CN1071577A

CN1071577A - Handle the toxicity of chemotherapy reagent and Anti-virus agent with acylated pyrimidine nucleosides

Info

Publication number: CN1071577A
Application number: CN92108868A
Authority: CN
Inventors: R·W·凡伯尔斯特尔; M·K·贝马特
Original assignee: Pro Neuron Inc
Current assignee: Pro Neuron Inc
Priority date: 1991-07-05
Filing date: 1992-07-04
Publication date: 1993-05-05
Anticipated expiration: 2007-07-04
Also published as: IL102407A; IL102407A0; CN1050996C; MX9203963A

Abstract

The invention discloses and be used for the treatment of and prevent by toxic chemical, preparation and method due to chemical treatment reagent and the Anti-virus agent.The acylated derivatives of the methylated pyrimidine nucleoside of disclosed right and wrong.These chemical compounds can be alleviated and accepted the suffered infringement of promoting erythrocyte generation system in antiviral or the chemotherapeutic animal of antitumor.

Description

Handle the toxicity of chemotherapy reagent and Anti-virus agent with acylated pyrimidine nucleosides

The present invention relates generally to handle the toxicity of chemotherapy reagent and Anti-virus agent with the acylated derivatives of non-methylated pyrimidine nucleoside.These chemical compounds can alleviate and align the infringement of accepting promoting erythrocyte generation system in antiviral or the chemotherapeutic animal of antitumor.The invention still further relates to other tissue that influenced by antiviral or antitumor chemotherapy of protection, these tissues comprise gastrointestinal epithelial.

The chemotherapeutic main trouble of cancer chemotherapy and antiviral is damaged bone myelocyte or the function that suppresses them.Particularly, the mother cell of the promoting erythrocyte generation that mainly is gathered in bone marrow and the spleen can be damaged or destroy to chemotherapy, reduces the output of new hemocyte (granulocyte, lymphocyte, erythrocyte, mononuclear cell, platelet etc.).Such as, the number of their leukocyte (lymphocyte and/or granulocyte) can be reduced with 5-fluorouracil (5-FU) treatment cancer patient, and the sensitivity of patient can be improved infecting.Many cancer patients die from infection or other consequence that hemopoietic inefficacy caused after the chemotherapy.Chemotherapy reagent also can make hematoblastic growing amount be lower than normal level, hemorrhage tendency can occur again thus.Erythropoietic inhibition can cause greedy blood.The danger of infringement promoting erythrocyte generation system or other vital tissue is that it can hinder the using dosage that makes chemotherapy reagent even as big as the antitumor of bringing into play or the degree of antiviral efficacy.

Many antitumor or antiviral chemotherapy reagent play a role by biosynthesis, metabolism or its function that suppresses nucleotide, and perhaps in fact they are normal oligodeoxynucleotides in the substituted nucleic acids, produce the nucleotide substitutive derivative of defective RNA or DNA.

5-fluorouracil (5-FU) is a kind of very important clinically cell reduction antitumor chemotherapy reagent, and it partly is by entering RNA, producing defective RNA and play a role; Monophosphate with the fluorescence BrdU suppresses the cytotoxicity that thymidylate synthetase also may improve 5-FU.The clinical practice of 5-FU (on bone marrow) is subjected to its toxic restriction.Particularly, its clinical practice is subjected to treating the restriction than low; Treatment is than being exactly TD and the ratio of effective dose, and high treatment is than meaning that medicine has hypotoxic treatment effectiveness.

5-FU and a lot of other chemotherapy reagent also influence other tissue, particularly influence gastrointestinal mucosa, cause mucositis, diarrhoea and ulcer.Stomatitis (ulcer of mucosa in mouthful) special trouble concerning the patient can make feed and swallow very painful.

People such as D.S.Martin are at Cancer Res.42: 3964-70[1982] go up report, if use 5-FU begin after several hours to mice use heavy dose of uridnine, to be administered to mice can be harmless for TD with 5-FU of intensive antitumor vigor.Proved that now this " remedying " strategy can increase the therapeutic index of 5-FU in animal tumor model; can allow to use heavy dose of, virose 5-FU; Da Jiliang 5-FU makes tumor regression or prevents that tumor growth is necessary like this; meanwhile by using uridnine subsequently with priority protection normal structure (particularly importantly bone marrow) (D.S.Martin etc., Cancer Res 43: 4653-61[1983]).

Because uridnine self biological property comprises that the clinical trial of using uridnine is very complicated.Oral back uridnine absorbs very poorly; Diarrhoea is dose limitation factor (the Van Groeningen etc. in the human body; Proceedings of the AACR 28: 195[1987]).The result, for significantly changing the toxicity of 5-FU clinically, need non-intestinal to use uridnine, this need use a radicular vein inner conduit, early stage afterwards clinical trial just shows, when injecting uridnine by a little intravenous conduit, phlebitis just becomes a problem (Van Groeningen etc., Cancer Treat Rep.70: 745-50[1986]).Owing to inculcate and to send into hospitalize to the patient for a long time by the vein inner conduit.In addition, also exist some to make the patient feel very uncomfortable and very inconvenient problem.

With regard to the situation of uridnine, the very poor such problem of the oral artifact utilization rate of medicine has limited uses the clinical use value that this several drugs of deoxycytidine, cytidine and BrdU slows down the chemotherapy reagent toxicity.

Arabinosylcytosine (Ara-C) is the leukemic important reagent of a kind of treatment, and is simultaneously also fine as a kind of immunosuppressant result of use.Can partly prevent to use Ara-C to bone marrow (myelocyte and erythrocyte) and toxicity (Belyanchikova etc. by using deoxycytidine, Bull.Exp.Biol.Med, 91: 83-85[1981]), and deoxycytidine to Arp-C to the effect of lymphocytotoxicity comparison leukocyte cell strong (K.Bhalla etc., Blood 70: 568-571[1987]).Deoxycytidine also can alleviate 5-azepine-2 in the cell culture fluid '-toxicity of deoxycytidine and arabinose 5-azepine cytosine (K.Bhalla etc., Leukmia 1: 814-819[1987]).The perfusion that suggestion is carried out for a long time (5 days) heavy dose of deoxycytidine with a radicular vein inner conduit is used as realizing clinically that taking off glycosides with deoxidation alleviates the toxic a kind of means of Ara-C (K Bhall etc., Leukemia 2: 709-710[1988]).

N-phosphono acetyl group-L-aspartic acid (PALA) is a kind of anti-tumor agent comprising salmosin, and it suppresses to be called as this kind of enzyme of aspartic acid carbamylrtansferase, and this kind of enzyme participates in the biosynthesis of pyrimidine nucleotide indirectly.The side effect of PALA mainly is to gastrointestinal toxic damages and mucositis.Pyrazofurin (pyrimidine analogue that a kind of carbon connects), 6-aza uridine and 6-azacytidine all can hinder the synthetic and generation of pyrimidine nucleotide to penetrate.

3 '-patient that zidovudine (AZT) is used to be subjected to human immune deficiency virus (being HIV, the Vector of infection of AIDS) to infect clinically.AZT has prolonged the life-span that is subjected to the HIV infected patient, but has also damaged hemopoietic, causes leukopenia and greedy blood.In cell culture, uridnine has reduced the toxicity that AZT brings the progenitor of granulocyte/macrophage, do not reduce antivirus action (Sommadossi etc., (1988) Antimicrobial Agents and Chemotherapy, 32: 997-1001) of AZT simultaneously; And thymidine has reduced toxicity and the antiviral activity of AZT simultaneously.Use heavy dose of uridnine can alleviate the greedy blood that AZT causes to a certain extent to mice in non-intestinal mode, just have such effect but find in the research to have only when uridnine dosage reaches the degree that mortality rate is increased; Uridnine lower, non-toxic agent amount (500mg/Kg/d) can not reduce hematological toxicity due to the AZT (A.Falcone etc., Blood 76: 2216-21[1990]).Sommadossi and el Kouni propose to use uridnine to reduce the toxicity of AZT with periodically intravenous method in United States Patent (USP) 5077280.According to Bhall etc., deoxycytidine can protect the normal human marrow progenitor of live body outside to avoid the Cytotoxic infringement of AZT, can keep the activity of its degeneration-resistant virus simultaneously again.（Blood 74∶1923-1928[1989]）。

5-fluororotic acid ester is phonetic a kind of analog of coughing thuja acid precursor orotic acid, it has antiproliferative effect to the human cell, but it is specially adapted to treat the parasitic infection of malaria, these malaria parasite are such as being Yoelii plasmodium or Plasmodium falciparum, and these plasmodiums depend on new pyrimidine biosynthesis.Use uridnine can reduce the host toxicity of 5-fluororotic acid ester to the mice for the treatment of with 5-fluororotic acid ester, this is because the latter can not destroy its antimalarial activity (ZM Gomez and PK Rathod, Antimicrob, Agents.Chemother.34: 1371-1375[1990]).

Zalcitabine (ddc) also can be used for the anti-infection that comprises the retroviral of HIV, and the side effect of ddc comprises the initiation peripheral neuropathy, and oral ulcer reduces hematoblastic quantity.Can alleviate the toxicity of ddc with deoxycytidine to the human marrow progenitor in the culture, and can be not corresponding the effectiveness of the degeneration-resistant virus of infringement ddc, AIDS 4: 427-31[1990 such as (]) K Bhalla.

Disclosed in the above-mentioned prior art, use these pyrimidine nucleosides to improve in the clinical treatment chemotherapeutic method or poor practicability (to inculcate deoxycytidine or the uridnine required time is oversize so that need send into hospitalize by a vein inner conduit, there is infected danger, it is uncomfortable that the patient feels), perhaps can not be satisfactory (oral uridnine absorbs very poorly; Oral uridnine diarrhoea can occur when reaching the treatment required dosage).

For the public had, serial number is how 438493 U.S. Patent application has illustrated that the acylated derivatives with cytidine and uridnine improves cytidine or uridnine content in the blood.

The acyl derivative that has now synthesized some pyrimidine nucleosides is used for protecting the intermediate product of oligonucleotide or nucleoside analog building-up process, these derivants as 5 '-O-N-Benzoylurea, triacetyl cytidine and Triacetyluridine.See Sigma chemical company product index in 1991, the 155th, 980 and 981 page.

A main purpose of the present invention provides a kind of method that can effectively prevent or treat antiviral or the chemotherapeutic poisoning symptom of antitumor, and these symptoms include, but is not limited to the promoting erythrocyte generation system with to the infringement of gastrointestinal mucosa.

A further purpose of the present invention provides the Compounds and methods for that some can allow to use heavy dose of chemotherapy reagent.

A further purpose of the present invention provide some by oral a kind of or some chemical compounds to improve the method for uridnine and cytidine and their corresponding deoxynucleosides, deoxycytidine and the BrdU content in blood and tissue.

A further purpose of the present invention provides and a kind ofly prevents or alleviate the method for cytotoxicity chemotherapy reagent to the infringement of gastrointestinal epithelial.

The realization of these purposes of the present invention and other purpose is by the oral or non-intestinal of animal (comprising mammals such as people) is used the acylated derivatives of non-methylated pyrimidine nucleoside, as the acylated derivatives of uridnine BrdU, cytidine or deoxycytidine.Use these chemical compounds to help to prevent separately or together or alleviate the chemotherapeutic toxic action of cell deoxidation in the animal.

So, use chemical compound of the present invention to help the hemopoietic due to the therapeutical chemistry reagent not normal separately or together; Help to cooperate cancer and antiviral chemotherapy; Help to treat other pathological symptom.

An importance of the present invention is that the acylated derivatives of finding non-methylated pyrimidine nucleoside has beat all therapeutic effect.

Chemical compound of the present invention

In all scenario except that special the appointment, in the chemical constitution of The compounds of this invention, represent those letters of variable substituent not subscripting and subscripting to be added in to be located on that structure before the described position of this symbol.

It is as follows to be used to alleviate due to anticancer or the Anti-virus agent universal architecture of toxic chemical compound:

(1) acyl derivative of uridnine, structural formula is

R wherein ₁, R ₂, R ₃And R ₄Can be identical or different, can be respectively an acyl group (be have in the described R substituent group at least be not hydrogen atom) or substituent group acceptable a kind of salt on materia medica of hydrogen atom or metabolite.

(2) acyl derivative of cytidine.Structural formula is

R wherein ₁, R ₂, R ₃And R ₄Can be identical or different, can be respectively hydrogen atom or metabolite an acyl group (having only and having in the described R substituent group at least is not hydrogen atom) or substituent a kind of on materia medica acceptable salt.

(3) acyl derivative of deoxycytidine, structural formula is

R wherein ₁, R ₂, and R ₃Can be identical or different, can be respectively hydrogen atom or metabolite an acyl group (having only and having in the described R substituent group at least is not hydrogen atom) or substituent a kind of on materia medica acceptable salt.

(4) acyl derivative of BrdU, structural formula is:

The present invention is used to alleviate chemical compound anticancer or antiviral chemotherapy reagent toxicity and comprises following compounds:

(5) acyl derivative of uridnine, structural formula is:

R wherein ₁, R ₂And R ₃Can be identical or different, can be respectively an acyl group of hydrogen atom or following material, these materials are:

A. unbranched fatty acid with 5 to 22 carbon atoms,

B. a seed amino acid is selected from one group of aminoacid being made up of following material: glycine, L type alanine, valine, leucine, isoleucine, tyrosine, proline, hydroxyproline, serine, threonine, cystine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, carnitine and ornithine

C. dicarboxylic acids with 3 to 22 carbon atoms,

D. carboxylic acid, be selected from one or more of one group of material being made up of following material, these materials are: glycolic, acetone acid, lactic acid, enol acetone acid, thioctic acid, pantothenic acid, acetoacetic acid, P-amino benzoic Acid, beta-hydroxybutyric acid, orotic acid and creatine.

(6) a kind of acyl derivative of cytidine, structural formula is:

A. unbranched fatty acid with 5 to 22 carbon atoms,

B. a seed amino acid is selected from one group of aminoacid being made up of following material: glycine, L type phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, proline, hydroxyproline, serine, threonine, cystine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, carnitine and ornithine

C. dicarboxylic acids with 3 to 22 carbon atoms,

D. carboxylic acid, be selected from one or more of one group of material forming by following material, these materials are: glycolic, acetone acid, lactic acid, enol acetone acid, thioctic acid, pantothenic acid, acetoacetic acid, p-amino benzoic Acid, beta-hydroxybutyric acid, orotic acid, and creatine.

(7) a kind of acyl derivative of deoxycytidine, structural formula is:

R wherein ₁, R ₂, and R ₃Can be identical or different, can be respectively an acyl group of hydrogen atom or following material, these materials are:

A. unbranched fatty acid with 3 to 22 carbon atoms,

C. nicotinic acid,

D. dicarboxylic acids with 3-22 carbon atom, (condition is R ₁, R ₂And R ₃Not H entirely, and work as R ₃When being not H, R ₁And/or R ₂Also can be acyl group) or for its a kind of on materia medica acceptable salt.

(8) a kind of acyl derivative of BrdU, structural formula is:

A. unbranched fatty acid with 3 to 22 carbon atoms,

C. nicotinic acid,

D. (condition is R to the dicarboxylic acids with 3-22 carbon atom ₁, R ₂And R ₃Not H entirely, and work as R ₃When being not H, R ₁And/or R ₂Also acyl group) or be a kind of on materia medica acceptable salt.

(9) a kind of acyl derivative of uridnine, structural formula is:

R wherein ₁, R ₂Or R ₃Have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group being uncorrelated each other, can be alkyl oxidation carbonyl moiety or hydrocarbyl oxycarbonyl base section or H or phosphate.

(10) a kind of acyl derivative of cytidine, structural formula is:

R wherein ₁, R ₂, R ₃Or R ₄Have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group being uncorrelated each other, can be alkyl oxidation carbonyl moiety or hydrocarbyl oxycarbonyl base section or H or phosphate.

(11) a kind of acyl derivative of deoxycytidine, structural formula is:

R wherein ₁, R ₂, or R ₃Have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group is uncorrelated each other, can be alkyl oxidation carbonyl moiety or hydrocarbyl portion or H or phosphate.

(12) a kind of acyl derivative of BrdU, structural formula is:

R wherein ₁Or R ₂In have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group is uncorrelated each other, can be alkyl oxidation carbonyl moiety or hydrocarbyl oxycarbonyl base section or H or phosphate.

