JPS62103100A - 3'-azido-nucleosides, manufacture and antiviral - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 6'-azido-nucleosides, their pharmaceutically acceptable derivatives, formulations containing all of them, and their use in the treatment, particularly of certain viral and bacterial infections. and regarding their use for prophylaxis.

In the area of antiviral chemotherapy, only a few drugs exist that effectively combat the virus itself due to the difficulty of attacking the virus while leaving uninfected host cells intact. Due to the extremely parasitic nature of viruses, it has long been assumed that all necessary facilitation of viral replication is provided by the host cell. There is complete evidence that certain stages of the virus life cycle that differ between extremes are specified by the virus itself, and that those stages are susceptible to attack if they are significantly different from any corresponding host cell function. Shiuro has recently been established. However, due to the great similarities between virus and host function, effective treatments have proven very difficult to identify.

For this reason, compounds identified as suitable for the treatment of viral infections usually have some toxicity to the host. Therefore, an ideal drug would be nontoxic at antiviral effective concentrations, but in the absence of such treatment, the compound should have a good therapeutic ratio, i.e., the concentration at which treatment is toxic is the concentration at which antiviral activity is observed. This is significantly lower than the concentration reported.

A group of viruses for which special importance has recently been estimated are:
It's a retro virus. Retroviruses, a subgroup of RNA viruses, use their RNs to replicate.
A'i DNA must first be reversed.
1 transcription 'is usually DN
Full description of the synthesis of RNA from A]. In the form of DNA, the viral denominator is able to integrate into the host cell, allowing it to fully exploit the host cell's translation/translation machinery for replication. Once combined, Beerus DN
A is virtually indistinguishable from the host's DNA, and in this state the virus persists for as long as the life of the cell. In the Jin form, it is virtually invulnerable to attack, so any treatment must be directed to other stages of the virus's life cycle, and all virus-infected cells will inevitably die. must continue until.

Both HTLV-1 and HTLV-II are retroviruses and are known to be causative agents of leukemia in humans. HTLV-1 infections are particularly widespread and are responsible for many deaths worldwide each year.

One retrovirus has also been reproducibly isolated from patients with AIDS. Although it has been characterized in detail, there remains some controversy as to the internationally agreed upon name for Beerus. It is currently human T-cell parental lymph (1ymphotripic) virus (HT
LV*), AIDS-binding retrovirus (ARV
) or lymphadenopathy-associated virus (LAY), but an internationally agreed-upon name is expected to be human immunodeficiency virus (HIV). This virus (hereinafter referred to as HIV) is OKT 4
It has been shown to preferentially infect and destroy 5T-cells bearing surface labels and is now generally accepted as the etiological agent of AIDS. The patient is T-
By progressively losing a set of cells, he loses the overall balance of his immune system, diminishing his ability to fight off other infections, and from now on, infections that have proven fatal to him. create a predisposition to Therefore, the usual cause of death in AIDS victims is often due to infection, such as virally induced pneumonia or cancer, and not necessarily as a result of HIV infection. Other conditions associated with HIV infection include essential thrombocytopenia and Kaposi's sarcoma.

Recently, HIV has also been recovered from other tissue systems including B-cells expressing T4, macrophages and the non-blood-binding group Mk in the central nervous system. This central nervous system infection is not necessarily associated with classical AIDS and has been found in patients with subclinical HIV infection. HIV infection of the CNS is combined with progressive demyelination, leading to wasting and symptoms such as brain disease, progressive dysgraphia, ataxia, and disorientation. Other conditions associated with HIV infection include asymptomatic carrier status, progressive systemic lymphadenopathy (P
GL ) and AIDS-related complex (ABC
).

It is now believed that certain chronic nervous system infections are caused by retroviruses. Such infections include, for example, multiple sclerosis in humans, as well as arthritis encephalitis viral infection in Yai and visnnermite in sheep.
a-maedi) including all infections.

The paper describes testing of compounds against various retroviruses, such as Friend leukemia virus (FLY), murine retroviruses. The analogy is Cleve (
Krieg) et al. [Exezo Cell Res (gxp, C
e1l Res, ), 116, (1978 n 21-2
[9)] found that [3'-azido-6'-deoxythymidine] was active against FLY in in vitro experiments, and that ostyltag (○stertag) and others [
Proc, Nat,
Acad, Sci, ), (1974) 71.498
0-85), based on its FLv-related anti-healing activity and lack of cytotoxicity, 3'-azido-6'-dideoxythymidine has been proposed to be used as bromodeoxyuridine for the medical treatment of diseases that cause DNA viruses. All suitable substitutions may be made." However, De Clerq et al.
Biochem, Pharm, ), (1980) 29
．． 1849-1851) showed that 6 years later, 3'-azido-6'-dideoxythymidine was used in their tests, even though μ vaccinia, H8VI and Parisella
Seastar beers (varicella zost)
It was determined that the present invention had no appreciable activity against any viruses, including NA viruses such as V. eravis (VZV).

