N-H), 5.47 (s, 2H,, N-CH
2-O), 4.18 (t, 2H ,-O-CH
2-), 3.85 (t, 2H ,-CH
2-OAc), 2.00 (s, 3H ,-CH
3); ESI-MS:309.0[M+Na]
+, C
9H
10N
4O
7(Mr=286.05); Anal.Calcd for C
15H
16N
4O
111/2CH
3OH (302.226): C37.75, H4.00, N18.54; Found:C38.24, H3.69, N18.24
4-(2-hydroxyl base oxethyl methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
d)
0.2g (0.7mmol) compound
c, join in 2mL methyl alcohol/ammonia, dissolving back stirred overnight at room temperature, after concentrating faint yellow oily thing, column chromatographic isolation and purification (the eluent chloroform: methyl alcohol=10: 1) white solid 0.12g (
d), yield 70.6%; Mp129-131 ℃;
1H-NMR (Brucker AV-300, D
6-DMSO) δ: 12.05 (H s.1, N-H), 5.33 (s, 2H,, N-CH
2-O), 4.65 (t, 1H ,-OH), 3.63 (m, 2H ,-O-CH
2-), 3.50 (m, 2H ,-CH
2-OAc); ESI-MS:267.0[M+Na]
+, C
7H
8N
4O
6(Mr=244.04); Anal.Calcd for C
7H
8N
4O
61/4CH
3OH (252.18): C34.53, H3.59, N22.22; Found:C34.41, H3.26, N21.96
4-(1.3-diacetoxy-2-propoxy-methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
e)
With 0.2g (1.18mmol) compound VI I (in the formula: R
1=H), 0.27mL (1.27mmol) hexamethyldisilane amine (Hexamethyldisilazane), 2mL1,2-ethylene dichloride join in the 10mL round-bottomed flask, reflux 12 hours, be evaporated to dried then, add 0.5g (2mmol) triacetyl methoxy glycerine then, add 2mL1 again, the 2-ethylene dichloride, be chilled to below 0 ℃, add 0.15mLTiCl
4And 1mL1, the 2-dichloroethane solution finishes, stirred overnight at room temperature, and (method is together through aftertreatment
cSynthetic) white solid 0.07g (
e), yield 16.5%; Mp132-133 ℃;
1H-NMR (BruckerAV-300, CDCl
3) δ: 8.52 (s, 1H, N-H), 5.54 (s, 2H,, N-CH
2-O), 4.23,4.10,4.04 (m, 5H ,-O-CH-, 2 * [CH
2-OAc]), 1.99 (s, 6H ,-CH
3); ESI-MS:381.2.0[M+Na]
+, C
12H
14N
4O
9(Mr=358.08); Anal.Calcd for C
12H
14N
4O
9: C40.23, H3.94, N15.64; Found:C40.21, H3.80, N15.67
4-(1.3-dihydroxyl-2-propoxy-methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
f)
0.2g (0.56mmol) compound
e, join in 2mL methyl alcohol/ammonia, dissolving back stirred overnight at room temperature is separated out white solid, filter, white solid, mother liquor is separated out white solid after concentrating, combining solid use recrystallizing methanol, get white solid 0.11g (
f), yield 71.9%; Mp138-139 ℃;
1H-NMR (Brucker AV-300, D
6-DMSO) δ: 12.05 (s, 1H, N-H), 5.42 (s, 2H,, N-CH
2-O), 4.60 (t, 2H, ,-OH), 3.67 (m, 1H, ,-CH-) 3.45,3.35 (m, 4H, 2 * CH
2); ESI-MS:273.2[M-H]
-, C
8H
10N
4O
7(Mr=274.05).; Anal.Calcd forC
8H
10N
4O
71/2H
2O (283.2025): C33.93, H3.91, N19.78; Found:C33.89, H4.01, N19.66
6-methyl-4-(2,3,5-three-oxy-acetyl-1-β-D-ribofuranosyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
g)
With 0.2g (1.08mmol) compound VI I (in the formula: R
1=CH
3) join in 1g (3.14mmol) the tetrem acyl ribose under the molten state, add the catalytic amount tosic acid then, under the vacuum in 140 ℃ of insulated and stirred 30min, reaction is finished, the cooling back adds the 20mL chloroform, filter then, after filtrate concentrates, column chromatographic isolation and purification (the developping agent chloroform: sherwood oil=1: 1) white solid 0.08g (
g), yield 17%; Mp169-170 ℃;
1H-NMR (BruckerAV-300, CDCl
3) δ: 6.23 (d, 1H, J=4.2Hz, 1 '-H), 5.87 (m, 1H, 3 '-H), 5.48 (t, 1H, 2 '-H), 4.50 (m, 1H, 4 '-H), 4.31,4.19 (m, 2H, 5 '-H), 4.36 (s, 3H, N-CH