Read the following appended result who is described in detail the experiment of discussing in part and the following example of reference, can be clearer, understand the present invention and other purpose thereof all sidedly, characteristics and advantage.

This attached invention relates to the acyl derivative that uses non-methylated pyrimidine nucleoside-be uridnine, and BrdU, the acyl derivative of cytidine or deoxycytidine (as Triacetyluridine) are alleviated the chemotherapy reagent in the body of work and the toxicity of Anti-virus agent.The invention still further relates to animal is used these pyrimidine nucleoside compounds separately or together, use or do not use other reagent simultaneously.

For the situation of many antitumor or Anti-virus agent, the infringement of mentioned reagent to those cells can be avoided or alleviate to the cell that is subjected to their effects when being exposed to suitable natural nucleus glycoside following time.The Compounds and methods for of this attached invention makes keeping the treatment of antiviral or anti-tumor reagent and renders a service and reduce its toxicity in constant and become possibility.Conversely, also make the dosage that increases chemotherapy reagent when toxicity maintained an acceptable level become possibility.

The invention provides by oral or non-intestinal uses the acyl derivative of the non-pyrimidine nucleoside that methylates to treat or prevent the chemical compound or the method for the poisoning symptom of antiviral or anti-cancer chemotherapy.

A. definition:

Here used " non-methylated pyrimidine nucleoside " vocabulary shows naturally occurring nucleoside, rather than refers to similarly naturally occurring methylated nucleoside of thymidine (5-methyldeoxyuridine) or 5-methylcytidine and other.The example of non-methylated pyrimidine nucleoside comprises uridnine, cytidine, BrdU, and deoxycytidine.

Here used " acyl derivative " speech refers to a kind of derivant of non-methylated pyrimidine nucleoside; wherein a nontoxic substantially organic acidylate substituent group that derives with monocarboxylic acid is received by an ester bond on one or more free hydroxyl of a non-methylated pyrimidine nucleoside center sugar moieties, and/or such substituent group is received by an amido link on the amine substituent group on the pyrimidine ring of cytidine or deoxycytidine.Such acyl substituent group is from following carboxylic acid derivatives.These carboxylic acids include, but is not limited to be selected from one group of chemical compound that following material is formed; these materials are fatty acids; aminoacid; nicotinic acid; dicarboxylic acids, lactic acid, para-amino benzoic acid and orotic acid; reasonable acidylate substituent group is a carboxylic acid, they or be present in the body as the food composition composition or as mesostate.

Here used " analog " speech refers to by being different from acidylate or adhering to other at the method for unsettled substituent group (as the phosphorylation of the hydroxyl on the sugar) the biologically a kind of nucleoside through chemical modification on pyrimidine ring or ribose (or deoxyribose) part.Nucleoside analog in the scope of the invention refers in particular to those structures and naturally occurring nucleoside analogues, but has the medicine of antiviral, antitumor or cytotoxic effect.The example of antitumor nucleoside analog includes, but is not limited to following material: 5-fluorouracil (5-FU), the 5-FU prodrug is [as fluorofur (ftorafur), 5 '-doxifluridine, hexylamine formyl fluoride uracil (carmofur)], floxuridine, 2 '-doxifluridine, floxuridine or 2 '-prodrug derivatives of doxifluridine, flucytosine, arabinosylcytosine, the prodrug of arabinosylcytosine, ancitabine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine, 6-aza uridine, chinaberry alkali (azaridine) 6-azacytidine, three fluoro-methyl-2 '-BrdU, thymidine, and the assorted uridnine of 3-denitrogenation.The example of antiviral nucleoside analogue includes, but is not limited to following material: 5-ethyl-2 '-BrdU, 5-iodo-2 '-BrdU, 5-bromo-2 '-BrdU, 5-methylamino-2 '-BrdU, ara-U, di-deoxyuridine, zalcitabine, 2 ', 3 '-zalcitabine ,-2 '-alkene, 3 '-deoxyribosylthymine-2 '-alkene, 3 '-azido-2 ', 3 '-di-deoxyuridine, and 3 '-zidovudine (AZT).This speech has also comprised the analog (as N-phosphono acetyl group-L-aspartic acid, i.e. PALA) of pyrimidine nucleoside precursor.

It is believed that the structure of some nucleoside analogs and the structural similarity of specific naturally occurring nucleoside.In the scope of The compounds of this invention,, then can be subdivided into cytidine analog to these nucleoside analogs if nucleoside analog has an outer shroud amino (having an amino to show difference between cytidine and the uridnine in this position) in 4 positions of pyrimidine ring.Those nucleoside analogs that specially refer to cytidine analog include, but is not limited to: flucytosine, and arabinosylcytosine, the prodrug of arabinosylcytosine, ancitabine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine, 6-azacytidine and zalcitabine.Those nucleoside analogs that refer in particular to uridine analogs include, but is not limited to: 5-FU, the prodrug of 5-FU is [as fluorofur (ftorafur), 5 '-doxifluridine, hexylamine formyl fluoride uracil (carmofur)], floxuridine, 2 '-doxifluridine, the prodrug derivatives of floxuridine, 2 '-prodrug derivatives of doxifluridine, three fluoro-methyl-2 '-BrdU, the 6-aza uridine, chinaberry alkali (azaribine), the 3-denitrogenation uridnine of mixing, 5-ethyl-2 '-BrdU, 5-iodo-2 '-BrdU, 5-bromo-2 '-BrdU, 5-methylamino-2 '-BrdU, ara-U and di-deoxyuridine.Some cytotoxicity nucleoside analogs also are specific thymidine analog, as AZT.

Here used " at acceptable salt on the materia medica " speech refers to those salt of the addition salts of acceptable acid on materia medica that has derivant, and those acid include, but is not limited to sulphuric acid, hydrochloric acid or phosphoric acid.

Here used " common introducing " speech refers to introduce two kinds of chemical compounds of the present invention at least in the period of a time period overlaid during the corresponding pharmaceutically active of each medicine in this time period.

Here used " alkyl carbonyl " speech refers to an acyl group of carboxylic acid, and the atom that links to each other with carbonylic carbon atom in the carboxylic acid is another carbon atom.Female carboxylic acid is such as being a kind of fatty acid, a kind of aromatic acid, (as benzoic acid, nicotinic acid or congener), a seed amino acid, a kind of cycloalkyl carboxylic acid or a kind of dicarboxylic acids.

" alkyl oxidation carbonyl " speech used herein refers to an acyl group in the monocarboxylic acid, and adjacent with carbonylic carbon atom in the carboxylic acid is oxygen atom, and this oxygen atom is covalently bound with another carbon atom again.The base that also can regard this base as the carbonic ester of alcohol.When using the back when a kind of non-methylated pyrimidine nucleoside breaks apart, further to be degraded to carbon dioxide and a kind of alcohol.Proper alcohol should be that those toxicity are less, and particularly those are easy to enter the alcohol of homergy or drain passage.

Here used " fatty acid " speech refers to the aliphatic carboxylic acid with 2-22 carbon atom.Such fatty acid can be saturated, fractional saturation or the polymerization insatiable hunger closes.

Here used " aminoacid " speech includes, but is not limited to glycine, L type alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, hydroxyproline, serine, threonine, cysteine, cystine, methionine, tryptophan, aspartic acid, glutamic acid, arginine, lysine, histidine, ornithine, oxylysine, carnitine, and other naturally occurring aminoacid.

" dicarboxylic acids " speech used herein refers to the fatty acid with second carboxylic acid substituent.

" therapeutically effective amount " speech used herein refers to can reach a certain conditions and using method the amount of therapeutic effect.

B. chemical compound of the present invention

In all scenario except that special the appointment, in the chemical constitution of The compounds of this invention, represent those letters variable substituent not subscripting and subscripting to be added in to be located on that structure before the described position of this symbol.

It is as follows to be used to alleviate due to the anticancer Anti-virus agent universal architecture of toxic chemical compound:

(1) acyl derivative of uridnine, structural formula is

(2) acyl derivative of cytidine, structural formula is:

R wherein ₁, R ₂, R ₃And R ₄Can be identical or different, can be respectively an acyl group (be have in the described R substituent group at least be not hydrogen atom) of hydrogen atom or metabolite, or substituent a kind of on materia medica acceptable salt.

(3) acyl derivative of deoxycytidine, structural formula is

R wherein ₁, R ₂, and R ₃Can be identical or different, can be respectively hydrogen atom or metabolite an acyl group (be have in the described R substituent group at least be not hydrogen atom) or substituent a kind of on materia medica acceptable salt.

(4) acylated derivatives of BrdU, structural formula is:

R wherein ₁, R ₂And R ₃Can be identical or different, can be respectively hydrogen atom or metabolite an acyl group (be have in the described R substituent group at least be not hydrogen atom) or substituent a kind of on materia medica acceptable salt.

(5) acylated derivatives of uridnine, structural formula is:

A. unbranched fatty acid with 5 to 22 carbon atoms,

C. dicarboxylic acids with 3 to 22 carbon atoms,

(6) a kind of acyl derivative of cytidine, structural formula is:

A. unbranched fatty acid with 5 to 22 carbon atoms,

C. dicarboxylic acids with 3 to 22 carbon atoms,

(7) a kind of acyl derivative of deoxycytidine, structural formula is:

A. unbranched fatty acid with 3 to 22 carbon atoms,

C. nicotinic acid,

D. dicarboxylic acids with 3-22 carbon atom, condition is R ₁, R ₂And R ₃Not H entirely, and work as R ₃When being not H, R ₁And/or R ₂Also acyl group, or be its a kind of on materia medica acceptable salt.

(8) a kind of acyl derivative of BrdU, structural formula is:

A. unbranched fatty acid with 3 to 22 carbon atoms,

C. nicotinic acid,

D. dicarboxylic acids with 3-22 carbon atom, condition is R ₁, R ₂And R ₃Not H entirely, and work as R ₃When being not H, R ₁And/or R ₂But also acyl group, or be its a kind of on materia medica acceptable salt.

(9) a kind of acyl derivative of uridnine, structural formula is:

R wherein ₁, R ₂Or R ₃Have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group being uncorrelated each other, can be hydrocarbylation carbonyl moiety or hydrocarbyl oxycarbonyl base section or H or phosphate.

(10) a kind of acyl derivative of cytidine, structural formula is

R wherein ₁, R ₂, R ₃Or R ₄Have at least one to be the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group being uncorrelated each other, can be alkyl oxidation carbonyl moiety, or hydrocarbyl oxycarbonyl base section or H or phosphate.

(11) a kind of acyl derivative of deoxycytidine, structural formula is:

(12) a kind of acyl derivative of BrdU, structural formula is:

The present invention also comprises the acceptable salt on materia medica of above-claimed cpd.

Useful chemical compound is the fatty acid ester of uridnine and deoxycytidine among the present invention, particularly those in the acyl substituent group with the fatty acid ester of 4 or still less carbon atom.Useful especially chemical compound is with the uridnine of 2 or 3 carbon atoms or the fatty acid ester of deoxycytidine in the acyl substituent group.

The derivant of 3-6 carbon atom of band in the alkyl oxidation carbonyl derivative that other useful chemical compound is uridnine and deoxycytidine among the present invention, particularly those alkyl oxidation carbonyl moieties.

In one embodiment of the invention, on the free hydroxyl on the aldose part of phosphate being received the acylated non-pyrimidine nucleoside that methylates, prepared the prodrug of the The compounds of this invention that water solublity improved.

C. preparation of the present invention

Preparation of the present invention comprises and a kind of one or more above-claimed cpds that acceptable carrier combines on materia medica.

In another embodiment, except that one or more chemical compounds of the present invention, preparation of the present invention also comprises the following at least a reagent that can strengthen the promoting erythrocyte nucleus formation: the oxipurinol nucleoside; the congener of oxipurinol nucleoside; the acyl derivative of oxipurinol nucleoside and their congener as the fatty acid ester of guanosine or deoxyguanosine, (are seen what on February 8th, 1991 went into to hide; serial number is 653882 U.S. Patent application; be incorporated herein for your guidance), a kind of non-ionic surface active agent, a kind of interleukin; (as IL-1;-2 ,-3 ,-4;-5;-6 ,-7 ,-8; be IL-1 preferably; 3, or 6), a kind of colony stimulating factor; as granulocyte colony stimulating factor; (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), and stem cell factor; (SCF) erythropoietin; (EPO) glucosan, polyinosine-poly-cytidine, perhaps other is any to promoting erythropoiesis that the reagent of positive role is arranged.

Can improve the promoting erythrocyte nucleus formation and can be arbitrarily and the general structure of the acylated derivatives of the oxipurinol nucleoside that together uses of chemical compound of the present invention as follows:

R _A=H or with the acyl group of the carboxylic acid of 2 to 30 carbon atoms, and

R _B=H or with the acyl group of the carboxylic acid of 2 to 30 carbon atoms, and

Z=H, OH ,=O, perhaps NHRc, the acyl group of the carboxylic acid of Rc=H or 2-30 carbon atom of band wherein, and

L=H or OR _D, R here _D=H, or the acyl group of the carboxylic acid of 2-30 carbon atom of band, and

M=H or OR _E, R here _E=H, or the acyl group of the carboxylic acid of 2-30 carbon atom of band, and

Q=H ,-halogen, NHR _F, R here _FFor H or contain acyl group of 1 to 10 carbon atom or alkyl, S(S are connected on the carbon with two valence links, in this case, adjacent carbon-to-nitrogen double bon is that a key and a H receive on the N subsequently), SR _G(R here _GBe H or the acyl group that contains 1 to 10 carbon atom or alkyl), O(O and C bivalence bonding, adjacent in this case carbon-to-nitrogen double bon is that a key and a H receive on the N subsequently), or OR _H(R here _HBe H or an acyl group or an alkyl that contains 1 to 10 carbon atom), and

2 of aldose part ' and 3 ' position between the C-C key not essential.

In another embodiment of the present invention, the acylated non-pyrimidine nucleoside that methylates is by a kind of nucleoside that can promote is taken in cell and the chemical compound of phosphorylation, and (as insulin or a kind of carbohydrate that can generate insulin) made.

In another embodiment of the present invention, preparation comprises that (face is entitled as being described in detail these reagent in " therapeutic use of The compounds of this invention and reagent " part as follows at least a chemical compound of the present invention and a kind of antiviral or anti-tumor agent comprising salmosin.）

In another embodiment, reagent of the present invention comprises acyl derivative and a kind of chemical compound that can suppress E.C. 2.4.2.3 of a kind of uridnine or BrdU.Uridnine phosphatization enzyme is a kind of elementary enzyme, participates in the catabolism of uridnine, generates uracil and ribose phosphate ester after the metabolism.Use the chemical compound that suppresses E.C. 2.4.2.3 will improve the pharmacokinetics and the biologic activity of uridnine and BrdU, described uridnine and BrdU are to carry out desacylation by the acylated derivatives to these two kinds of non-methylated pyrimidine nucleosides to generate, the example of the suitable inhibitor of E.C. 2.4.2.3 includes, but is not limited to the derivant of 5-benzyl barbiturate or 5-benzal barbiturate, comprise 5-benzyl barbiturate, 5-benzyloxy benzyl barbiturate, 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate, 5-benzyloxy benzyl acetyl group-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate, the acyclic barbiturate of 5-methoxybenzyl acetyl group, 2 ', 2 '-dehydration-5-ethyl uridnine; And acyclic uridine compound, particularly the acyclic uridnine congener that is replaced by the 5-benzyl includes, but is not limited to the acyclic uridnine of benzyl, the acyclic uridnine of benzyloxy benzyl, the acyclic uridnine of aminomethyl-benzyl, the aminomethyl-acyclic uridnine of benzyloxy benzyl, the acyclic uridnine of methylol-benzyl and methylol-acyclic uridnine of benzyloxy benzyl.Other sees WO89/09603 and WO91/16315, is incorporated herein for your guidance.

In another embodiment of the present invention; preparation comprises a kind of acyl derivative and a kind of chemical compound of the non-pyrimidine nucleoside that methylates; this chemical compound can suppress cell and take in or drain the non-pyrimidine nucleoside that methylates; and then nucleoside content in the blood takes place at the acyl derivative of the non-pyrimidine nucleoside that methylates that uses doses to help to keep after the desacylation of enzyme; such uridnine is carried or excretory regulator includes, but is not limited to persantin (dipyridamole); 4 benzoic acid, lidoflazine (lidoflazine) or nitrobenzyl mercapto inosine (nitrobenzylthioinosine).