Bacteria are also important in treatment because all living organisms undergo very similar life processes to each other and therefore substances that are toxic to one have proven to be equally toxic to others. provide a problem.

In addition, experience has shown that bacterial strains prematurely develop resistance to commonly used antimicrobial agents.

Certain 3'-azido nucleosides described below are useful for viral and viral infections, including HIV infections and Gram-negative bacterial infections, including certain strains of Durum-negative bacteria that are resistant to commonly used antimicrobial agents. It has now been found useful in the treatment of bacterial infections, particularly retroviral infections.

Accordingly, in a first aspect of the invention, formula (1) for use in animal or veterinary therapy, wherein A is 9-
or a zoline or pyrimidine base other than thymine attached at positions 1 to 1, with the proviso that A is not a thymine residue, or pharmaceutically acceptable derivatives thereof.

Compounds of formula (1) and their pharmaceutically acceptable derivatives are indicated herein as compounds according to the invention.

Retroviral infections affect the central nervous system of patients, and in this connection, the particular advantage of the compounds according to the invention is that, as experiments have demonstrated, blood pressure is reduced in clinically effective amounts.
It is their ability to cross the brain barrier.

It has been found that the compounds according to the invention have particularly potent activity against retroviral and Gram-negative bacterial infections. Thus: (a) a compound according to the invention for use in the treatment or prevention of a retroviral or gram-negative bacterial infection; and <1)) a compound according to the invention for use in the treatment or prevention of a retroviral or gram-negative bacterial infection; Uses of compounds according to the invention are provided.

As used herein, the term "lutrovirus infection" refers to any virus that uses reverse transcriptase for an integral part of its life cycle.

Specific bacteria that have been found to have good activity are as follows.

Vibrio cholerae
), Vipri causes diseases such as traveler's diarrhea, urinary tract infections, shigellosis, typhoid fever and cholera in humans, and also for example neonatal enteritis in cattle, post-weaning enteritis in pigs and colisepticaemia in chickens.
) that cause animal diseases.

The compounds according to the invention have a particularly good activity against the following viruses: single cell lymphotropic virus (HTLV)
), especially HTLV-1, HTLV-1 and HT
LV-1 (HIV); feline leukemia virus, infectious anemia virus, caprine arthritis virus and other lentiviruses, and also other human viruses such as hepatitis B virus, rainbow stein-perr virus (
Epstein-Barr virus (EBV)
) and the causative agent of multiple sclerosis (MS).

Compounds according to the invention have also been found to be effective in the treatment of Kaposi's sarcoma (KS) and thrombocytopenic purpura (TP). For those last indications (M8% KS and TP) and for the caprine arthritis virus, the present invention describes compounds of formula (1) in which A is thymine for use in the treatment and prophylaxis thereof, and also for use in the treatment or prophylaxis thereof. and the use of said compound in the manufacture of a medicament for.

The activity of the compounds according to the invention against such a wide range of bacterial and viral infections is clearly of great advantage in medicine, and the novel mode of action makes it possible to use them in combination therapy to reduce the chances of developing resistance. All uses are permitted. However, such formulations are particularly useful because 6'-azido nucleosides have a surprising capacity for potentiating effects with other therapeutic agents, such as those described below.

6'-Azido nucleosides work synergistically with a wide range of other therapeutic agents, thereby disproportionately enhancing the therapeutic potency of both agents. Significantly smaller amounts of each compound are required for treatment, increasing the therapeutic ratio and thus reducing toxicity from either compound.

Accordingly, in accordance with yet another aspect of the invention, the formula (
1) Compounds of A wherein B is a purine or pyrimidine base attached at the 9- or 1-position, respectively, or pharmaceutically acceptable derivatives thereof are provided.

In particular, there is provided a compound of formula (1)A, or a pharmaceutically acceptable derivative thereof, for use in combination therapy as described above, where the two active agents are present in a potentiating ratio.

1 enhancement ratio" is the ratio of a compound of formula (1) A, or a pharmaceutically acceptable derivative thereof, to a second therapeutic agent that provides a therapeutic effect that is greater than the sum of the therapeutic effects of the individual components. It is a ratio.

Although there will usually be an optimal ratio to ensure maximum potentiation, even very small amounts of one drug can be sufficient to potentiate the effects of the other to some degree, and thus 2
It will be appreciated that any ratio of the two enhancing drugs may still possess the necessary synergistic effect. However, the greatest synergy is when the two drugs are present at a ratio of 500:1 to 1:50.
0, preferably from 100:1 to 1:100, in particular from 20:1 to 1:20, and especially from 10:
Observed when present between 1 and 1:10.