3), 2.09 (m, 9H, 3 * CH
3); ESI-MS:465.1[M+Na]
+, C
16H
18N
4O
11(Mr=442.1); Anal.Calcd forC
16H
18N
4O
111/4CH
3OH (450.355): C43.34, H4.25, N12.44; Found:C43.70, H4.05, N11.89
6-methyl-4-(2-acetoxyethoxy methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide compound (
h)
With 0.2g (1.08mmol) compound VI I (in the formula: R
1=CH
3) join 1g (5.68mmol) 2-oxa--1, in the 4-butyleneglycol diacetate esters, add a small amount of tungsten phospha polyacid then, under the vacuum in 140 ℃ of insulated and stirred 60min, reaction is finished, and the cooling back adds the 20mL chloroform, filters then, after filtrate concentrates, column chromatographic isolation and purification (the developping agent chloroform: sherwood oil=1: 1) white solid 0.075g (
h), yield is 23%; Mp75-77 ℃;
1H-NMR (BruckerAV-300, CDCl
3) δ: 5.53 (s, 2H,, N-CH
2-O), 4.18 (m, 2H ,-O-CH
2-), 3.87 (m, 2H ,-CH
2-OAc), 3.35 (s, 3H, N-CH
3), 2.01 (s, 3H ,-CH
3); ESI-MS:301.1[M+H]
+, C
10H
12N
4O
7(Mr=300.07); Anal.Calcd for C
10H
12N
4O
7: C, 40.01; H, 4.03; N, 18.66; Found:C40.05, H4.00, N18.46
2. biological activity test
(1) material
Cell: the Wish cell, the Shanghai cell provides;
Virus strain: VSV (vesicular stomatitis virus), Wuhan virus provides;
The positive control drug of sample: AXLW (acyclovir), sample
a,
b,
c,
d,
e,
f,
gBe synthetic also [3,4-d] the pyrimidine glycoside derivative of De oxadiazole that obtains.Be mixed with the mother liquor that final concentration is 10mg/mL with DMSO ,-20 ℃ of preservations are standby.
(2) experimental technique:
1. virus virulence is measured, TCID
50Be 3000, be diluted to 300 times during use.
2. the cytotoxicity experiment of sample: mother liquid medicine is done continuous 2 times be diluted to 10 dilution soups with keeping nutrient solution (2%MEM), add in the Wish cell that on 96 orifice plates, basically forms individual layer, every hole 0.1mL, each extent of dilution 2 hole, and the cell do not add soup is set makes normal control.Put to cultivate and observe CPE (cell causes change effect).Calculate maximal non-toxic concentration.
3. the anti-VSV of sample virus effect experiment:
A: the preparation cell plate, the inoculating cell number is 300,000/mL, cultivates 24h, allows cell form unit layer;
B: preparation 10TCID
50Viral liquid, join in the cell in the A item, every hole 0.1mL, in 37 ℃, 5%CO
2Cultivate 1h in the incubator;
C: the soup of maximal non-toxic concentration is made continuous 2 times of serial dilutions become 10 dilution soups (2 with keeping nutrient solution (2%MEM)
-1-2
-10), the viral liquid in the B item is discarded, add the good sample solution of dilution, join in the cell plate by from low to high order, each sample adds 1 row, does two blocks of plates altogether, as parallel control.
D: the cell plate that will add sample are put into 37 ℃, 5%CO
2Cultivate about 24h in the incubator, observe CPE, 75-100% appears in the cell for the treatment of the virus control hole to be attacked, and then takes out dyeing, calculating.
4. indicate:
The nontoxic drug level of selecting is: sample AXLW,
a-
fBe 1/16,
gBe 1/64.
AXLW and
aArrive
fBe to get from 1/16 li, by 1/2,1/4 until 1/1024, VII gets from 1/64 li, by 2 times of serial dilutions, calculates medium effective concentration (ED by the Reed-Muench method at last again
50), be listed in the table below.