In another embodiment of the present invention, preparation comprises a kind of acyl derivative and a kind of chemical compound that can suppress the E.C. 2.4.2.3 this kind of enzyme of cytidine.Because when the acyl derivative of cytidine through cytidine after the desacylation in blood by the part deamination, help to provide uridnine together with cytidine so suppress this kind of enzyme to tissue.

In another embodiment of the present invention, preparation comprises a kind of acyl derivative and a kind of chemical compound that can suppress the deoxycytidine deaminase of cytidine or deoxycytidine.By suppressing the deamination of deoxycytidine or cytidine, the inhibitor of cytidine deaminase or deoxycytidine deaminase (as tetrahydrouridine or tetrahydrochysene-2 '-BrdU), improved the effectiveness of the acyl derivative of cytidine or deoxycytidine.In another embodiment of the present invention, use the inhibitor of a kind of cytidine deaminase or deoxycytidine deaminase to alleviate the toxicity (seeing example 11) of a kind of antiviral or anticancer nucleoside analog

In another embodiment of the present invention, in particular for preventing or treat infringement to gastrointestinal mucosa, preparation comprises that a kind of a kind of acyl derivative of the non-pyrimidine nucleoside that methylates and one or more are used to help mucosa to recover or reduce the reagent of uncomfortable degree.The example of such reagent includes, but is not limited to that sucralfate (sacralfate), two or more on April 21st, 1989 go into to hide, serial number is 341,925, U.S. Patent application (being incorporated herein for your guidance) in the mixture formed of disclosed dezyribonucleoside, allopurinol, antibiotics [as chlorhexidine gluconate (chlorhexidine gluconate)] or local anesthetic (as benzocaine).

According to the purposes of expection, can make liquid to preparation, suspended substance, tablet, capsule, dragee, injectable solution, variforms (discussion in the face of filling a prescription as follows) such as local solution that uses or suppository.

As a kind of alternative to the prescription of the preparation that contains a kind of chemical compound of the present invention and another kind of active reagent (seeing above-mentioned discussion), in another embodiment, chemical compound of the present invention and other active agent are used jointly.

D. the therapeutic use of The compounds of this invention and reagent

Chemical compound of the present invention can be used for preventing or treats infringement to hemopoietic process and function of immune system in the animal body.These chemical compounds cause to the damage of bone marrow or after suppressing in the examination of antiviral or antitumor and reduce hemopoietic infringement by the loss of blood cell count being reduced to minimum mode that described antiviral or anti-tumor agent comprising salmosin influence biosynthesis, metabolism and the utilization of nucleotide.Chemical compound of the present invention can be used for the treatment to the people: but, the present invention does not plan to only limit to this, and the present invention expects to be used for treating all that and used respond well animal behind the reactive compound of the present invention.

The present invention also is further embodied in respectively or together uses a kind of medical compounds of the present invention or reagent, to reach prevention, weaken or change and antiviral or the relevant toxic purpose of anti-tumor agent comprising salmosin of using biosynthesis, metabolism or the utilization that can influence nucleotide.

Use chemical compound of the present invention, preparation and method and the particular case that benefits comprises that the promoting erythrocyte generation system has been subjected to or has been subjected to probably the situation of chemotherapy (particularly can influence the biosynthesis of nucleotide, the chemotherapy of metabolism or utilization) infringement.Such situation comprises that treatment is subjected to the animal (as human patients) of cell reduction cancer chemotherapy or the influence of antiviral chemotherapy, in addition, also keeps application on the veterinary of blood cell count particularly including needs.

Chemical compound and preparation also can be used for preventing and treat the infringement that anticancer or antiviral chemotherapy reagent causes other tissue (comprise-but be not limited to-gastrointestinal epithelial).When being used for this purpose, can choosing oral, suppository or non-intestinal mode wantonly and use these chemical compounds and preparation.

By alleviate anticancer or the antiviral chemotherapy to promoting erythrocyte generation system and immune infringement, Compounds and methods for of the present invention can reduce opportunistic infection or superinfection (antibacterial, virus or the fungal infection) danger that sensitivity is high.

By together being used by the reagent of cell absorption and phosphorylation, can improve the effectiveness of The compounds of this invention with promoting pyrimidine nucleoside.Such reagent comprise promoting erythrocyte growth factor (as G-CSF, GM-CSF, SCF; acylated oxipurinol nucleoside ex hoc genus anne thing; erythropoietin, and interleukin), insulin, and the carbohydrate (as monosaccharide or monosaccharide polymer) that can generate insulin.

Treatment with the anti-cancer chemotherapy complications associated with arterial system

White blood cell count (particularly neutrophil number) with the patient of the anti-tumor chemotherapeutic reagent of standard [as 5-fluorouracil, fluorodeoxyuridine, vinca alkaloids (vinca alkafoids), the alkanisation reagent of cyclophosphamide and other nitrogen mustard, daunoblastin, Dao Kesuo erythromycin, amycin (doxorubicin) methotrexate, cytosine arabinose (cytosine arabinosine), Ismipur, sulfo-crow purine, podophyllotoxin, two hydrazine dichloride platinum or these cells reduction combination of agents thing] treatment sharply reduces through regular meeting.To by influencing the biosynthesis of nucleotide; metabolism or utilization and the situation of the cytotoxic reagent that plays a role; use of the present invention a kind of chemical compound (as the acyl derivative of Triacetyluridine or other uridnine, cytidine, deoxycytidine or BrdU) of (oral or non-intestinal uses) effective dose (as the 0.1-10.0 gram) every day; used several days continuously; can reduce the order of severity of neutropenia, and this disease occurred after the beginning chemotherapy of being everlasting in several days to several weeks.So just reduced the infected probability of patient in the whole course of treatment, make patient may accept more heavy dose of chemotherapy reagent and/or accept the treatment of the repeated doses medicine more frequent than the patient of the matched group that does not use uridine derivatives, similarly, chemical compound of the application of the invention and reagent can remedy the variation of other type hemocyte (lymphocyte, platelet, the erythrocyte etc.) number due to the chemotherapy.

Use useful especially anti-tumor reagent to comprise with Compounds and methods for of the present invention: 5-fluorouracil (5-FU); the prodrug of 5-FU (as fluorofur ftorafur); 5 '-doxifluridine; hexylamine formyl fluoride uracil (carmofur); floxuridine; 2 '-doxifluridine; floxuridine or 2 '-prodrug derivatives of doxifluridine; flucytosine (it also has antifungal activity); arabinosylcytosine; the prodrug of arabinosylcytosine; ancitabine; 5-azepine-2 '-deoxycytidine; arabinose 5-azepine cytosine; N-phosphoryl acetyl group-L-aspartic acid (PALA); pyrazofurin; the 6-aza uridine; 6-azauridine triacetate (azaribine); the 6-azacytidine; three fluoro-methyl-2 '-BrdU; thymidine, and the assorted uridnine of 3-denitrogenation.The nucleoside analog of such anti-tumor agent comprising salmosin and various other treatment usefulness is by influencing the biosynthesis of nucleoside or nucleotide, and utilization or metabolism are worked, so, but the pyrimidine compound of the application of the invention reduces their toxic and side effects.

Can be before using antitumor or Anti-virus agent process, among and/or use chemical compound of the present invention afterwards.Typical situation is, uses chemical compound of the present invention after having used the cancer chemotherapy reagent of doses, as after having used the anti-tumor reagent of effective dose to " remedying " measure of normal structure.

Gastrointestinal epithelial is very sensitive to cancer chemotherapy reagent (as fluorouracil).The mucositis of gastrointestinal mucosa, stomatitis or ulcer are the very common side effect of chemotherapy, can cause diarrhoea, electrolyte imbalance and become thin.Chemical compound of the present invention and preparation can be used for preventing or treat by cancer chemotherapy reagent cause to the gastrointestinal channel infringement of (comprising the oral cavity).Can arbitrarily make them the solution or the suspension (as collutory, as a kind of preparation of swallowing or as enema) of flow morphology when using chemical compound of the present invention and preparation, capsule, dragee, tablet, injection solution or suppository for this purpose.In a planned way use chemical compound of the present invention and preparation also can alleviate infringement anticancer or that antiviral nucleoside analogue causes gastrointestinal mucosa.

The local chemical compound of the present invention (as to scalp) that uses can be used to prevent baldness due to the chemotherapy.

The acyl derivative of uridnine help to prevent or treat since the relevant fluorinated analogues of fluorouracil or uridnine (as floxuridine or its prodrug; fluorodeoxyuridine and prodrug thereof, fluorofur (ftorafur), 5 '-doxifluridine) toxic reaction that causes.Concerning oral situation, useful uridnine acyl derivative is those derivants that replace with short-chain fatty acid, (particularly acetate), the derivant of perhaps using short chain carbyl oxygen base carbonate (as the ethyoxyl carbonic ester) to replace.The acyl derivative of cytidine or deoxycytidine also helps to treat fluorouracil or relevant fluoridizes the toxic reaction that pyrimidine analogue causes.

In typical therapeutic process, the patient accepts the fluorouracil of doses, fluorouracil can be used as a kind of treatment reagent of independent usefulness, or as a part that also comprises the Therapeutic Method that uses other antitumor drug (as methotrexate, formyl tetrahydrofolic acid, PALA or cyclophosphamide).Use 5-FU after several hours to one day, the Triacetyluridine of oral 1 to the 10 gram dosage of patient.The 5-FU of patient's also oral once same dosage in 2 to 4 days subsequently the course of treatment every 6 to 8 hours.The patient also can be weekly (or longer time at interval in) accepts 5-FU in addition and adds the TAU treatment of the course of treatment.

The acyl derivative of uridnine (secondly being cytidine) also be of value to treatment or prevention by N-phosphono acetyl group-L-aspartic acid (PALA), pyrazofurin, 6-aza uridine, 6-azauridine triacetate (azaribine), three fluoro-methyl-2 '-toxic reaction that BrdU and the assorted uridnine of 3-denitrogenation cause.

The acyl derivative of deoxycytidine helps the toxic reaction for the treatment of or preventing to be caused by the antitumor nucleoside analog; above-mentioned analog refers in particular to the analog of cytidine; as arabinosylcytosine or its prodrug, ancitabine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine or 6-azacytidine.To oral situation, the acyl derivative that deoxycytidine is useful is those derivants that replaced by short-chain fatty acid (particularly acetas)

In a typical clinical process that relates to the antitumoral analogue (mainly treating leukemia) that uses arabinosylcytosine or relevant cytidine with them, before or after using doses Ara-C or with the acyl derivative of the deoxycytidine of its simultaneously oral 0.5-10 gram dosage.After this continued to take the acyl derivative 1 to 4 day of the deoxycytidine of this dosage every 6 to 8 hours.According to clinical response, jede Woche (or in longer interval) repeats this Therapeutic Method.

We are intended that the tumor for the treatment of those types that they are commonly used to treat with anti-tumor agent comprising salmosin, effective to leukemia such as, Ara-C and relevant cytidine analog thereof, fluorouracil and the relevant uridine analogs of fluoridizing thereof then are used for the treatment of colon, stomach, the tumor of pancreas and incidence.In one embodiment, use these anti-tumor agent comprising salmosins with common dosage, in this case, chemical compound of the present invention mainly is a degree of having alleviated toxic and side effects.In another embodiment, effect is higher than the anti-tumor agent comprising salmosin of common dosage, and it is higher to guarantee to use such dosage in this case, the safety of the dosage cancer therapy drug that curative effect is positive.In addition, owing to use chemical compound of the present invention and preparation to improve the therapeutic index of antitumor and anticancer agent, can use some specific anti-tumor agent comprising salmosins to treat those tumors for the treatment of without them in the present standard treatment.

The treatment of the complication that viral infection causes

The patient who infected by HIV, particularly those infection develop into " acquired immunodeficiency syndrome " patient (AIDS), symptom and disease that the panimmunity system is badly damaged and causes can occur, and these symptoms and disease have further increased the weight of the degree that immune system is badly damaged in some cases.Have among these patients and much all used antiviral chemotherapy reagent (as AZT), these reagent have adverse effect to the immunologic function and the hemopoietic of human body simultaneously, can further reduce the resistance that human body infects form of ownership.Use chemical compound of the present invention (oral, the injection of intravenous injection or non-intestinal) can improve the blood cell count of reduction because of antiviral chemotherapy reagent (particularly those promote the reagent of the synthesizing of nucleotide, metabolism or utilization, as AZT or zalcitabine).Because anemia and be the factor of dose limitation and limiting speed in patient's AIDS chemotherapy to infecting than high sensitive, so can reduce chemotherapeutical side effect (and then improving people's health degree) with these compounds for treating patient, if and be fit to, allow to adopt the bigger chemical therapeutic method of intensity.AZT and zalcitabine have disadvantageous side effect to the tissue (comprising muscle and peripheral nervous system) beyond the bone marrow.Chemical compound of the present invention and preparation also can be used for treating or preventing such side effect.

Multiple antiviral nucleoside analogue beyond AZT and the zalcitabine all is used for the treatment of viral infection, includes, but is not limited to HIV, herpes or hepatitis.The example of such reagent comprises: 5-ethyl-2 '-BrdU, 5-iodo-2 '-BrdU, 5-bromo-2 '-BrdU, 5-methylamino-2 '-BrdU, 2 '; 3 '-zalcitabine-2 '-alkene, 3 '-deoxyribosylthymine-2 '-alkene, 3 '-azido-2 '; 3 '-di-deoxyuridine, ara-U, di-deoxyuridine, 2 '; 3 '-dideoxy-3 '-fluorothymidine and (S)-1-(3-hydroxyl-2-phosphonium mesitoyl methoxy propyl group) cytosine (HPMPC); referring to WO89/09603, be incorporated herein for your guidance.Chemical compound of the present invention can be used to treat or prevents the harmful side effect of these and relevant other antiviral nucleoside analogue.

In the toxic reaction process that treatment or prevention antiviral chemotherapy cause, can be before using the Anti-virus agent process, among and/or use these chemical compounds and preparation afterwards.Antiviral chemotherapy commonly used (especially for the treatment chronic viral infection, as the therapy of HIV infection) relates to every day, and (often being several every day) uses one or more Anti-virus agents.The clinical effectiveness that arrives according to the observation, the use of The compounds of this invention can every day several times, once a day or number of times still less.In all situations, press common Therapeutic Method, treat with these antiviral drugs and confirmed the viral infection of said medicine clinically their effective those types.Treat patient with antiviral nucleoside analogue, the side effect of the dose drug that perhaps can debase the standard perhaps can allow to use the Anti-virus agent that is higher than that routine is allowed or the dosage that uses.

Toxic reaction for treatment AZT causes can use the acyl derivative of uridnine and/or cytidine or the acyl derivative of deoxycytidine.The acyl derivative of deoxycytidine is useful especially.Concerning oral using method, with short-chain fatty acid (particularly acetas), or with the deoxycytidine of short chain carbyl oxygen base carbonic ester (as the ethoxy carbonic ester) replacement, the acyl derivative of uridnine and cytidine is comparatively desirable.

Under common clinical condition, the patient need accept AZT2 to 4 time every day, and generally must use down indefinitely.According to clinical response, can be once in a week so that every day through the acyl derivative of uridnine, cytidine or the deoxycytidine (perhaps two kinds or whole above-mentioned nucleoside mixture) of 4 oral 1-10 gram dosage.

The acyl derivative of deoxycytidine is of value to treatment or prevents the toxic reaction that zalcitabine causes.

Treatment with the malaria infection complications associated with arterial system

Malaria parasite (as yoelli plasmodium or Plasmodium falciparum) depend on the synthetic passage (de novo sythesis pathway) of the biosynthetic new life of pyrimidine nucleotide; Mammiferous cell generally can utilize newborn passage or " rescue " passage, is incorporated into intracellular nucleotide by these passage high grade nucleotide precursors (as uridnine or cytidine) and concentrates the place.