Accordingly, the present invention further provides therapeutic combinations of a compound of formula (1)A or a pharmaceutically acceptable derivative thereof and at least one other therapeutic agent.

The above formulation is indicated here as a formulation according to the invention.

Therefore, a formulation according to the invention for use in the treatment or prophylaxis of any infection or indication as mentioned above, or the use of such a formulation in the manufacture of a medicament for the treatment or prevention of any infection or indication as mentioned above. is further provided.

The formulations according to the invention can be used - together, for example in a single pharmaceutical preparation, or as a combination of tablets and injections administered separately, at the same time or at different times, in order to achieve all the necessary therapeutic effects. , conveniently administered.

In antiviral tests, for example, azidonucleosides are used as interferons, nucleoside transport inhibitors,
It is enhanced by a wide variety of drugs such as glucuronidation inhibitors, renal excretion inhibitors, and even by other therapeutic nucleosides that may not necessarily have all the activity of compounds of formula (I)A in the same organism. It was found that

Particularly preferred types of interferons are alpha, beta and gamma, while nucleoside transport inhibitors are dirazep, diviridamol, <5-((4-nitrobenzoyl)thio)-
9-(β-21ribofuranosyl)purine, papaverine,
Encompasses all drugs such as myoflagine, hexobendine, lidoflazine and their acid addition salts.

Probenecid has the formula (1) as it possesses both renal excretion inhibiting activity and glucuronidation blocking activity.
It is particularly useful in combination with A's 3'-azido nucleosides. Examples of other compounds useful in this embodiment are acetaminophen, asgirin, lorazepam, cimetidine, ranitidine, zomeviratuk, clofibrate, indomethacin, ketonorophen, nazoloxene,
It also includes all other compounds that compete for glucuronidation or otherwise undergo significant glucuronidation.

3'-azido nucleosides of formula 1 (/IJ) and pharmaceutically acceptable derivatives thereof are described, for example, in British Patent Specification No. 1.523.865, United States Patent Specification No. 4.3.
No. 60.522, European Patent Specification No. 74306.
55239 and 146516 and European Patent Application Nos. 434393 and 434395, including all acytallic nucleosides of the type described in European Patent Application Nos. 434393 and 434395,
and in particular the general formula [wherein 2 represents a hydrogen atom or a hydroxy or amino group; X represents (a) an oxygen or sulfur atom or a methylene group; and Y represents a hydrogen atom or a hydroxymethylene group ; or (b) methyleneoxy group (-QC) (2)? and wherein Y represents a hydroxy group], and all pharmaceutically acceptable derivatives thereof. Examples of said derivatives are salts or esters and basic salts, such as alkali metal (eg sodium) or alkaline earth metal salts, and pharmaceutical Mineral acids also include pharmaceutically acceptable salts of hydrochloric acid or sulfuric acid.

Esters of compounds of formula (4) which may be conveniently used according to the invention include formyloxy or haC1-16 (eg C1-6 ) alkanoyloxy (e.g. acetoxy or propionyloxy), optionally substituted aralkayloxy (e.g. phenyl-cl+4alkanoyloxy such as phenyl-acetoxy)" or optionally substituted aroyloxy ( For example, all those containing benzoyloxy or naphthoyloxy) ester groups are included. The aralkyloxy and aroyloxy ester groups include, for example, one or more halogen (e.g. chlorine or bromine) atoms, or amino , nitrile or sulfamide groups, the nitrile part of the group advantageously containing from 6 to 10 carbon atoms.

Particularly preferred examples of compounds of general formula (A) above for use according to the invention are 9-((2-hydroxyl-hydroxymethylethoxy)methyl]guanine, 2-amino-9-(2-hydroxy ethoxymethyl] purine, and especially 9-(2-hydroxyethoxymethyl)guanine (acyclovir). The latter compound is particularly suitable for formula I
6'-Azide-6 as described in the Examples
It has been found that it has a particularly good reinforcing effect when it is '-deoxythymidine.

In the antibacterial area, a broad spectrum of antibiotics has also been found to be effective in enhancing the activity of azidonucleosides. They include a wide variety of drugs, such as:
Benzylserimidines, such as British patent specification 1,
The analogy as described in No. 405.246 is 2.4-
Diamino-5-(3', 4', 5'-)rimethoxypenzyl)pyrimidine (trimethoprim) and their congeners; sulfonamides, such as sulfacimidine; rifampicin: tobramycin; fusidic acid; chloramphenicol; Includes clindamycin and yohyerythromycin.

Accordingly, in a further aspect there is provided a formulation according to the invention, wherein the second agent is at least one of the antiviral or antibacterial agents or types of agents described above.