The table acyclovir is with oxadiazole [3,4-d] pyrimidine glycoside derivative also
To the toxicity of Wish cell and the effect of anti-VSV virus
| Sample number into spectrum | AXLW | a | b | c | d | e | f | g |
| Maximal non-toxic concentration (μ M) | 2778 | 1459 | 2095 | 2083 | 2561 | 1745 | 2279 | 1460 |
| ED 50(μM) | 783.1 | 345 | 555 | 651.3 | 636.4 | 520 | 78.4 | 345.7 |
Claims (11)
1, the glycosides compound that has following general formula (VIII) expression:
R
1Represent hydrogen; The C of hydroxyl replacement or unsubstituted
1-C
8The alkyl of straight or branched; C
1-C
8The alkoxyl group of straight or branched; C
3-C
8Cycloalkyl; C
1-C
5The aryl of the alkyl of straight or branched or alkoxyl group replacement or unsubstituted
R
2Represent furanose, pyranose, or ring-opened saccharides is like thing.
2, the compound described in claim 1, wherein R
2The structure that following general formula I X is arranged:
In the formula:
X represents O, N, S, CH
2Y represents CH, S, O;
When Y is CH, R
3, R
4, R
5Identical or different, independently represent group separately, and R
4, R
5α position or β position at the sugar ring;
R
3Representation hydroxy, halogen and acyloxy;
R
4, R
5Represent hydrogen; Hydroxyl; Amino; Azido-; Halogen and acyloxy;
When Y is O, S, then there is not R
4, and R
3, R
5Represent aforesaid situation.
3, compound as claimed in claim 1, wherein R
2The structure that following general formula X is arranged:
B is also [3,4-d] pyrimidine derivatives of the Zhong of formula IX described in the claim 2 De oxadiazole;
X represents O, N, S, CH
2
R
3Representation hydroxy; Halogen and acyloxy.
4, compound as claimed in claim 1, wherein R
2The structure that following general formula X I is arranged:
B is also [3,4-d] pyrimidine derivatives of the described formula IX Zhong of claim 2 De oxadiazole;
R
3, R
7, R
8, R
9Identical or different, independently represent group separately, and R
7, R
8, R
9α position or β position at the sugar ring;
R
3Representation hydroxy, halogen and acyloxy;
R
7, R
8, R
9Represent hydrogen respectively; Hydroxyl; Amino; Azido-; Halogen and acyloxy.
5, compound as claimed in claim 1, wherein R
2The structure that following general formula X II is arranged:
B is also [3,4-d] pyrimidine derivatives of the described formula IX Zhong of claim 2 De oxadiazole;
X represents O; N; S; CH
2
R
3Representation hydroxy, halogen and acyloxy.
6, compound as claimed in claim 1, wherein R
2The structure that following general formula X III is arranged:
B is also [3,4-d] pyrimidine derivatives of the described formula IX Zhong of claim 2 De oxadiazole;
X represents O; N; S; CH
2
R
3, R
10Representation hydroxy, halogen and acyloxy.
7, the described compound of claim 1 is intermediate X IV and the replacement sugar with corresponding replacement, with scorification or Silyl-method, is making in the presence of the different catalyzer or under the catalyst-free condition; Catalyzer is selected from Lewis acid or mineral acid, organic acid, heteropolyacid, iodine, salt compounded of iodine.
8, any described compound of claim 1-6 can discharge NO in vivo and form the non-natural nucleoside derivative in preparation, bring into play antitumor, the antiviral application that waits in the medicine that acts on.
9, any described compound of claim 1-6 is antitumor in preparation, antiviral and the application in the rejection medicine of preparation prevention and treatment allosome organ and tissue transplantation.
10, any described compound of claim 1-6 is at the medicine of preparation treatment and prevention cardiovascular and cerebrovascular diseases, and treatment and prevent the diastole of human cavernous body and the medicine of the disease of penile erectile function obstacle, and preparation treatment body internal cause NO reduces and application in the medicine of the disease of mediation.
11, a kind of pharmaceutical composition wherein contains any described compound of the claim 1-6 that treats significant quantity and contains conventional pharmaceutical carrier.
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| CN102153606B (en) * | 2011-02-25 | 2013-07-17 | 连云港笃翔化工有限公司 | Nucleoside derivatives as well as stereo isomers, pharmaceutically acceptable salts and application thereof |
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| 一氧化氮供体药物的研究进展与应用前景 邱相君 等，中国临床药理学与治疗学，第8卷第1期 2003 * |
| 心血管疾病预防与药物治疗的新信息——一氧化氮供体 宋晓凤 等，职业与健康，第16卷第5期 2000 * |
| 心血管疾病预防与药物治疗的新信息——一氧化氮供体 宋晓凤 等，职业与健康，第16卷第5期 2000;一氧化氮供体药物的研究进展与应用前景 邱相君 等，中国临床药理学与治疗学，第8卷第1期 2003 * |
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