5-fluororotic acid ester (a kind of analog of pyrimidine nucleotide precursor orotic acid) is poisonous to depending on the biosynthetic malaria parasite of de novo pyrimidine.The biosynthetic inhibitor of other de novo pyrimidine (also has similar toxicity to the malaria parasite as PALA, pyrazofurin or 6-aza uridine.The biosynthetic inhibitor of pyrimidine (particularly including the fluororotic acid ester) is also poisonous to mammal.But use uridnine can weaken the former host toxicity and can not reduce its antimalarial activity to the mammal for the treatment of with 5-fluororotic acid ester (or the biosynthetic inhibitor of other pyrimidine).The active agent that can improve uridnine content in the blood for oral use is the useful source of uridnine herein.Such reagent comprises the acyl derivative of uridnine of the present invention.In treatment malaria process, used the fluororotic acid ester of effective malaria dosage.Before using the fluororotic acid ester, afterwards or meanwhile, used the acyl derivative (Triacetyluridine is useful especially) of uridnine or cytidine, its using dosage is enough to alleviate the toxicity of fluororotic acid ester.The common dose of acylated uridnine or cytidine derivatives (as Triacetyluridine) is the 1-10 gram; access times should satisfy the toxicity that makes the fluororotic acid ester and reduce to minimum requirement; as every day one to four time; the fluororotic acid ester or the uridnine of reusable above-mentioned dosage as required are to overcome malaria infection respectively and to reduce host toxicity.

E. The compounds of this invention and reagent uses and forms

According to the treatment situation, can adopt oral, non-intestinal injection, intravenous injection, local use or alternate manner uses chemical compound of the present invention and reagent.

By monitoring therapeutic effect, those skilled in the art can determine Triacetyluridine at an easy rate, the optimal dose and the medicining times arrangement of (or other acyl derivative of uridnine, cytidine, deoxycytidine or BrdU).

Can be for a long time or use chemical compound of the present invention and reagent off and on.According to the toxic characteristic of chemical treatment reagent, can be chosen in and use before cell reduction or the antiviral chemical treatment reagent, among or use these chemical compounds and reagent afterwards.

The useful acyl derivative that is used for oral uridnine, cytidine, deoxycytidine or BrdU is the derivant that the hydroxyl on those ribose or the deoxyribose ring is replaced by short chain (2-6 carbon atom) fatty acid.Being used for oral, useful derivant also has hydroxyl to be contained the pyrimidine nucleoside of the alkyl oxidation carbonyl substituted of 3-7 carbon atom.

Generally between every day, 0.5-20 restrained, modal be between every day, 2-10 restrained to the dosage of the acyl derivative of oral uridnine, cytidine, deoxycytidine or BrdU.

The acyl derivative of pulverous uridnine, cytidine, deoxycytidine or BrdU all is oral with capsule or tablet form, and is oral although solution, Emulsion or form of suspension also can be used for.

Chemical compound of the present invention can be biodegradable with being intended to, but formulated in biological corrosion or other substrate that discharges gradually, so that continue to discharge these chemical compounds in oral or subcutaneous injection back.To the situation of intravenous or intramuscular injection, can be with being intended to prepare above-claimed cpd in the liposome.

To have the chemical compound of pharmacological activity and suitable acceptable carrier on materia medica and combine arbitrarily, above-mentioned carrier comprises excipient and the auxiliary agent that makes above-mentioned active chemical compound be convenient to handle.Can make tablet to them, dragee, capsule and suppository use.Preparation is such as getting by mouth, and the mode of per rectum or vagina is used, or discharges by the cheek pouch in oral cavity, and can be arbitrarily with the form injection of solution, oral or local use.Preparation can contain about 0.1-99%, the reactive compound of (preferably about 50-90%), and its () and excipient are combined.

To injection or the so non-intestinal using method of intravenous infusion, reactive compound suspends or is dissolved among the water-soluble medium (as sterilized water or saline solution).Injectable solution or suspension can arbitrarily contain a kind of surfactant, as Sorbitan ethoxylate, Isosorbide Dinitrate, polyvinylether or solvent (as propylene glycol or ethanol).Solution contains the reactive compound of 0.01-5% usually.Reactive compound can arbitrarily be dissolved in medicine and the vegetable oil and use for intramuscular injection.Such preparation is the reactive compound that a kind of oil solution wherein contains about 10%-50%.

Suitable excipient comprises filler and binding agent, filler such as can be sugar, as lactose, sucrose, mannitol or sorbitol, the phosphate of cellulose preparation and/or calcium (as tricalcium phosphate, calcium hydrogen phosphate); Binding agent can be to use gelatinized corn starch or gelatin, Tragacanth, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium carboxy methyl cellulose and/or the polyvinylpyrrolidone of making such as corn starch, wheaten starch, rice starch or potato starch.

Adjuvant comprises flow adjustment reagent and lubricant, such as Silicon stone, Talcum, stearic acid and salt thereof (such as magnesium stearate or calcium stearate and/or Polyethylene Glycol.The core of dragee has a suitable covering outward, and it should be able to resist the corrosion of gastric juice the words that need.For this reason, adopted spissated sugar juice, solution can arbitrarily contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, Polyethylene Glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.For preparing the corrosive covering of anti-gastric juice, adopted the solution of suitable cellulose preparation (as phthalic acid acetylcellulose or Monophalic acid ester of hydroxypropyl).Such as, also can arbitrarily add dyestuff or pigment in the covering of tablet or dragee, be used for distinguishing or showing the characteristic of various dose chemical compound.

The method itself for preparing pharmaceutical preparation of the present invention is well-known, such as, can finish by common mixing, pelletize, manufacturing sugar-coat, separation and freeze-dry process.So the method for producing oral drug preparation is, reactive compound is combined with solid excipients, and if want or needs, can arbitrarily pulverize the mixture of gained and process granulous mixture, obtain tablet or dragee at last.

Other is used for the capsule that oral pharmaceutical preparation comprises the extrusion molding of making of gelatin, and the Soft Roll hide glue capsule of making of gelatin and plasticizer (for example glycerol or sorbitol).The capsule of extrusion molding contains granulous reactive compound, and these chemical compounds can be arbitrarily (mix as Talcum or magnesium stearate and plasticizer mutually with filler (as lactose), binding agent (as starch) and/or lubricant.In soft capsule, reactive compound preferably is dissolved or suspended in the suitable liquid (as fatty acid, liquid paraffin or Polyethylene Glycol).In addition, also can arbitrarily add stabilizing agent.

Non-intestinal uses the suitable prescription of reagent to comprise the aqueous solution of water soluble active compound (as water soluble salt).In addition, also can use the suspension that is suitable for the reactive compound that holds altogether with the oil-soluble injectable suspensions.The lipophilic solvent or the media that are suitable for comprise fatty oil (as Oleum sesami or Oleum Cocois) or synthetic fatty acid ester (such as ethyl oleate or triglyceride).The water solublity injectable suspensions can arbitrarily comprise the material that can improve suspension viscosity, and these materials are such as comprising sodium carboxy methyl cellulose, sorbitol and/or glucosan.Suspension can arbitrarily contain stabilizing agent.

In another embodiment, reactive compound can be mixed with the part of skin lotion, is used for local the use.The lipophilic solvent or the media that are suitable for comprise fatty oil (as Oleum sesami or Oleum Cocois) or synthetic fatty acid ester (such as ethyl oleate or triglyceride).

In another embodiment, reactive compound is fitted over the media that is used for directly treating the gastrointestinal mucosa disease.Such example comprises oral washing liquid, i.e. the liquid that will swallow (solution or suspension), or viscous liquid (for example methylcellulose, carboxy methyl cellulose, the solution of xanthan gum etc.These liquid are by oral or use by rectum.

The other medicines preparation that rectum uses (especially for the preparation of treatment colon and rectum) comprises as the suppository by the base be combined into of reactive compound and a kind of suppository.The suppository base that is suitable for is such as being natural or synthetic triglyceride, alkane, Polyethylene Glycol or higher alkanols.In addition, also available gelatin rectal capsule by reactive compound and a kind of base be combined into.The base material is such as comprising liquid triglyceride, Polyethylene Glycol or alkane.

F. The compounds of this invention is synthetic

By making a kind of pyrimidine nucleoside and a kind of carboxylic acid reaction that is activated; the acylated derivatives that can synthesize non-methylated pyrimidine nucleoside; the carboxylic acid that is activated is the carboxylic acid of crossing with suitable agent treated, and the C that handles its carboxylate radical of back is more responsive more to nucleophilic invasion and attack than the C in the original carboxylic acid.The example that is used for the useful active carboxylic acid of synthetic The compounds of this invention is acid chloride, anhydride, n-hydroxy-succinamide ester or with the activatory carboxylic acid of BOP-DC.Select as another kind, carboxylic acid also can pass through coupling agent (as dicyclohexylcarbodiimide, as DCC) and be connected with pyrimidine nucleoside.

In the process of preparation acyl compounds of the present invention; when the acid source of the acyl derivative of expectation had the group (for example hydroxyl or amino) that influence acylation reaction, these groups protected respectively group such as tert-butyl group dimethyl silane ether or t-BOC group before preparing acid anhydride stopped.Such as the 2-t-butyldimethylsilyloxy propanoic acid that lactic acid is converted into the band tert-butyl chloro-silicane, the monosilane ester that is generated then is by the hydrolysis of water solublity base.Protected acid and can be generated acid anhydride by making with DCC reaction.Adopt standard technology, prepare N-t-BOC or N-CBZ derivant with aminoacid, N-t-BOC or N-CBZ are converted into acid anhydride by DDC again then.In the presence that contains the acid (as succinic acid, fumaric acid or adipic acid) more than a carboxylate radical, the anhydride of desired dicarboxylic acids and pyrimidine nucleoside add in dimethyl formamide or the dimethyl acetylamide in pyrimidine or at pyrimidine and react.

According to standard method, in an appropriate solvent, particularly in the mixture of dimethyl acetylamide or dimethyl formamide, use DCC at (ⅰ) dichloromethane and (ⅱ), make aminoacid and cytidine and deoxycytidine exocyclic amino and with the aldose part of pyrimidine nucleoside on hydroxyl coupling mutually.

By make nucleoside in solvent (for example pyrimidine or pyrimidine add dimethyl formamide) under the acid anhydride condition with the reaction of suitable carbyl chloro-formate, can prepare the carbyl oxidation carbonyl derivative of the non-pyrimidine nucleoside that methylates.Under vacuum environment, get rid of solvent, with the column chromatography residue of purifying.

Those of ordinary skills are obviously clear, also can prepare chemical compound of the present invention with other synthetic method.

Following example has been illustrated (but not limiting) method and formulation of the present invention.Other it is obvious to those skilled in the art that and often run in clinical treatment, and other suitably improves and coadapted multinomial condition and parameter also should be included among spirit of the present invention and the protection domain.

Embodiment

Example 1: oral Triacetyluridine is alleviated the haematics toxicity of 5-fluorine pyrimidine

Purpose: the purpose of carrying out this research be want to determine oral TAU so that the effect that mice breaks away from the 5-FU toxic effect whether better than oral uridnine itself.With medullary cell constitute (Bone marrow Cellularity) and on every side blood cell count as the toxic index of 5-FU.

Method: use 5-FU[150mg/Kg to 45 female Balb/C mices (each 20 grammes per square metre) at 12 o'clock at the noon that begins that day in experiment, peritoneal injection (i.p.)] then these animals are divided into 5 groups: matched group [water, oral (i.p.)], oral uridnine 400mg/Kg dosage, oral uridnine 800mg/Kg dosage, non-intestinal uses (peritoneal injection) uridnine 400mg/Kg dosage and oral TAU500mg/Kg/ dosage.

Use after 5-FU2 hour, begin to rescue with uridnine or Triacetyluridine.Each group is being used 2 o'clock that afternoons of 5-FU,, accepts specified treatment at 6 o'clock at 11 o'clock at 3 o'clock at 5 o'clock in and at 9 o'clock in morning next day,, at 1 o'clock in afternoon, and at 4 o'clock.According to circumstances, the uridnine of every dosage or TAU are dissolved in the 0.2ml water and use with gavage, or are dissolved in the 0.2ml saline with the use of i.p. injection.

Use after 5-FU7 days, gather 0.2-0.3ml blood the hole under the eye socket of every group of 5 mices, be injected among the EDTA, supply differential blood count usefulness subsequently.Put to death mice with cervical region dislocation method, take off femur, the hemocyte of discharging is wherein used for counting; The taking-up spleen is also weighed.Use after 5-FU13 days, every group of 5 remaining mices are carried out blood-letting, execution and take out their spleen.

The result

The 7th day

Use 5-FU to cause the hemocyte of all detected types all to descend.Use after 5-FU7 days, neutrophil, lymphocyte and platelet count in the animal for the treatment of by oral TAU all are higher than animals of control group (table 1) significantly.It should be noted that especially leukocyte count in the mice of having accepted TAU is than the mice height of the uridnine of the equal molal quantity dosage of peritoneal injection.Cell number in the mice of oral TAU is also than the mice height of the uridnine of oral same molal quantity (400mg/Kg/ dosage) or twice molal quantity (800mg/Kg/ dosage) dosage.

Platelet count in the mice of oral TAU and peritoneal injection uridnine is (700-800K/ μ l) in normal range.Platelet count is lower than normal level in other groups, in control group mice minimum (table 1).

Use bone marrow cell in the mice that uridnine ruling by law treated to be significantly higher than other any one (tables 2) in organizing with oral TAU and non-intestinal.

The 11st day

An important result is, accepts neutrophil of mice in the group of TAU and the content of RBC and is higher than the group for the treatment of with additive method, comprises those mices (table 3) of the equal molal quantity dosage of peritoneal injection uridnine.

Spleen heavily is that promoting erythrocyte generates an active index in the mice that recovers from bone marrow injury.Use after 5-FU11 days, the spleen representation work in the mice of oral TAU is greater than the other treatment group, and the spleen in the matched group weighs minimum (table 4).

Conclusion

The result of this research shows that oral TAU makes mice save the uridnine that the effect of coming out is better than only oral equal molal quantity or twice molal quantity from 5-FU toxicity, and is better than the effect of the equal molal quantity dosage of peritoneal injection uridnine.

Table 2 uses 5-FU7 days juvenile cell numbers and spleen heavy

It is heavy that myelocyte is counted spleen

Contrast 1.5 ± 0.2 * 10 ⁶/ femur 71 ± 2.6mg

Uridnine 400 oral 1.6 ± 0.2 * 10 ⁶74 ± 2.4

Uridnine 800 oral 2.9 ± 0.9 * 10 ⁶74 ± 6.4

Uridnine 400i.p. 5.0 ± 0.7 * 10 ⁶* 78 ± 5.5

TAU 500 oral 3.0 ± 0.5 * 10 ⁶* 78 ± 3.5

*=and greater than control value, P＜0.05

*=greater than control value, P＜0.01

Table 4 uses the spleen after 5-FU11 days heavy

Spleen is heavy

Contrast 76 ± 7mg

Uridnine 400 oral 103 ± 15

Uridnine 800 oral 99 ± 6*

Uridnine 400i.p. 104 ± 6*

TAU 500 oral 143 ± 11**

*=and greater than control value, P＜0.05

*=greater than control value, P＜0.01

Example 2 is quickened the recovery of the promoting erythrocyte generation system of the animal treated with 5-FU by a kind of dose-dependence TAU

Purpose

The purpose of this test be for confirm and develop before some discoveries, be that oral TAU can quicken the recovery with promoting erythrocyte growing system in the mice treat of 5-fluorouracil (5-FU), and the relation between the response of the promoting erythrocyte generation system of the mice treated with 5-FU of the increase of observation TAU dosage and these.

Method

In experiment beginning at 1 o'clock in afternoon that day, in the female Balb/C mices of 70 each heavily about 20 grams each at peritoneal injection 5-FU(1500mg/Kg).Then these animals are divided into 5 different treatment groups: matched group (water) and dosage are respectively 100,250,500 and the oral TAU group of 1000mg/Kg/ treatment.At the chemical compound that uses 5-FU 3 o'clock that afternoons,, and 9 o'clock the next mornings,, at 1 o'clock in afternoon,, and 10 o'clock service tests at 5 o'clock at 7: 30,10 o'clock at 11 o'clock at 3 o'clock at 6 o'clock; Last use chemical compound is to inject 5-FU at 11 o'clock in the morning two days later in that time.Each treatment all is simultaneously oral with the water of gavage and 0.2ml volume, has only the TAU of last doses and 0.4ml water to use together.