Other formulations suitable for use in accordance with the invention include those in which the second agent is, for example, interleukin II, suramin, phosphonoformates, HPA 23.2',3'-dideoxynucleosides, such as 7.6'- Examples include dideoxycytidine and 7,6'-dideoxyadenosine, or drugs such as repamisole or thymosin to increase lymphocyte number and/or function.

It is recognized that the compounds and formulations according to the invention may also be used in conjunction with other immunomodulatory treatments, including, for example, bone marrow and lymphocyte transplantation.

Those infected with the above retroviruses, such as AIDS
It is commonly associated with infection compared to a mortar. Thus, for example, a combination of 3'-azido-3'-deoxythymidine (AZT) and acyclovir has proven particularly useful in the treatment of AIDS patients with apparent herpes infections, whereas a combination of AZT and 9-(( Formulations of 2-hydroxy-1-hydroxymethylethoxy)methyl]guanine are increasingly being recognized as useful in the treatment of AIDS patients with cytomegalovirus infections.

Generally preferred formulas (1) and (1) for use according to the invention
) A nogi rimidine has the formula (II) [wherein R1 is hydroxy, mercapto, amino, alkylthio, aralkoxy, alkoxy, cyan, alkylamino or dialkylamino, and the alkyl group is optionally bonded to form a heterocyclic ring. R2 is hydrogen, acyl, alkyl, aroyl or sulfonate; R3 is hydroxy, mercapto, amino, triazolyl, alkylamino, dialkylamino in which the alkyl groups are optionally combined to form a heterocycle; , aralkoxy, alkoxy or alkylthio, and V: R'i, furkyl, substituted alkyl, halo, perhalomethyl, hydroxy, alkoxy, cyano, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or hydrogen; is a pharmaceutically acceptable derivative of.

In general formula (1), the dotted line from the 2- to 6-position is
The relative positions of the single and double bonds are intended to indicate the presence of single or double bonds at those positions, and the relative positions of the single and double bonds indicate whether the substituents RA and R2 are, for example, keto-enol tautomeric groups. Depends on what happens.

A preferred class of pyrimidine nucleosides according to the invention are cytidine derivatives, for example those in which R3 is amino or alkylamino, especially those in which the 3' azido group is in the erythro configuration (1
thymidine and uridine derivatives in which the 6′ azide is in either the erythro or threo (“atuzoazido”) configuration (e.g. compounds of formula (n) in which R3 is other than amino or alkylamino); Compound 1) is a nucleoside that is unsaturated between the 5C and 60 positions.

Generally preferred formulas (I) and (1) for use according to the invention
) A purine of the formula (II) A [where Re and R7 may be equal or different, preferably from amino, hydrogen, hydroxy, mercapto, alkylthio, alkoxy, aralkoxy, cyano or alkylamino [selected] and pharmaceutically acceptable derivatives thereof.

Preferred classes of purine nucleosides according to the invention are adenine derivatives, such as compounds of formula (II) A, where R6 is amino or substituted amino, and guanine derivatives, such as those with limitation, where R6 is other than amino or substituted amino. , and a compound of formula (1) in which R7 is amino or substituted amino.

The above acyl groups advantageously include alkyl or aryl groups such as those described below. With respect to the compounds of formula (If) and GIGA above, the alkyl group advantageously contains from 1 to 8 carbon atoms, in particular from 1 to 4 carbon atoms, and is, for example, a methyl or ethyl group, optionally as described below. may be substituted with one or more suitable substituents, such as The aryl group included in the radical moiety of a group such as aralkoxy is preferably a phenyl group optionally substituted with one or more substituents as described below. The above alkenyl and alkynyl groups advantageously contain from 2 to 8, especially from 2 to 4 carbon atoms, such as ethenyl or ethenyl, optionally with one or more suitable substituents as described below. Replaced with 5.

Suitable substituents on the above alkyl, alkenyl, alkynyl and aryl groups include halogen, hydroxy, C1-
4 alkoxy, 01-4 alkyl, 06-. 2 aryl, 06~. 2Aralkoxy, carboxy, amino, and substituted amino in which the alkyl group may optionally be bonded to form a heterocycle when amino is single or double substituted by C1-4 alkyl and doubly substituted. advantageously selected from.

Still other types of preferred compounds of formula (...) are %R"%R
, one or more of R3 and R4 are as limited below, i.e., H1 is hydrogen, mercapto, C1~ alkoxy or amino; R2 is hydrogen, methyl, 01-2 alkanoyl or benzoyl; R3 is hydroxy, mercapto, amino or substituted amino; R4 is hydrogen when R3 is amino or substituted amino; and halogen, perhalomethyl, when R3 is other than amino or substituted amino; alkyl,
02-3 alkenyl or substituted ethenyl, as well as carboxy groups (e.g. succinate),
01-6 thioesters, including all straight or branched alkyl esters optionally substituted with esters, mesylates, glucuronides, or mono-, di- or tri-phosphates. 5 derivatives of the compound.