Use the 7th day and the 11st day behind the 5-FU, gathers 0.2-0.3ml blood and inject EDTA from every group of 7 mices with depletion method behind the eye socket, confession is differential blood count usefulness subsequently.Put to death mice with cervical region dislocation method, take out their right femur, discharge the interior material of bone and use for cell counting; Taking out their spleen weighs.

The result

The 7th day

When TAU dosage increased, the quantity of nucleated cell also increased in the bone marrow.Accept such cell number in this group of TAU100 and be similar to, equal cell number in the matched group, and compare the difference obviously bigger (table 5) that medullary cell constitutes in TAU500 and the TAU1000 group with matched group.

TAU dosage be 500 and the therapeutic process of 1000mg/Kg/ treatment make its leukocyte count significantly greater than matched group.

The increase that total neutrophil number also demonstrates with dosage increases, and the above-mentioned quantity in the TAU1000 group reaches 3 times of matched group approximately.

Compare with matched group, the lymphocyte number in TAU500 and the TAU1000 group significantly improves.

Platelet count among the TAU250,500 and 1000 groups significantly improves.Dose response curve reaches straight portion (table 6) in 500mg/Kg/ treatment place.

Table 5 TAU dosage increases use influence of erythrocyte growth effect in the mice after 5-FU7 days.All blood cell count units all are K/ μ l.

Myelocyte WBC has a liking for middle lymph

Contrast 1.70 ± .35 2.46 ± 0.13 0.026 ± 0.011 2.43 ± 0.13

TAU100 1.77±0.18 2.47±0.04 0.014±0.008 2.46±0.04

TAU250 2.91±0.48 2.76±0.20 0.027±0.012 2.71±0.20

TAU500?3.93±0.39*?4.06±0.14*?0.037±0.020?3.99±0.15*

TAU1000?4.42±0.34*?3.57±0.25*?0.071±0.027?3.44±0.23*

* expression is different from matched group, P＜0.01

Table 6 TAU dosage increases using after 5-FU7 days the influence of Red blood corpuscle (RBC) and platelet (PLT) in the mice

RBC(M/μl) PLT(K/μl)

Contrast 8.38 ± 0.18 308 ± 52

TAU100 8.20±0.07 440±46

TAU250 8.51±0.06 601±46**

TAU500 8.43±0.16 712±42**

TAU1000 8.65±0.15 715±35**

* shows and is different from matched group, P＜0.01

The 11st day

Compare with matched group, the spleen at the TAU place of each dosage is heavy all to be increased slightly, and (104.2 ± 3.5mg is than 79.7 ± 3.1 but only in the TAU250 group statistical significance is arranged; P＜0.05)

Compare with control value, the total neutrophil digital display work among the TAU250,500 and 1000 groups improves.

Concerning RBC number, with control value (every microlitre 7.90 ± 0.09 * 10 ⁶) compare, at TAU500 group (every microlitre 8.72 ± 0.18 * 10 ⁶) and TAU1000 group (every microlitre 8.63 ± 0.16 * 10 ⁶) in the hemocyte capacity that significantly increased follow a kind of similar pattern (table 7).

Conclusion

The result of this test confirms and has developed discovery in the past, promptly treat the animal of having accepted 5-FU chemotherapy reagent with TAU and can reverse the illeffects of 5-FU to the erythropoiesis system rapidly, and the effect of TAU is relevant with the dosage of use.

The acyl derivative of example 3. uridnine has alleviated the toxicity of 5-FU to bone marrow

Purpose

The purpose of this experiment is the effectiveness that test and the derivant that compares uridnine and uridnine are damaged mice promoting erythrocyte generation system alleviation chemotherapy reagent 5-fluorouracil (5-FU).

Method

In at 1 o'clock in afternoon that day of research beginning, carry out disposable peritoneal injection 5-FU(150mg/Kg) to every in the female Balb/c mice of 98 heavily about 20 grams.Then these animals are divided into 7 groups, contrast (saline), uridnine (300mg/Kg/ treatment), Triacetyluridine (TAU; 455mg/Kg/ treatment), N-Benzoylurea (BU, 428mg/Kg/ treatment), ECU Diethyl iminodicarboxylate (ECU, 389mg/Kg/ treatment), Caprylurea (OU; 455mg/Kg/ treats) and VU (VU; The 403mg/Kg/ treatment).All these dosage all are to wait molal quantity, and medicine is dissolved in the 0.4ml water and uses by peritoneal injection.At the 3:30 in afternoon of beginning day, 6:00 and 8:30 treat these mices in organizing with its corresponding reagent.The morning next day 9:30, noon 12:00, afternoon, 2:30 and 5:00 used these chemical compounds.The 10:00 in the morning of next day treats for the last time again.

Use the 7th day and 11 days behind the 5-FU, from every group of 7 mices, gather 0.2-0.3ml blood and inject EDTA with depletion method behind the eye socket, supply differential blood count usefulness subsequently, put to death mice with cervical region dislocation method, take out their right femur, discharge hemocyte and use for cell counting; Take out their spleen and weigh.

The result

The 7th day

Even at this some place, each uridine derivatives can both quicken the process that the one or more aspects of promoting erythrocyte generation system are recovered from the 5-FU damage very first time.Like this, compare with the saline control group, the spleen in all groups is heavy all have been improved.(difference of the group of 80.4 ± 7.8mg) ECU(75.7 ± 5.0mg) and VU(69.1 ± 1.7mg) and contrast 62.7 ± 1.8 has reached and has had statistical significance (the degree of P＜.05) to uridnine.

The bone marrow cell of TAU has improved 40%(than control value and has been respectively every microlitre 4.50 ± .77 * 10 ³With every microlitre 2.78 ± .45 * 10 ³).

For white blood cell count, with saline control (every microlitre 4.60 ± .70 * 10 ³) compare (every microlitre 7.26 ± .31 * 10 for the treatment of with ECU ³, P＜.01) and (every microlitre 6.57 ± .49 * 10 for the treatment of with VU ³; P＜.05) all significantly improve.

For platelet, with the contrast that brine treatment is crossed, (every microlitre 523.2 ± 71.4 * 10 ³) compare, with uridnine (every microlitre 785.3 ± 57.5 * 10 ³: P＜.02), the every microlitre 829.6 of BU(± * 10 ³, P＜.01) and the every microlitre 825.7 ± 26.7 * 10 of VU( ³; Be significantly increased in the group of P＜.002) treated.

With saline control group (every microlitre 0.013 ± 0.009 * 10 ³) compare, the total neutrophil number in almost all treatments all has trend of rising, but has only VU group (every microlitre 0.141 ± .027 * 10 ³) raising have statistical meaning (P＜.002) really.

For lymphocyte number, with the every microlitre 7.19 ± 0.32 * 10 of ECU( ³; P＜.01) and the every microlitre 6.42 ± 0.49 * 10 of VU( ³) group for the treatment of is significantly greater than the matched group of brine treatment, (every microlitre 4.59 ± 0.70 * 10 ³).

Only with regard to dosage used in this experiment, compare the longest Caprylurea of carbochain with any other derivant and be proved to be slightly toxicity.Size of animal deficiency in this group can't provide the 11st day data.Overtreatment optimization study (seeing routine 3A) does not show use the recovery of promoting erythrocyte nucleus formation has good effect behind the 5-FU to using than the Caprylurea of low dosage.

The 11st day

By utilizing the treatment of uridine derivatives used in this experiment, in fact each index of promoting erythrocyte systematic function all significantly improves, and these indexes comprise spleen weight, white blood cell count, Red blood corpuscle number, hemocyte capacity, neutrophil number and lymphocyte number (table 8).The spleen of each treatment group is heavy all be higher than matched group (94.7 ± 7.4) wherein the difference of uridnine group (121.6 ± 9.7) BU group (126.9 ± 12.3) and VU group (139.4 ± 8.0) and matched group have statistical significance (P＜.05).

Conclusion

The miscellaneous uridine derivatives of the present invention all helps alleviate the infringement of using chemotherapy reagent 5-FU to be caused.

* show and be different from matched group, P＜.05

* shows and is different from matched group, P＜.01

The Con=contrast, the Urd=uridnine; The TAU=Triacetyluridine; The BU=N-Benzoylurea; The ECU=ECU Diethyl iminodicarboxylate; The VU=VU

Example 3A Caprylurea has been alleviated the haematics toxicity of 5-FU.

Purpose

The purpose of this experiment is to check Caprylurea (Oct-U) to alleviate the effectiveness of 5-fluorouracil (5-FU) to hemopoietic toxic action.

Method

At the research beginning 11:00 in the morning on the same day, every in 14 Balb/c female mices of about 20 grams of counterweight is carried out disposable peritoneal injection 5-FU75mg/Kg.Subsequently in these animals half carried out Oct-U treatment (100mg/Kg/ treatment, peritoneal injection), simultaneously to second half (contrast) injecting normal saline.At 2:30 in afternoon, 4:30 and 7:00 and the morning next day 9:30, at 12 o'clock at the noon of beginning day, afternoon, 2:30 and 5:00 used Oct-U and saline.Other one group 7 mices (basis) are not accepted 5-FU, do not receive treatment yet.

The result

Each top and all each top indexes of being adopted in utilizing the research of this top are measured, use 5-FU to cause the infringement that the promoting erythrocyte generation system is had statistical significance, these indexes comprise that spleen is heavy, medullary cell formation, WBC number, total neutrophil number, lymphocyte number, RBC number, hemocyte volume percent and platelet count (table 9 and 10).Accepted the mice of 5-FU subsequently with Oct-U treatment, the result makes each and parameters of promoting erythrocyte nucleus formation get significantly to improve (table 9 and 10).

Conclusion

The mice of having accepted 5-FU with the Caprylurea treatment can be alleviated 5-FU to hemopoietic toxic action.

The influence that table 9. Caprylurea generates medullary cell formation and medullary cell in the mice of use after 5-FU7 days.

The white thin lymphocyte number of medullary cell leukocyte neutrophilia

(WBC) born of the same parents' number (Nent) (Lym)

Basis 8.96 ± .32,6.89 ± .25,1.85 ± .24,4.78 ± .23

Contrast 4.16 ± .40* 4.04 ± .19* 0.26 ± .03* 3.74 ± .19*

Oct-U 7.73±.68** 5.96±.47** 1.19±.22** 4.62±.29**

* show base set P＜.01

* shows matched group P＜.01

Table 10. Caprylurea is to mice Red blood corpuscle (RBC), platelet (PLT) and the spleen heavy influence of use after 5-FU7 days

RBC PLT spleen is heavy

(M/μl) (K/μl) (mg)

Basis 8.56 ± .17 897 ± 21 83.6 ± 1.7

Contrast 7.98 ± .13* 963 ± 13* 75.4 ± 2.4*

Oct-U 8.13±.14 1243±59* 87.2±3.7**

* represent basic P＜.05

* represents matched group P＜.05

Blood plasma uridnine content behind the acyl derivative of example 4. use uridnine.

Method

In making use-case 3, be used for alleviating a plurality of time points place behind the acyl derivative of toxic uridnine due to the 5-FU (15 minutes, 30 minutes, 1 hour, 2 hours),

Measure the uridnine content of blood plasma in the mice.(every kind of chemical compound is every for mice

The n=3 of individual time point) accepts the peritoneal injection of following compounds: uridnine (300mg/Kg) Triacetyluridine (TAU, 455mg/Kg/ treatment), N-Benzoylurea (BU; The 428mg/Kg/ treatment), ECU Diethyl iminodicarboxylate (ECU; The 389mg/Kg/ treatment); Caprylurea (OU; 455mg/Kg/ treats) and VU (VU; The 403mg/Kg/ treatment).The dosage of the acyl derivative of uridnine equates with the molal quantity of 300mg/Kg uridnine.At the reasonable time point, the Dou Chu behind the mice eye socket takes out blood sample (200 μ l) and carries out centrifugal treating at once.With the methanol of 2 times of volumes the blood plasma of 75 μ l gained is carried out Deproteinization after the centrifugal treating.(PH6.0) carries out lyophilization and reconstruction to the supernatant with the 50mM buffer solution of sodium phosphate, and analyzes uridnine content with the HPLC method on a paraphase (C13) post.With methanol gradient method (in 15 minutes from 2% to 35%) uridnine the 50mM buffer solution of potassium phosphate (PH6.0) is separated from other plasma fraction.UV with the 260nM place absorbs quantification detection uridnine.

The result

As shown in table 11, use the uridnine acyl derivative of all tests can both improve blood plasma uridnine content.Blood plasma uridnine content in the control animal (not accepting any external uridnine or the mice of cytidine derivatives) is 1.1 ± 0.1 μ m.

Blood plasma uridnine concentration behind the acyl derivative of table 11 use uridnine in the mice

Time: 15 minutes 30 minutes 1 hour 2 hours

Chemical compound: blood plasma uridnine concentration (μ M)

Uridnine 911 415 185 5.3

±35 ±86 ±21 ±1.5

Triacetyluridine 666 348 24.5 15.1

±70 ±28 ±7.5 ±1.6

N-Benzoylurea 1,160 353 178 8.6

±45 ±87 ±54 ±1.7

VU 1,001 347 266 7.4

±113 ±117 ±41 ±0.4

Caprylurea 56 14 17 2.2

±22 ±7.4 ±2.9 ±0.04

ECU Diethyl iminodicarboxylate 250 83 44 2.0

±18 ±0.1 ±12 ±1.6

Use the acyl derivative of all uridnine can both improve blood plasma uridnine content, as shown in table 11, by desacylation, acyl derivative forms uridnine continuously.This can not reflect from blood plasma uridnine content, because when the desacylation by the acylate uridine derivant generates uridnine, the uridnine cell that is ingested can make the uridnine that generates in the process constantly reduce.Be important to note that the acylate uridine derivant is to alleviating the toxic effect of 5-FU usually than the uridnine better (seeing the table 8 in the example) of equimolar amounts.

Example 5. has improved the therapeutic index (I) of 5-FU: TAU to separately 5-FU being used to the salvage with mice with tumor.

Purpose

The purpose of this experiment is to estimate and compare the ability of 5-FU therapeutic index in uridnine and the TAU raising band mice with tumor pattern.

Method

To 60 CD8F1(BALB/C * DBA/8) female mice (having transplanted the spontaneous mammiferous adenocarcinoma of first generation CD8F1) carries out weekly chemotherapy treatment, treatment comprises disposable use 150mg/Kg 5-FU, takes various remedial measures then.The average tumor size was 157mg when chemotherapy began.So weekly chemotherapy process is repeated three times.

For estimating the various therapies of remedying, these animals are divided into 6 groups, 10 every group, various situations are as follows:

1. saline: saline (not having 5-FU)

2. use 5-FU:5-FU(150mg/Kg i.p. separately)

3.5-FU+ media: 5-FU(150mg/Kg i.p.)

+ media ¹

4.5-FU+i.p uridnine: 5-FU(150mg/Kg i.p.)

+ uridnine (3500mg/Kg i.p.)

5.5-FU+ oral uridnine: 5-FU(150mg/Kg i.p.)

+ uridnine (5000mg/Kg p.o.) ²

6.5-FU+ oral TAU:5-FU(150mg/Kg i.p.)

+TAU（7582mg/Kg p.o.） ²

¹.1: 1 profit Emulsion+2.5% tween 80

².7582 mg TAU and 5000mg uridnine for etc. molal quantity dosage.

The result

In the conclusion of this three all chemotherapy, compared the mortality rate in each group, and to the surviving animals of sufficient amount, relatively their body weight and the size of tumor.The result is summarized in the following table 12.

Table 12 is united the effect of using 5-FU and TAU or uridnine

The average final tumor weight (mg) of group mortality rate

1. saline 3,/10 7391

2. only use 5-FU 9/10 *

3.5-FU+ media 10/10 *

4.5-FU+i.p. uridnine 1,/10 1604

5.5-FU+ oral uridnine 0,/10 896

6.5-FU+ oral TAU 1,/10 1013

* become nonsensical owing to mortality rate is high

Only accept death in brinish group and be because advancing of disease, accepted 5-FU but death in the group not accepting to remedy is because the toxicity of 5-FU itself.

Conclusion

TAU and uridnine have the effect of the toxic action of rescuing band mice with tumor disengaging 5-FU.Two kinds of reagent have all improved the therapeutic index of 5-FU to the band mice with tumor, and allow and use the more strong dose thing that matches with the raising anticancer effect.