Yet another type of preferred compound of formula (It) B is R
6 is amino, C1-4 alkylamino, mercapto, hydroxy or CX-a alkoxy; and/or R7 is amino, 01-4 alkylamino or hydrogen, and a carboxy group (eg succinate)
), C1-6 thioesters, optionally substituted alkyl esters, mesylates, glucuronides, or straight-chain or branched alkyl esters optionally substituted with mono-, di- or triphosphates. All inclusive five derivatives of the compound are included.

Compounds of formula (1) suitable for use in the treatment or prophylaxis of viral infections are those in which Bl is hydroxy, mercapto, 01-5 alkoxy,
amino, C6-12 aralkoxy, or an 〇-anhydride bond connecting gold at the 2 and 5'positions; R2 is hydrogen, methyl or benzoyl; R3 is hydroxy,
mercapto, amino, substituted amino or C6-1□aralkoxy: compounds of formula (II), as defined, with the proviso that A in formula (I) is not a thymine residue, and their pharmaceutically acceptable It is a possible derivative. The azido group is advantageously in the erythro configuration. Particularly preferred is that only one of the substituents R1 to R4 of the girimidine mass differs from that of the thymine residue, in which R1 and R3 are hydroxy, R2 is hydrogen and R4 is methyl. Preferred compounds of formula (1) for use in the treatment or prevention of viral infections are those of formula (1) as described above for formula (1), but additionally those of formula (1) wherein B is a thymine residue. I) includes the compound of A;
and especially when the compound is 3'-azido-6'-deoxythymidine.

Compounds of formula (1) which are suitable for use in the treatment or prevention of bacterial infections include: R1 is oxygen, sulfur, benzyloxy or methoxy; R2 is hydrogen or benzoyl; R3 is as defined above. ; R4 is methyl or halogen, provided that formula (1)
In compounds of formula (II) where A is not a thymine residue, and in their pharmaceutically acceptable derivatives, the 3'-azido group can be in any configuration, but the erythro configuration is particularly preferred and is a preferred pharmaceutical agent. The physically acceptable derivatives are the 5' esters of simple organic acids, preferably 01-18 acids.

Particularly preferred are substituents B+L to R' on the pyrimidine ring.
The compound differs from that of a thymine residue in which R1 and R3 are hydroxy, R2 is hydrogen, and R4 is methyl.

Preferred formulas for use in the treatment or prevention of bacterial infections (
1) Compounds of A are as described above for formula (1), but also include compounds of formula (1)A in which B is a thymine residue, and in particular the core compound is 5-azido-3' -deoxythymidine.

1. ``Pharmaceutically acceptable derivative'' means any pharmaceutically acceptable salt, ester, or salt of such ester, or a parent 3'-azido nucleoside, or a therapeutically effective metabolite thereof, which upon administration to a recipient. or any other compound capable of providing a residue (directly or indirectly). Examples of non-ester compounds include 5'-C- and 2-C
- A derivative in which atoms are bonded through oxygen atoms to form an anhydro radical.

Preferred esters of compounds of formula (1) include straight-chain or branched alkyl, alkoxyalkyl (eg, methoxymethyl), aralkyl (eg, benzyl), oryloxyalkyl (eg, Carboxylic acid esters selected from phenoxymethyl-containing aryls (e.g. phenyl optionally substituted by halogen, Cl-+4 alkyl or C1-4 alkoxy); sulfonate esters such as alkyl- or aralkylsulfonyl (e.g. methanesulfonyl) and mono-, di- or triphosphate esters. Any reference to any of the above compounds also includes reference to their pharmaceutically acceptable salts.

Regarding the above esters, unless otherwise indicated, any alkyl moieties present advantageously contain from 1 to 18 carbon atoms, in particular from 1 to 4 carbon atoms. Any aryl moieties present in the ester advantageously consist of phenyl groups.

Examples of pharmaceutically acceptable salts of compounds of formula (1) and their pharmaceutically acceptable derivatives include basic salts derived from suitable bases, such as alkali metals (such as sodium), alkaline earth metals, etc. (eg magnesium) salts, ammonium and Nx4+ (wherein X is cl-4 alkyl), and mineral salts such as hydrochloride salts.

Particular examples of pharmaceutically acceptable derivatives of compounds of formula (1) that may be used in accordance with the present invention include the monosodium salts and the 5' esters of: monophosphate; disodium monophosphate; diphosphate. ;triphosphate;acetate;6-methyl-butyrate:octanoate:palmitate;3-chlorobenzoate:
Benzoate; 4-methylbenzoate: hydrogen succinate; bivalate; and mesylate.