The raising (II) of example 6:5-FU therapeutic index: rescue the band mice with tumor in conjunction with chemotherapy with TAU.

Purpose

The purpose of this experiment be to estimate and relatively TAU and uridnine in the ability that improves the therapeutic index of 5-FU with phosphono acetyl group-L-aspartic acid (PALA), methotrexate sodium (MTX) and LV (LV) when using, employing be a kind of drug dose dosing mode that can improve the cytotoxicity potentiality of 5-FU.

Method

40 male CD8F1 mices of having transplanted the spontaneous breast tumor of CD8F1 (initial tumor weight is 155mg) are carried out the weekly treatment of following method.

PALA-19 hour → MTX-2.5 hour → 5-FU-

100mg/Kg 300mg/Kg 150mg/Kg

2 hours → LV-19 hour → LV

300mg/Kg 300mg/Kg

For estimating and compare the effectiveness of TAU and uridnine, mice is divided into four groups, every group of 10 animals.

1. contrast saline

2. uridnine i.p.: uridnine (3500mg/Kg)

3. uridnine (oral): uridnine (4000mg/Kg)

4.TAU(oral): TAU(6066mg/Kg) ¹

¹With the equal molal quantity dosage of 4000mg/Kg uridnine

After the 5-FU that brings into use doses weekly two hours, used primary brine, uridnine or TAU every 8 hours, carry out 5 such treatments altogether.Weekly like this treatment was carried out for three weeks altogether continuously.After a week of the three phases of embolic chemotherapy, check every group mortality rate, to the surviving animals of sufficient amount, measure their body weight and the weight of tumor.

The result

Table 13 TAU is to the influence of the band mice with tumor mortality rate of the embolic chemotherapy of acceptance associating

The average final tumor weight of group mortality rate

Contrast 10/10 * *

Uridnine i.p. 0,/10 110

Uridnine p.o. 5/10 * *

TAUp.o. 1/10 162

* becomes meaningless owing to mortality rate is high

The death of matched group is because the toxicity of 5-FU.Do not treat mice and be about 3000mg in the tumor weight meansigma methods of this time point.

Conclusion

TAU and uridnine have improved the therapeutic index of the 5-FU of the clinical correlation combiner of using such reagent.Oral TAU and peritoneal injection uridnine are effective equally, and than the uridnine better effects if of oral equal molal quantity dosage.

Example 7 oral DADC have been alleviated the toxicity of arabinosylcytosine to the promoting erythrocyte generation system.

Purpose

The purpose of this experiment is to check DADC (DAdC) and PDC (PdC) to alleviating the effectiveness of chemotherapy agents arabinosylcytosine (Ara-C) to the toxic action of promoting erythrocyte growing system.

Method

Each of peritoneal injection Ara-C100mg/Kg in the Balb/C female mice of 21 heavily about 20g injected 5 days every day altogether.These mices are divided into three treatment groups: oral water (matched group); Oral DAdC(411mg/Kg./ treat) and peritoneal injection PdC(200mg/Kg/ treatment, in 0.2% tween 80, use).9 o'clock every mornings and at 6 o'clock in afternoon twice water, DAdC or PdC treatment mice.The treatment capacity is 0.2ml in each case.Other 7 mices are not accepted Ara-C, do not receive treatment (base set) yet.

After using 5-FU the 7th day and the 11st day gathered 0.2-0.3ml blood with hole depletion method behind the eye socket, and injected EDTA from every group of 7 mices, confession is differential blood count usefulness subsequently.Put to death mice with cervical region dislocation method, take off their spleen and weigh.

The result

Compare with basic mice, use Ara-C significantly to suppress spleen weight, WBC number, total neutrophil number, lymphocyte number and the platelet count (table 14) of control group mice.Do not find that Ara-C has any toxicity to promoting erythrocyte growth effect itself (RBC number, hemoglobin and blood cell capacity).

Oral DAdC and peritoneal injection PdC treat mice and have significantly reversed Ara-C to hemopoietic murder by poisoning.Its spleen weight, WBC number, total neutrophil number and platelet count all are significantly higher than control group mice (table 14).

Conclusion

Use DAdC and PdC to alleviate the toxic action of Ara-C to the mice of having accepted Ara-C to the promoting erythrocyte growing system.

Table 14. DADC (DAdC) or PDC (PdC) are to accepting the hemopoietic therapeutic effect of the mice of arabinosylcytosine (Ara-C) for 5 days.

Spleen WBC Neut PLT

Basis 93.0 ± 2.5 8.66 ± 0.53 1.84 ± 0.12 854 ± 30

Contrast 37.1 ± 1.3 3.60 ± 0.55 0.04 ± 0.02 230 ± 21

DAdC 87.8±3.5** 5.00±0.42 0.42±0.05** 728±64**

PdC 126.0±5.3** 5.20±0.35* 1.22±0.27** 327±30*

* represent with respect to matched group P＜0.05

* represents with respect to matched group P＜0.001

Example 8: oral TAU has been alleviated the illeffects of the antiviral chemotherapy agents azidothymidine AZT (AZT) in the drinking water to the promoting erythrocyte generation system.

Purpose

This experiment purpose is that the oral Triacetyluridine of check (TAU) is to alleviating the infringement of antiviral chemotherapy agents azidothymidine AZT (AZT) to the promoting erythrocyte growing system.

Method

42 Balb-C female mices of each heavily about 19 gram are divided into three different groups, every group each 14.These three groups are respectively base set (do not take AZT, do not receive treatment), matched group (AZT, water) and TAU group (AZT, the dosage of TAU are the 460mg/Kg/ treatment).In whole experiment AZT is arbitrarily put into drinking water and use, concentration is 1.5mg/ml.The amount of used AZT solution is similar in all treatment groups, average every mice 2.25ml every day, and making the dosage of AZT every day is about 170mg/Kg every day.In preceding 24 days of research, water and TAU use 3 times every day, and each consumption 0.2ml changes twice of every day later on into.

Begin that day in experiment, jede Woche once and is just weighed to all animals before execution.After weighing to mice in the 24th day and the 35th day, in every group of 7 mice bodies, gather 0.2-0.3ml blood, and inject EDTA, use for hemocyte (comprising reticulated red blood cells) differential counting subsequently with hole depletion method behind the eye socket.Put to death mice with cervical region dislocation method subsequently, take out their right femur, discharge the usefulness of its inner blood, take off their spleen and weigh for cell counting.

The result

Compare with base set animal (weighing 19.78 ± 0.38), the body weight of only having accepted the mice of AZT at the 7th day significantly reduces (17.55 ± 0.47 grams, P＜0.002), and point at one time, the body weight (19.51 ± 0.38) of the mice for the treatment of with TAU is but basic identical with base set, and significantly greater than (P＜0.005) matched group.At the 13rd day,, still can find this trend though the data between each group do not have the marked difference on the statistics.The 24th day of this experiment, the body weight of AZT matched group all is lower than base set (P＜0.001) equally and treated with TAU on statistical significance mice (P＜0.05).At this time point, the body weight of the animal for the treatment of with TAU also is lower than the base set animal.

The 24th day

RBC number (8.49 ± 0.16) to the mice of only accepting AZT significantly is lower than (P＜0.01) base set (9.07 ± 0.11).RBC number (9.01 ± 0.09) of the animal for the treatment of with TAU and not obviously difference of base set, and be significantly higher than (P＜0.02) matched group.

Total neutrophil number (0.67 ± 0.09) of only accepting in the mice of AZT also significantly is lower than (P＜0.02) base set (1.02 ± 0.08).The amount (0.91 ± 0.06) of the neutrophil in those animals for the treatment of with TAU and not significantly difference of base set, and significantly only accept the group of AZT greater than (P＜0.05).

The 35th day

Basically from this time point, can find out that AZT has very strong illeffects measured each parameter.As RBC number, hemoglobin and blood cell capacity, to compare with basic mice, medullary cell formation, WBC number and lymphocyte number also significantly reduce (table 15).Compare with the base set mice, the mean corpuscular volume of control group mice, average cell blood cell capacity and platelet count all significantly improve (table 14).All these parameters show that all AZT has caused the infringement to the promoting erythrocyte generation system.

Just as making mean corpuscular volume, average cell blood cell capacity the same with the value (table 16) that platelet count significantly is lower than matched group, the therapy of oral TAU also makes RBC number, hemoglobin and blood cell capacity be significantly higher than AZT matched group (table 15).

Reticulated red blood cells number (every microlitre 0.256 * 10 at matched group ⁶, P＜0.001) and than base set number (every microlitre 0.129 * 10 ⁶) when significantly improving, reticulated red blood cells number (every microlitre 0.371 * 10 of those mices for the treatment of with TAU ⁶) be significantly higher than base set (P＜0.001) and matched group (P＜0.01).

Conclusion

From these numbers as can be seen, the therapeutic effect that the infringement that oral TAU causes the promoting erythrocyte growing system AZT is useful.

Table 15.TAU has been alleviated the illeffects of AZT to the mouse red blood cell nucleus formation.The unit of Red blood corpuscle (RBC) number is M/ μ l, and blood cell capacity (HCT) represents that with percentage ratio the unit of hemoglobin (HGB) is gm/dl.

RBC HCT HGB

Basis 9.04 ± 0.08 42.52 ± 0.34 15.57 ± 0.09

Contrast 7.53 ± 0.13 39.29 ± 0.59 14.57 ± 0.26

TAU 8.20±0.20** 41.26±0.62* 15.14±0.12*

* represent with respect to matched group P＜0.05

* represents with respect to matched group P＜0.01

Table 16.TAU has been alleviated the primary cellular defect due to the AZT.Platelet count (PLT) unit is K/ μ l, and the unit of mean corpuscular volume (MCV) is fl, and the unit of mean corpuscular blood cell capacity (MCH) is a microgamma.

PLT MCV MCH

Basis 736 ± 24 47.03 ± .16,17.23 ± .13

Contrast 903 ± 18 52.16 ± .37 19.37 ± .20

TAU 809±06** 50.41±.48* 18.49±.28

* represent with respect to matched group P＜.05

* represents with respect to matched group, P＜.01

Example 9: oral TAU has been alleviated the illeffects of peritoneal injection AZT to the promoting erythrocyte generation system.

Purpose

The purpose of this experiment is to check oral TAU to reversing the effectiveness that non-intestinal uses the infringement that azidothymidine AZT (AZT) causes the promoting erythrocyte generation system.

Method

9 o'clock every mornings, at 4 o'clock in afternoon and, the female Balb/C mice of 56 every heavily about 19 grams is used AZT(100mg/Kg i.p at 10 o'clock) three times.Every day three times (at 9 o'clock in the morning, at 4 o'clock in afternoon and 10 o'clock) with oral dose be 230,460 or the water (contrast) of 920/Kg/ treatment or the mode of TAU treat these animals.The treatment dose is: for matched group and TAU460 group 0.2ml, to TAU230 group 0.1ml, to TAU920 group 0.4ml.14 mices of another group are not accepted AZT and any treatment (base set).

In experiment beginning day, all animals were weighed in the 6th day and the 13rd day.After weighing in the 6th day and the 13rd day, from every group of 7 mices, gather 0.2-0.3ml blood with depletion method behind the eye socket, and inject EDTA, use for hemocyte (comprising reticulated red blood cells) differential counting subsequently.Put to death mice with cervical region dislocation method then, take out their right femur, discharge its inner material and use for cell counting; And take off their spleen, weigh.

The result

The 6th day

Medullary cell in the group for the treatment of with 230mg/Kg TAU constitutes (Bone marrow cellularty) (8.89 ± 0.46) and is significantly higher than that (P＜.05) only accepts the group (7.54 ± 0.23) of AZT.

White blood cell count in the base set is every microlitre 8.23 ± 0.38 * 10 ³AZT makes the WBC number be reduced to every microlitre 6.8 ± 0.66 * 10 ³If, but except that accepting AZT, also use TAU(920mg/kg) treatment, then the amount of WBC returns to foundation level (per minute is counted liter 8.46 ± 0.63 * 10 ³).

Use AZT to make the RBC level from every liter 9.14 ± 0.10 * 10 ⁶(base set) is reduced to every microlitre 8.80 ± 0.31 * 10 ⁶(matched group).Accepting TAU(460mg/Kg/ treatment) mice and accept the every microlitre 9.15 ± 0.07 * 10 of AZT( ⁶) mice in do not find the decline of such amplitude.

The 13rd day

Each used parameter all can become the evidence that statistical significance is arranged that those promoting erythrocyte generation systems that used AZT13 days mice suffer damage in this research.So WBC number, RBC number, hemoglobin, blood cell capacity, reticulated red blood cells number, total neutrophil number and lymphocyte number all significantly reduce, simultaneously, average cell blood cell capacity and platelet count all significantly improve.Treatment (460mg/Kg/ treatment) makes all these measured values that each the raising (table 17 and 18) of statistical significance all occurs to following of carrying out of TAU to the mice of accepting AZT.

Conclusion

With AZT and TAU the treatment of following that mice carries out has significantly been improved the promoting erythrocyte systematic function.This is not always the case to leukocyte and Red blood corpuscle index.

The oral TAU of table 17 has been alleviated the infringement of AZT to bone marrow generation system in the mice.These data are to obtain at the 13rd day that studies.

WBC Neutro lymph platelet

K/μl K/μl K/μl K/μl

Basis 6.8 ± 0.6 1.27 ± 0.11 5.14 ± 0.33 680 ± 30

Contrast 5.1* ± 0.28 0.49* ± 0.07 4.02 ± 0.27 1025* ± 44

TAU 7.0**±0.37 0.62±0.03 6.06**±0.38 863**±26

*=be different from base set, p＜.05

*=be different from matched group, p＜.05

The oral TAU of table 18. has been alleviated the infringement of AZT to bone marrow generation system in the mice.These data are to obtain at the 13rd day that studies.

RBC HGB HCT reticulated red blood cells

M/μl G/dl % M/μl

Basis 9.16 ± 0.06 15.32 ± 0.18 43.18 ± 0.54 0.298 ± 0.028

Contrast 8.15* ± 0.07 14.08 ± 0.13 38.90 ± 0.43 0.086* ± 0.007

TAU?8.58**±0.08?14.54**±0.13?40.83±0.37?0.162**±0.014

*=be different from base set, p＜.05

*=be different from matched group, p＜.05

Example 10: oral DADC (DAdC) has been alleviated the toxicity that intraperitoneal uses AZT that DBA mice promoting erythrocyte generation system is caused.

Purpose

The purpose of this experiment is to check DAdC to reversing the effect that non-intestinal uses the infringement that antiviral chemotherapy reagent azidothymidine AZT (AZT) caused the promoting erythrocyte generation system.

Method

In 9 o'clock every mornings, at 4 o'clock in afternoon and 10 o'clock, to the female mice use AZT three times (100mg/Kg i.p.) of 28 every heavily about 20 grams.9 o'clock every mornings, at 4 o'clock in afternoon and, use method during pipe injected mouthful that animal is carried out three water (contrast) or DAdC(411mg/Kg/ treats at 10 o'clock) treatment.The treatment dose is 0.2ml.14 mices of another group are not accepted AZT and any treatment (basis)

In several days therapeutic process of beginning, have 8 mices and die from fortuitous event in oral water and the DAdC process.So the animal number when putting to death day among matched group and the DAdC is as follows: at the 6th day, 4 mices are arranged in matched group, in the DAdC group 5 mices are arranged; At the 13rd day, 7 mices are arranged in matched group, 3 mices are arranged in DAdC.At these two time points, the number of base set animal all is 7.

At the 6th day and the 13rd day, from every group of 7 mices, gather 0.2-0.3ml blood with depletion method behind the eye socket, and inject EDTA, use for hemocyte (comprising reticulated red blood cells) differential counting subsequently.Put to death mice with cervical region dislocation method then; Take off their right femur, discharge its internal liquid and use for cell counting; And take off their spleen, weigh.

The result

The 6th day

At the 6th day, use AZT causes the infringement to the promoting erythrocyte generation system, and was particularly all the more so to those mices (matched group) of not accepting DAdC.Like this, as RBC number, hemoglobin (HGB) blood cell capacity (HCT) and reticulated red blood cells number, WBC and lymphocyte number also significantly are lower than base set (table 17).Platelet count in these control group mice significantly improves.Compare with base set, myeloma cell's number of matched group has also reduced by 23%.