Certain of the compounds according to the invention are new.

Accordingly, the present invention further provides formula (1) B[
wherein C is a purine or pyrimidine base bonded in the 9- or 1-position, respectively, and pharmaceutically acceptable derivatives thereof; a) C is adenine, guanine, uridine; , cytidine or thymine bases, and their 5'-mono- or di-triphosphate esters: (b) c is a uridine base and the 6'-azido group is in the erythro configuration; Go0 of a compound of formula (1)H
-acetate, go0-trityl and 5/ -o-
(4-methylbenzenesulfonate) derivative: (C)
C (1) 5-bromovinyl uridine or 5-
trifluoromethyluridine residue, and 6'-
the azide group is in the erythro configuration: (1) is a uridine residue, and the 3'-azido residue is in the threo configuration: and (m) is a 5-iodo or 5-fluorouridine residue, and 3' - Compounds of formula (1) H in which the azide group is in the pentathro or threo configuration; and 5'-0-) lythyl derivatives of the compounds: (d) C is (1)5-
a bromovinyl uridine or cytidine residue and the 5-azido group is in the threo configuration; (i) s-
a fluorocytidine residue and the 6'-azido group is in the erythro configuration: or (iti) a 5-methylcytidine residue and 3'(1) a compound of B; (e) C is 4-chloro -2(IH)pyrimidinone or 4-(IH-1,2,4-)lyazol-1-yl)-2(IH)pyrimidinone (optionally substituted at the 5-position by fluorine or methyl) and the 3'-azido group is in the erythro configuration (I
) 5'-0-acetate ester of the compound of B; (f) 5'-0-acetate ester of the compound of formula (1)H in which C is a cytidine residue and the 6'-azido group is in the erythro configuration;
〇-((4-methoxyphenyl)diphenylmethyl] derivative; and (g) 5' of a compound of formula (1) B in which C is an adenine residue and the 6'-azido group is in the threo configuration
-〇-trityl derivative.

Preferred compounds are those described above in conjunction with therapy, beyond those specifically excluded above.

Formulas (I) and (I) also shown herein as active ingredients
) The compounds of A, and their pharmaceutically acceptable derivatives, may be administered orally, enterally, intranasally, topically (including buccal and sublingually), intravaginally and parenterally (subcutaneously, subcutaneously,
Administration may be by any suitable route, including intramuscular, intravenous, and intradermal. It will be appreciated that the preferred route will vary depending on the condition and age of the recipient, the nature of the infection, and the active ingredient selected.

In general, suitable doses range from v3.0 to 120'■
/kI! The recipient body weight is preferably within the range of 6 to 90 In9/) cp body weight per day, and most preferably within the range of 15 to 60 In9/) cp body weight per day. The desired dose is preferably presented as 2, 3, 4, 6 or more divided doses administered at appropriate intervals throughout the day.

The divided doses may be, for example, 10 to 1 per unit dosage form.
It may be administered in unit dosage forms containing up to 500 n9, preferably from 20 to 10001 n9, and most preferably from 50 to 700 n9. Experiments with 3'-azido-3'-deoxythymidine showed that doses of ca.
All indications are that the dose must be administered to achieve a peak plasma concentration of the active compound of from about 75 μM to about 75 μM, preferably from about 2 to 50 μM, most preferably from about 3 to about 30 μM. This can be administered, for example, by intravenous injection of a solution of 0.1 to 5 ts't of active ingredient, optionally in saline solution, or orally as a gunpowder containing a total of about 1 to about 100 ts't of active ingredient. This can be achieved by The desired blood level is about 0.01 to about 5.0 m9
The active ingredient may be maintained by continuous perfusion providing 0.4 to 151 ng of active ingredient with a waiting time of 9 to 151 ng.

Formulations according to the invention may be administered in a manner similar to that described above to provide the desired therapeutic amounts of the active ingredient and other associated therapeutic agents. The dosage of the formulation will depend on the condition being treated, the particular active ingredient and other agents involved, and other clinical factors such as the weight and condition of the patient and the route of administration of the formulation. As indicated above, the active ingredient and other therapeutic agents may be administered simultaneously (eg, in a single pharmaceutical formulation) or separately (eg, in separate pharmaceutical formulations), and generally ,
The formulations may be administered by topical, oral, enteral or parenteral (eg, intravenous, subcutaneous or intramuscular) routes.

In particular, formulations according to the invention in which the second agent is a nucleoside transport inhibitor may be administered to the relevant subject in a conventional manner. However, for administration by oral route, from 1 to 200119/kg/day, preferably from 5 to 50
Doses of active ingredient up to 1 v/kg/day are generally sufficient. For administration by parenteral route, 1 to 100!
A dose of active ingredient of up to 2 to 30 w/kg/day, preferably 2 to 30 w/kg/day, is generally sufficient. The amount of nucleoside transport inhibitor in the formulation is independent of the amount of active ingredient specified above and is sufficient to effectively inhibit nucleoside transport, and is preferably 0.1
in the range from 1 to 9/day in 2019, and in particular in the range from 1 to 9/day in 2019/2019.