In contrast, those have accepted AZT but the medullary cell of also having accepted the mice of DAdC treatment only constitutes slightly that (2.5%) reduces, and compare with base set and not have a statistical difference.RBC number, HGB, HCT and reticulated red blood cells number in the DAdC group are compared with base set and indistinction, but are significantly higher than matched group (table 19).

The 13rd day

Compare with the base set animal, the mice of only accepting AZT13 days almost all becomes the evidence that statistical significance arranged of AZT to the promoting erythrocyte system damage in the data aspect each.As in the 6th day data, being seen, follow treatment significantly to alleviate mice carried out or reversed infringement (table 20) due to the AZT the promoting erythrocyte nucleus formation with DAdC.(769 ± 32, P＜.02) also is significantly higher than control animals (950 ± 34) to platelet count in the mice for the treatment of with DAdC.

Conclusion

Treat the function, particularly hemopoietic that the mice of having accepted AZT can significantly be improved the promoting erythrocyte generation system with DAdC.

Table 19 DADC (DAdC) is to hemopoietic therapeutical effect in the mice of having accepted AZT and reaching 6 days

RBC HGB HCY reticulated red blood cells

Basis 9.47 ± .18,13.93 ± .20,40.83 ± .83 .326 ± .039

Contrast 8.53 ± .33* 12.60 ± .40* 36.32 ± 1.54* .017 ± .004*

DAdc?9.49±.32**?13.96±.40**?40.84±1.35**?.205±.075**

* expression is different from base set, P＜.05

* represents to be different from matched group, P＜.05

Table 20 DADC (DAdC) is to hemopoietic therapeutical effect in the mice of having accepted AZT and reaching 13 days

RBC HGB HCT reticulated red blood cells

Basis 9.95 ± .13,14.83 ± .19,42.83 ± .41 .637 ± .044

Contrast 8.51 ± .05* 13.06 ± .07* 37.21 ± .13* .365 ± .022*

DAdc?9.16±.32**?13.97±.39**?41.53±1.17**?.814±.069**

* expression is different from basis, P＜.05

* represents to be different from contrast, P＜.05

Example 11: oral diacetyl cytidine (DAdC) or tetrahydrouridine (THU) have been alleviated the illeffects of peritoneal injection use AZT to the promoting erythrocyte generation system of Balb/C mice.

Purpose

The purpose of this experiment is to check oral DAdC or non-intestinal to use THU to use the effectiveness of antiviral chemotherapy agents azidothymidine AZT (AZT) to the infringement of promoting erythrocyte generation system to reversing non-intestinal.

Method

In 9 o'clock every mornings, at 4 o'clock in afternoon and 10 o'clock, female Balb/C mice to 21 every heavily about 20 grams is used AZT three times (100mg/Kg/i.p), 9 o'clock every mornings, at 4 o'clock in afternoon and 10 o'clock, 7 animals are carried out water (contrast, p.o.) or DAdC(300mg/Kg/p.o.) or the THU(12.5mg/Kg/ treatment, in 0.2% Tween 80, peritoneal injection) treatment.The treatment dose is 0.2ml.7 mices of another group are not accepted AZT and any treatment (basis).

At the 13rd day, from every group of mice, take 0.2-0.3ml blood with depletion method behind the eye socket, and inject EDTA, use for hemocyte (comprising reticulated red blood cells) differential counting subsequently.Put to death mice with cervical region dislocation method then, take off their right femur, discharge its internal liquid and use for cell counting; And the spleen that takes off them is weighed.

The result

Follow treatment significantly to alleviate or reversed the infringement (table 21) of AZT what mice carried out with DAdC the promoting erythrocyte nucleus formation.Total neutrophil number (1.39 ± 0.14 in the mice for the treatment of with DAdC; P＜.01) also is significantly higher than control animals (0.74 ± 0.10).

As hemopoietic, the myeloid tissue of accepting AZT and accepting the mice of THU treatment generates and also is significantly improved than matched group.(6.06 ± 0.35, P＜.05) also is significantly higher than matched group (4.73 ± 0.36) to total white blood cell count in the THU group.Observe in addition, the total neutrophil number (1.16 ± 0.15) in the group for the treatment of with THU has been compared marked difference (P＜.05) with matched group (0.74 ± 0.10).Lymphocyte number also has improvement, but its difference does not have statistical significance in this experiment.In addition, the reticulated red blood cells index (percentage ratio and M/ μ l) in the THU group for the treatment of also is significantly higher than (the matched group of P＜.05).

Conclusion

Accept the Balb/C mice of AZT with DAdC or THU treatment and can improve promoting erythrocyte growth function.

Table 21 DADC (DAdC) is to hemopoietic therapeutical effect in the Balb/C mice of having accepted AZT and reaching 13 days

RBC HGB HCT reticulated red blood cells

Basis 8.63 ± .11,15.37 ± .08,41.01 ± 0.52 .089 ± .009

Contrast 7.55 ± .11* 13.71 ± .22* 35.96 ± 0.46* .039 ± .004*

DAdc?8.26±.13**?14.97±.15**?39.51±0.61**?.059±.006**

* expression is different from basis, P＜.05

* represents to be different from contrast, P＜.05

The blood plasma uridnine level of example 12. behind oral uridnine or diacetyl uridnine (TAU) under the situation that is with or without the persantin participation.

Purpose

The purpose of this experiment is to prove that TAU is a kind of Orally active reagent than the more effective raising blood plasma of uridnine uridnine level itself, and the proof persantin (is DPM, a kind of absorption-blocking agent of nucleoside also has antiviral activity) to using the influence of blood plasma uridnine level behind TAU or the uridnine.

Method

The female Balb/C mice of about 20 grams of body weight is divided into 4 groups, 8 every group:

1. uridnine (1000mg/Kg) p.o.

2.TAU（1500mg/Kg）p.o.

3. uridnine (1000mg/Kg) p.o+DPM(25mg/Kg i.p)

4.TAU(1500mg/Kg) p.o+DPM(25mg/Kg i.p.) (1500mg/Kg TAU is the dosage with molal quantitys such as 1000mg/Kg uridnine)

Before using uridnine or TAU, used persantin with the mode of peritoneal injection in 30 minutes.

Aqueous solution with the 0.4ml of oral gavage uridnine.

With gavage TAU is fitted over a kind of Emulsion media (Semen Maydis oil/water of 1: 1 is to 2.5% Tween 80).

Get 2 mices from the vasoganglion blood-letting of eye socket bottom from every group: after using TAU or uridnine in the basic uridnine level of following each time point: 0(before TAU or uridnine use) 0.5,1,2 and 4 hour.

Add 0.2ml methanol, (0.1ml) carries out deproteinization to plasma sample, carries out centrifugal treating then.With HPLC buffer solution (100mM ammonium acetate, PH6.5 is for measuring uridnine with the Uv absorption process at 254nm place by paraphase HPLC subsequently) sample is carried out lyophilization and reconstruction.

Data point is the meansigma methods of each two sample in time point place.

The result

Behind the oral uridnine, the uridnine in the blood plasma reaches 6 micromolar peak concentrations.On the contrary, the oral TAU of molar dose that waits makes peak value blood plasma uridnine level reach 260 micromoles, so just proves that TAU is much outstanding than uridnine as a kind of Orally active reagent that improves blood plasma uridnine level.

Persantin has further improved behind (about 2 times) oral TAU in the blood amplitude (peak value uridnine level reaches 460 micromoles) of uridnine level and has had persistency.

Similarly, persantin has also improved the persistency of blood uridnine level behind the oral uridnine, though above-mentioned level is more much lower than the corresponding mice of having accepted TAU, (honeybee value blood plasma uridnine level is 20 micromoles).

These results are summarized in the table 22.

The blood plasma uridnine concentration of table 22. behind oral uridnine or TAU under the situation that is with or without the persantin participation.

Blood plasma uridnine level after oral TAU or the uridnine

Treated 0 hour 0.5 hour 1 hour 2 hours 4 hours

Uridnine 24642

TAU 2 240 260 110 12

Uridnine+DPM 2 10 20 10 4

TAU+DPM 2 280 460 440 32

Conclusion

Blood plasma uridnine level behind the oral TAU than oral uridnine after viewed level much higher.TAU is exactly a blood plasma uridnine source more much better than uridnine itself after oral like this.Persantin has suppressed the uridnine into cell of certain some type that is ingested, and has so just improved the amplitude and the persistency of blood plasma uridnine concentration behind oral TAU or the uridnine.

Example 13: ECU Diethyl iminodicarboxylate synthetic

With 2.64mM(1.5 times of equivalent) ethyl chloroformate one after another drop of join 0.5 gram 2 ', 3 '-the ice-cold solution of isopropylidene uridnine (1.76mM) and 10ml pyrimidine, add fashionable continuous stirring.Can be heated to reaction under the room temperature (25 ℃) and carry out, and stir (18 hours) whole night up to TLC(9: 1 chloroform/methanol) demonstrate all initial substances and all be transformed into a kind of single product.Go down to desolventize at condition of high vacuum degree with the rotary evaporation method, obtain a kind of light ecru juice, this juice is moved to following deproteinization step.

Juice is dissolved in the formic acid of 15ml50%, heated 2 hours down at 60-70 ℃, the propylidene component that demonstrates capacity up to TLC is removed fully.Under condition of high vacuum degree, remove water and formic acid, obtain a kind of light ecru juice, then it is put into a silicagel column with evaporation, and with 95: 5 chloroform/methanol elution.Collect, concentrate and evaporation contains the component of product, obtain a kind of peach slightly glassy product.

Foregoing is intended to set forth the present invention rather than restriction the present invention.The present invention can have various effective modification and improvement under the situation that does not deviate from true spirit of the present invention and scope.

Claims

1, a kind ofly prevents and treat toxic method due to a kind of pyrimidine nucleoside analoys, comprise a kind of acylated derivatives that a kind of animal is used a kind of non-methylated pyrimidine nucleoside with materia medica therapeutically effective amount.

2, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates are a kind of acyl derivatives of uridnine, cytidine, deoxycytidine or BrdU.

3, a kind of the method for claim 1, wherein said toxicity are the infringements to hemopoietic tissue.

4, a kind of the method for claim 1, wherein said toxicity are the infringements to mucosal tissue.

5, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are a kind of anti-tumor agent comprising salmosins.

6, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are a kind of Anti-virus agents.

7, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are a kind of malaria reagent.

8, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are a kind of cytotoxicity analog of uridnine.

9, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are a kind of cytotoxicity analog of cytidine.

10, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are the biosynthetic a kind of inhibitor of pyrimidine nucleoside.

11; a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are to be selected from one group of material that following material is formed: 5-fluorouracil (5-FU); the prodrug of 5-FU; floxuridine; 2 '-doxifluridine; floxuridine or 2 '-prodrug derivatives of doxifluridine; flucytosine; three fluoro-methyl-2 '-BrdU; arabinosylcytosine; the prodrug of arabinosylcytosine; ancitabine; 5-azepine-2 '-deoxycytidine; arabinose 5-azepine cytosine; the 6-azacytidine; N-phosphono acetyl group-L-aspartic acid (PALA); pyrazofurin; the 6-aza uridine; 6-azauridine triacetate; thymidine and 3-denitrogenation uridnine.

12, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys be selected from one group of material: AZT that following material forms, zalcitabine, 5-ethyl-2 '-deoxycytidine, 5-iodo-2 '-deoxycytidine, 5-bromo-2 '-BrdU, 5-methylamino-2 '-BrdU, ara-U, di-deoxyuridine and (S)-1-(3-hydroxyl-2-phosphonium mesitoyl methoxy propyl group) cytosine.

13, a kind of the method for claim 1, wherein said pyrimidine nucleoside analoys are 5-fluororotic acid esters.

14, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a Triacetyluridine.

15, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is an ECU Diethyl iminodicarboxylate.

16, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates are the triacetyl cytidines.

17, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a DADC.

18, a kind of the method for claim 1; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is the acylated derivatives of uridnine, BrdU or cytidine, and described use step also comprises the inhibitor that uses a kind of E.C. 2.4.2.3.

19; a kind of the method for claim 1; the inhibitor of wherein said E.C. 2.4.2.3 is to be selected from one group of material that following material is formed: the acyclic uridnine of benzyl; the acyclic uridnine of benzyloxy benzyl; the acyclic uridnine of aminomethyl-benzyl; aminomethyl-acyclic the uridnine of benzyloxy benzyl; the acyclic uridnine of hydroxymethyl-benzyl; hydroxymethyl-benzyloxy benzyl-acyclic uridnine and 2; 2 '-dehydration-5-second uridnine; 5-benzyl barbiturate; 5-benzyloxy benzyl barbiturate; 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate; 5-benzyloxy benzyl acetyl group-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate and the acyclic barbiturate of 5-methoxy-benzyl acetyl group.

20, a kind of the method for claim 1, the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates are the acylated derivatives of cytidine, deoxycytidine, and described use step also comprises the inhibitor that uses a kind of cytidine deaminase.

21, a kind of method as claimed in claim 20, the inhibitor of wherein said cytidine deaminase are to be selected from one group of material that following material is formed: tetrahydrouridine or tetrahydrochysene-2 '-BrdU.

22, a kind of the method for claim 1; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine, cytidine or deoxycytidine, and described use step also comprises the inhibitor that uses a kind of nucleoside to shift.

23, a kind of method as claimed in claim 22, the inhibitor that wherein said nucleoside shifts are to be selected from one group of material that following material is formed: persantin, 4 benzoic acid, lidoflazine (lidoflazine) or nitrobenzyl mercapto inosine.

24, a kind of the method for claim 1, wherein said use step also comprise uses a kind of energy to improve hemopoietic reagent.

25, a kind of the method for claim 1, wherein said use step also comprise using and a kind ofly can promote the absorption of cell and the chemical compound of nucleoside phosphorylaseization.

26, a kind of method of preventing to use the opportunistic infection after the chemotherapy comprises a kind of acyl derivative that a kind of animal is used a kind of non-methylated pyrimidine nucleoside of the amount with curative effect of medication.

27, a kind of treatment method for cancer comprises:

(a) use a kind of pyrimidine nucleoside analoys, and

(b) use a kind of acyl derivative of non-methylated pyrimidine nucleoside of the amount with curative effect of medication.

28; a kind of method as claimed in claim 27, wherein said pyrimidine nucleoside analoys are to be selected from one group of material that following material is formed: 5-fluorouracil (5-FU); the prodrug of 5-FU; floxuridine; 2 '-doxifluridine; floxuridine or 2 '-prodrug derivatives of doxifluridine; flucytosine; three fluoro-methyl-2 '-BrdU; arabinosylcytosine; the prodrug of arabinosylcytosine; ancitabine; 5-azepine-2 '-deoxycytidine; arabinose 5-azepine cytosine; the 6-azacytidine; N-phosphono acetyl group-L-aspartic acid (PALA); pyrazofurin; the 6-azauridine; 6-azauridine triacetate; thymidine and 3-denitrogenation uridnine.

29, a kind of method as claimed in claim 27; wherein said pyrimidine nucleoside analoys is the analog of 5-fluorine pyrimidine or 5-'-fluoropyrimidine nucleosides, and the acylated derivatives of described a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine, cytidine or BrdU.

30, a kind of method as claimed in claim 29, wherein said 5-fluorine pyrimidine or 5-fluoropyrimidine nucleoside analogue are to be selected from one group of material that following material is formed: the prodrug of 5-fluorouracil (5-FU), 5-FU, floxuridine, 2 '-prodrug derivatives, 2 of doxifluridine, floxuridine '-prodrug derivatives of prodrug derivatives, 5-flurocytosine, 5-fluorine cytidine or the 5-fluorine cytidine of doxifluridine.

31, a kind of method as claimed in claim 27; wherein said pyrimidine nucleoside analoys be N-phosphono acetyl group-L-aspartic acid (PALA), pyrazofurin, 6-azauridine, 6-azauridine triacetate, three fluoro-methyl-2 '-BrdU or the assorted uridnine of 3-denitrogenation, and the acyl derivative of described a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine or cytidine.

32, a kind of method as claimed in claim 27, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates are a kind of acyl derivatives of uridnine, cytidine, deoxycytidine or BrdU.

33, a kind of method as claimed in claim 27, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a Triacetyluridine.

34, a kind of method as claimed in claim 27, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is an ECU Diethyl iminodicarboxylate.

35, a kind of method as claimed in claim 27, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is the triacetyl cytidine.

36, a kind of method as claimed in claim 27, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a DADC.

37, a kind of method as claimed in claim 27, wherein said pyrimidine nucleoside analoys are a kind of antitumoral analogues of cytidine, and the acyl derivative of the described non-pyrimidine nucleoside that methylates is a kind of acyl derivative of deoxycytidine.

38, a kind of method as claimed in claim 27, the antitumoral analogue of wherein said cytidine be arabinosylcytosine or its prodrug, ring cytosine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine or 6-azacytidine.

39, a kind of method as claimed in claim 27; wherein said pyrimidine nucleoside analoys is a kind of analog of uridnine; the acylated derivatives of described a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine, BrdU or cytidine, and described use step (b) also comprises a kind of inhibitor that uses E.C. 2.4.2.3.

40; a kind of method as claimed in claim 39; the inhibitor of wherein said E.C. 2.4.2.3 is to be selected from one group of material that following material is formed: the acyclic uridnine of benzyl; the acyclic uridnine of benzyloxy benzyl; the acyclic uridnine of aminomethyl-benzyl; aminomethyl-acyclic the uridnine of benzyloxy benzyl; the acyclic uridnine of hydroxymethyl-benzyl; hydroxymethyl-benzyloxy benzyl-acyclic uridnine and 2,2 '-dehydration-5-second uridnine; 5-benzyl barbiturate; 5-benzyloxy benzyl barbiturate; 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate; the acyclic barbiturate of 5-methoxy-benzyl acetyl group.

41, a kind of method as claimed in claim 27; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of cytidine or deoxycytidine, and described use step (b) also comprises a kind of inhibitor that uses the cytidine deaminase.

42, a kind of method as claimed in claim 27, the inhibitor of wherein said cytidine deaminase are to be selected from one group of material that following material is formed: tetrahydrouridine or tetrahydrochysene-2 '-BrdU.

43, a kind of method as claimed in claim 27; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine, cytidine or deoxycytidine, and described use step (b) also comprises the inhibitor that uses a kind of nucleoside to shift.

44, a kind of method as claimed in claim 43, the inhibitor that wherein said nucleoside shifts are to be selected from one group of material that following material is formed: persantin, 4 benzoic acid, lidoflazine (lidoflazine) or nitrobenzyl mercapto inosine.

45, a kind of method as claimed in claim 27, wherein said use step (b) also comprise uses a kind of energy to promote hemopoietic reagent.

46, a kind of method as claimed in claim 27, wherein said use step (b) also comprise using and a kind ofly can strengthen the absorption of cell and the chemical compound of nucleoside phosphorylaseization.

47, a kind of method as claimed in claim 27, wherein said use step (b) also comprise uses AZT.

48, a kind of method for the treatment of viral infection comprises:

(a) use a kind of pyrimidine nucleoside analoys, and

(b) use a kind of acyl derivative with a kind of non-methylated pyrimidine nucleoside of curative effect of medication amount.

49, a kind of method as claimed in claim 48, wherein said viral infection is AIDS.

50, a kind of method as claimed in claim 48, wherein said viral infection is a herpes.

51, a kind of method as claimed in claim 48, wherein said viral infection is a hepatitis.

52; a kind of method as claimed in claim 48; wherein said pyrimidine nucleoside analoys is to be selected from one group of material: AZT that following material is formed; zalcitabine; 2 '; 3 '-zalcitabine-2 '-alkene; 3 '-deoxyribosylthymine-2 '-alkene; 3 '-nitrine-2 '; 3 '-di-deoxyuridine; 5-ethyl-2 '-BrdU; 5-iodo-2 '-BrdU; 5-bromo-2 '-BrdU; 2 ', 3 '-dideoxy-3-fluorothymidine; 5-methylamino-2 '-BrdU; ara-U; di-deoxyuridine and (S)-1-(3-hydroxyl-2-phosphonium mesitoyl methoxy propyl group) cytosine.

53, a kind of method as claimed in claim 48, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates are a kind of acyl derivatives of uridnine, cytidine, deoxycytidine or BrdU.

54, a kind of method as claimed in claim 48, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a Triacetyluridine.

55, a kind of method as claimed in claim 48, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is an ECU Diethyl iminodicarboxylate.

56, a kind of method as claimed in claim 48, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is the triacetyl cytidine.

57, a kind of method as claimed in claim 48, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a DADC.

58, a kind of method as claimed in claim 48, wherein said pyrimidine nucleoside analoys is AZT, and the acyl derivative of described a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine, cytidine or deoxycytidine.

59, a kind of method as claimed in claim 48, wherein said pyrimidine nucleoside analoys is a zalcitabine, and the acyl derivative of described a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of deoxycytidine.

60, a kind of method as claimed in claim 48; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine, BrdU or cytidine, and described use step (b) also comprises the inhibitor that uses a kind of E.C. 2.4.2.3.

61; a kind of method as claimed in claim 48; the inhibitor of wherein said E.C. 2.4.2.3 is to be selected from one group of material that following material is formed: the acyclic uridnine of benzyl; the acyclic uridnine of benzyloxy benzyl; the acyclic uridnine of aminomethyl-benzyl; aminomethyl-acyclic the uridnine of benzyloxy benzyl; the acyclic uridnine of hydroxymethyl-benzyl; hydroxymethyl-benzyloxy benzyl-acyclic uridnine and 2; 2 '-dehydration-5-second uridnine; 5-benzyl barbiturate; 5-benzyloxy benzyl barbiturate; 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate; 5-benzyloxy benzyl acetyl group-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate and the acyclic barbiturate of 5-methoxy-benzyl acetyl group.

62, a kind of method as claimed in claim 48; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of cytidine or deoxycytidine, and described use step (b) also comprises the inhibitor that uses a kind of cytidine deaminase.

63, a kind of method as claimed in claim 48, the inhibitor of wherein said cytidine deaminase are to be selected from one group of material that following material is formed: tetrahydrouridine or tetrahydrochysene-2 '-BrdU.

64, a kind of method as claimed in claim 48; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine, cytidine or deoxycytidine, and described use step (b) also comprises the inhibitor that uses a kind of nucleoside to shift.

65, a kind of as the described method of claim 64, the inhibitor that wherein said nucleoside shifts is to be selected from one group of material that following material is formed: persantin, 4 benzoic acid, lidoflazine (lidoflazine) or nitrobenzyl mercapto inosine.

66, a kind of method as claimed in claim 48, wherein said using method (b) comprise that also a kind of energy promotes hemopoietic reagent.

67, a kind of method as claimed in claim 48, wherein said use step (b) comprise that also effect a kind ofly can promote the absorption of cell and the chemical compound of nucleoside phosphorylaseization.

68, a kind of method for the treatment of viral infection comprises:

(a) use a kind of pyrimidine nucleoside analoys, and

(b) use a kind of inhibitor with a kind of deoxycytidine deaminase of curative effect of medication amount.

69, a kind of as the described method of claim 68, wherein said pyrimidine analogue is to be selected from one group of material being made up of AZT and zalcitabine.

70, a kind of as the described method of claim 68, the inhibitor of wherein said deoxycytidine deaminase be tetrahydrouridine or tetrahydrochysene-2 '-BrdU.

71, a kind of method for the treatment of malaria infection comprises:

(a) use a kind of pyrimidine nucleoside analoys, and

(b) use a kind of acyl derivative of a kind of non-pyrimidine nucleoside that methylates of the amount with curative effect of medication.

72, a kind of as the described method of claim 71, wherein said pyrimidine nucleoside analoys is a 5-fluororotic acid ester, and a kind of acyl derivative of the non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine or cytidine.

73, a kind of as the described method of claim 71; the acylated derivatives of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acylated derivatives of uridnine or cytidine, and described use step (b) also comprises the inhibitor that uses a kind of E.C. 2.4.2.3.

74; a kind of as the described method of claim 73; the inhibitor of wherein said E.C. 2.4.2.3 is to be selected from one group of material that following material is formed: the acyclic uridnine of benzyl; the acyclic uridnine of benzyloxy benzyl; the acyclic uridnine of aminomethyl-benzyl; aminomethyl-acyclic the uridnine of benzyloxy benzyl; the acyclic uridnine of hydroxymethyl-benzyl; hydroxymethyl-benzyloxy benzyl-acyclic uridnine and 2; 2 '-dehydration-5-second uridnine; 5-benzyl barbiturate; 5-benzyloxy benzyl barbiturate; 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate; 5-benzyloxy benzyl acetyl group-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate and the acyclic barbiturate of 5-methoxy-benzyl acetyl group.

75, a kind of preparation comprises: a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; With a kind of anti-tumor agent comprising salmosin.

76; a kind of as the described reagent of claim 75, wherein said anti-tumor agent comprising salmosin is to be selected from one group of material that following material is formed: 5-fluorouracil (5-FU); the prodrug of 5-FU; floxuridine; 2 '-doxifluridine; floxuridine or 2 '-prodrug derivatives of doxifluridine; flucytosine; three fluoro-methyl-2 '-BrdU; arabinosylcytosine; the prodrug of arabinosylcytosine; ancitabine; 5-azepine-2 '-deoxycytidine; arabinose 5-azepine cytosine; the 6-azacytidine; N-phosphono acetyl group-L-aspartic acid (PALA); pyrazofurin; the 6-azauridine; 6-azauridine triacetate; (azaribine); thymidine and 3-denitrogenation uridnine.

77, a kind of as the described reagent of claim 75, the acyl derivative of the wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of cytidine, and described anti-tumor agent comprising salmosin is a kind of analog of cytidine.

78, a kind of as the described reagent of claim 77, the antitumoral analogue of wherein said cytidine be arabinosylcytosine or its prodrug, ancitabine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine or 6-azacytidine.

79, a kind of the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a deoxycytidine as the described reagent of claim 75, and described anti-tumor agent comprising salmosin is a kind of analog of cytidine.

80, a kind of as the described reagent of claim 79, wherein said cytidine analog be arabinosylcytosine or its prodrug, ancitabine, 5-azepine-2 '-deoxycytidine, arabinose 5-azepine cytosine or 6-azacytidine.

81, a kind of preparation comprises: a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; With a kind of Anti-virus agent.

82, a kind of as the described reagent of claim 81, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine, cytidine or deoxycytidine, and described Anti-virus agent is AZT.

83; a kind of as the described reagent of claim 81; wherein said Anti-virus agent is to be selected from one group of material: AZT that following material is formed; zalcitabine; 2 '; 3 ' zalcitabine-2 '-alkene; 3 '-deoxyribosylthymine-2 '-alkene; 3 '-nitrine-2 '; 3 '-di-deoxyuridine; 5-ethyl-2 '-BrdU; 5-iodo-2 '-BrdU; 5-bromo-2 '-BrdU; 2 ', 3 '-dideoxy-3-fluorothymidine; 5-methylamino-2 '-BrdU; ara-U; di-deoxyuridine and (S)-1-(3-hydroxyl-2-phosphonium mesitoyl methoxy propyl group) cytosine.

84, a kind of preparation comprises: a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; With a kind of malaria reagent.

85, a kind of as the described reagent of claim 84, the acyl derivative of wherein said a kind of non-pyrimidine nucleoside that methylates is a kind of acyl derivative of uridnine or cytidine, and described malaria reagent is 5-fluororotic acid ester.

86, a kind of as the described reagent of claim 84, wherein said malaria reagent is to be selected from one group of material that following material is formed: 5-fluororotic acid ester, PALA or 6-azauridine.

87, a kind of preparation comprises: a kind of a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; Can promote hemopoietic reagent with a kind of.

88, a kind of as the described reagent of claim 87, wherein said can the hemopoietic reagent of promotion be to be selected from one group of material that following material is formed: a kind of non-ionic surface active agent, a kind of interleukin, a kind of colony stimulating factor, erythropoietin, glucosan and polyinosine-poly-cytidine.

89, a kind of as the described reagent of claim 87, wherein said can the hemopoietic reagent of promotion be a kind of congener or a kind of a kind of acyl derivative of oxipurinol nucleoside or a kind of congener of oxipurinol nucleoside of a kind of oxipurinol nucleoside, a kind of oxipurinol nucleoside.

90, a kind of preparation comprises: a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; Can promote the absorption of cell and the chemical compound of nucleoside phosphorylaseization with a kind of.

91, a kind of as the described reagent of claim 90, wherein saidly can promote the absorption of cell and the chemical compound of nucleoside phosphorylaseization.Be to be selected from one group of material that following material is formed: insulin and a kind of carbohydrate that can generate insulin.

92, a kind of preparation comprises: a kind of acyl derivative of the non-pyrimidine nucleoside that methylates; With a kind of reagent that can promote the mucosal tissue healing.

93, a kind of as the described reagent of claim 90, the wherein said reagent that can promote mucosal tissue to heal is to be selected from one group of material that following material is formed: the mixture of sucralfate (sucralfate), two or more dezyribonucleosides, other purine, a kind of antibiotics or a kind of local anesthetic.

94, a kind of reagent comprises: a kind of acyl derivative of uridnine; And a kind of chemical compound that can suppress E.C. 2.4.2.3.

95; a kind of as the described reagent of claim 94; the inhibitor of wherein said E.C. 2.4.2.3 is to be selected from one group of material that following material is formed: the acyclic uridnine of benzyl; the acyclic uridnine of benzyloxy benzyl; the acyclic uridnine of aminomethyl-benzyl; aminomethyl-acyclic the uridnine of benzyloxy benzyl; the acyclic uridnine of hydroxymethyl-benzyl; hydroxymethyl-benzyloxy benzyl-acyclic uridnine and 2; 2 '-dehydration-5-second uridnine; 5-benzyl barbiturate; 5-benzyloxy benzyl barbiturate; 5-benzyloxy benzyl-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate; 5-benzyloxy benzyl acetyl group-1-[(1-hydroxyl-2-ethyoxyl) methyl] barbiturate and the acyclic barbiturate of 5-methoxy-benzyl acetyl group.

96, a kind of preparation comprises: the acyl derivative of a kind of cytidine or deoxycytidine; With a kind of reagent that can suppress deoxycytidine deaminase.

97, a kind of as the described reagent of claim 96, the inhibitor of wherein said cytidine deaminase is to be selected from one group of material that following material is formed: tetrahydrouridine or tetrahydrochysene-2 '-BrdU.

98, a kind of preparation comprises: the acyl derivative of a kind of uridnine, cytidine or deoxycytidine and a kind of chemical compound that can suppress the nucleoside transfer.

99, a kind of as the described reagent of claim 98, the inhibitor that wherein said nucleoside shifts is to be selected from one group of material that following material is formed: persantin, 4 benzoic acid, lidoflazine (lidoflazine) or nitrobenzyl mercapto inosine.

100, a kind of acyl derivative of uridnine, its structural formula is

R wherein ₁, R ₂Or R ₃In at least one is the alkyl oxidation carbonyl moiety that contains 2-26 carbon atom, and remaining R substituent group is uncorrelated each other, can be an alkyl oxidation carbonyl or hydrocarbyl oxycarbonyl base section or H or phosphate.

101, a kind of acyl derivative of cytidine, its structural formula is

102, a kind of acyl derivative of deoxycytidine, its structural formula is

103, a kind of acyl derivative of BrdU, its structural formula is

104, a kind of acyl derivative of BrdU, its structural formula is

R wherein ₁, R ₂Or R ₃Can be the same or different, and each can be a hydrogen atom or an acyl group deriving from following material:

A. unbranched fatty acid with 3-22 carbon atom,

B. a seed amino acid, be selected from one group of aminoacid forming by following material: glycine, L type alanine, valine, leucine, isoleucine, tyrosine, proline, hydroxyproline, serine, threonine, cystine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, carnitine and ornithine

C. nicotinic acid,

D. dicarboxylic acids with 3-22 carbon atom, condition is R ₁, R ₂And R ₃Not H entirely, and work as R ₃When being not H entirely, R ₁And/or R ₂Also acetyl group, or its acceptable salt on materia medica.

105, a kind of pharmaceutical preparation, by claim 100,101,102,103 or 104 chemical compound and a kind of on materia medica acceptable carrier form.