Formulations according to the invention, in which the second agent is either a renal excretion inhibitor or a glucuronidation inhibitor, or both, are administered to the relevant subject in a conventional manner. However, for administration by the oral route, 1 to 200
1119/ to 9/day, preferably from 5 to 50111
Doses of the active ingredient are generally up to 9/97 days. For administration by parenteral route, from 1 to 100 Da/
Doses of active ingredient of up to 7 days per day, preferably from 2 to 60 η/day to 9 days per day, are generally used. The amount of renal excretion/glucuronidation inhibitor in the formulation is independent of the amount of active ingredient and is preferably from 4 to 100 kg/7 days, preferably from 5 to 60 kg/7 days, most preferably from 10 to 40 q/7 days.
J/day is sufficient.

Formulations according to the invention in which the second agent is an interferon conveniently contain the active ingredient at from 5 to 9 to 2501 n9/day; and suitable effective dosage ranges for interferon range from 3x10' to 9' body surface per day. 10
x 10' IU/77 m" up to body surface, preferably 1
From 4 x 106 to 6 x 10' IU/m2 per day. Active ingredients and interferon range from approximately 5 x 9 to 10 x interferon per day for interferon 3 x 10' IU/F7!2
Approximately 2501 active ingredients per day for 10'IU/m"
n9/to 9, preferably from about 5119/kg of active ingredient per day to 6 x 1 interferon per day for 4 x 10' IU/m2 per day of interferon
Approximately 100 I/day of active ingredient for 06 IU/77&”
It must be administered in a ratio of up to 9/n9.

Interferon is preferably administered by injection (e.g. subcutaneously,
The active ingredient is preferably administered orally or by injection, although the active ingredient may be administered by any of the modes described herein. The interferon and active ingredient may be administered together or separately, and the daily dose of each is preferably administered as divided doses.

For formulations according to the invention in which the second agent is another therapeutic Nucleosi V, a suitable effective oral dosage range of the active ingredient is from 92.5 to 50 kg/body weight per day, preferably 5 and a suitable effective oral dosage range of the second therapeutic nucleoside is from 5 to 1001 n97 to 9 body weight per day, preferably from 15 to 75 per day! / is up to 9. The ratio of active ingredient to second therapeutic nucleoside for oral administration is from about 1:1 to 1:10, more preferably about 1=2
Preferably, it is from 8 to 8.

Suitable effective oral dosage ranges for active ingredients generally range from about 1.5 to 15 da/kg per day, and suitable effective oral dosage ranges for therapeutic nucleosides generally range from about 5 to 60 da/kg per day. It is. Preferably, the ratio for intravenous administration of active ingredient to second therapeutic nucleoside is within the range of about 2=1 to 1=20, more preferably within the range of 1:2 to 1=10. .

Both components of the formulation are preferably administered orally or by injection and may be given together or separately. Each daily dose may be given as divided doses.

For formulations according to the invention where the second agent is an antimicrobial agent, a suitable effective dose range of active ingredient is from 2.5 to 50
up to m9/klil/day, preferably from 5 to 10 rII
and a suitable effective dosage range of the antimicrobial agent is within the range of 2 to 100011 g/klF/day, preferably from 50 to 50 ON/9/day. The preferred ratio of active ingredient to antimicrobial agent is 20
:1 to 1:500, in particular 2:1 to 1:125.

Although formulations containing three or more therapeutic agents are not specifically described herein, it will be appreciated that such formulations form part of the present invention. For example, a combination of 5-azido-3'-deoxythymidine (AZT) with acyclovir and probenecid is
It has the dual advantage of enhancing the activity of AZ'l' and increasing its availability.

Similarly, combinations of compounds of formula (1) A with two or more of the same collection of second therapeutic agents, such as AZT with sulfacymidine and trimethoprim, also form part of the invention. .

Although it is possible for the active ingredient to be administered alone,
Preferably it is present as a pharmaceutical formulation. The formulations of the present invention include at least one active ingredient as defined above, together with one or more acceptable carriers and optionally other therapeutic agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Formulations include those suitable for oral, enteral, intranasal, topical (including buccal and sublingual), intravaginal or parenteral (including subcutaneous, intramuscular, intravenous and subcutaneous) administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art; such methods include the combination of the active ingredient(s) and one or more accessory ingredients. Generally, the active ingredient is brought into uniform and intimate association with an all-liquid carrier or a finely divided solid carrier, and then, if necessary, by shaping the product. Manufactured.

Formulations of the invention suitable for oral administration may be presented in discrete units, each containing a predetermined amount of the active ingredient, such as capsules, cachets or tablets; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; It may be present as a suspension: alternatively as an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be present as an emulsion, a grind or a paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients.

Compressed tablets may optionally contain binders (e.g. povidone, gelatin, hydroxyzorobyl methylcellulose), lubricants,
such as powders or granules, mixed with inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersing agents. The active ingredient in free-flowing form may be produced by compacting it in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound t1 moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and contain slow or controlled amounts of the active ingredient, for example using human-roxypropyl methylcellulose in various proportions, to provide the desired release profile. Formulated to provide total release.

Formulations suitable for topical administration in the mouth are lozenges consisting of the active ingredient in a flavoring base, usually sucrose and gum acacia or gum tragacanth; an inert base such as gelatin and glycerin, or sucrose and gum acacia. Includes pastel agents, which consist of an active ingredient, as well as rutting agents, which consist of an active ingredient in a suitable liquid carrier.

Formulations for enteral administration may be presented as suppositories, for example with a suitable base consisting of cocoa butter or salicylates.

Suitable formulations for intrauterine administration include those present as pessaries, tampons, creams, roules, pastes, foams or soufflés containing, in addition to the active ingredient, carriers known to be suitable in the art. .

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient: and aqueous and non-aqueous sterile suspensions, including all suspending and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and transferred immediately before use to a sterile liquid carrier.
For example, it may be stored in a lyophilized state requiring only the addition of water for injection. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

Preferred unit dosage formulations are those containing daily doses or units, daily divided doses, or appropriate fractions thereof, as described above, of the active ingredient.

The compounds according to the invention may also be present for use in the form of veterinary preparations, which may be prepared, for example, by methods conventional in the art.

Examples of such veterinary preparations are:
Tablets or gunpowder: powders, granules or pellets for mixing with feed; pastes for application to the tongue; (b) suitable for parenteral administration, e.g. sterile, by subcutaneous, intramuscular or intraporal injection; solutions or suspensions; or (as appropriate) intramammary injections in which suspensions or solutions are introduced into the breast via the nipple: (C) those adapted for topical application, such as creams, ointments applied to the skin; or spray: or (d)
Compatible within II, such as pessaries, creams or foams: all inclusive.

Formulations as described above are also suitable for presenting the formulations according to the invention, whether in single or separate formulations,
And it will be recognized that it can be manufactured in the same way.

In addition to the ingredients specifically listed above, the formulations of the invention may include:
All other agents conventional in the art for the type of formulation in question may be included, such as those suitable for oral administration, such as sweeteners, thickeners and flavoring agents. That must be understood.

Compounds of formula (1) A and their pharmaceutically acceptable derivatives, the disclosures of which are incorporated herein by reference.
For example, Synthetic Procedures in New York Acid Chemistry (5ynt
hetic procedures in Nu
cleic acid chemistry ) (1,
321 (1968), Krenicki (T, A, Kre
nitsky) etc.], Die Met Chem(s, Me
d* Chem, ) (26,981, (1983)
); Nucleic Acid Chemistry, Insolvency and Nucleic
Ac1d Chemistry, Improveda
nd New 5ynthetic Process
s, Methods and Techniques
) (Parts 1 and 2, Townsend (L, D, To
wnsend), Tipson (R, 8, Tipson
), [J. Wiley]
1978) ; Horwitz, J.R.
) etc. (C, Org, C
hem, ), 29, (July 19754) 2076~
2078); Imadewa (M.

ImazaWa) etc. [Jie Org Kem (J, O
rg.

Chem, ), 43(15) (1978) 3044~
3048): Watanabe (K, A, Watanabe
) etc. [J, Org, Chem
, ), 45.3274 (1980)); and Glinski et al. [J, Chem, 8oc,
Chem, Commun, ), 915 (1970
)) are prepared in a conventional manner using all techniques well known in the art, such as those described in Section 5, or using techniques similar to those described therein.

The present invention further encompasses methods for preparing compounds of formula fI) and their pharmaceutically acceptable derivatives, which
) [In the formula, A is as limited to the above, and M is 3
'-a precursor group of the azide group] or a derivative thereof (e.g. an ester or salt) reacted with or under conditions that serve to convert the precursor group into the desired azide group; [In the formula, RA, H:, R:, R
8, pt: Oyo U R? h, each group R1% R
2, R3, R4, R6 and R7, or a precursor group therefor, with the proviso that at least one of R^, shield, shield and R8 in formula (IVa), or a group in formula (IVb) At least one of Rg and Rz represents a precursor group]
(C) a compound of formula (Va) or (vb) in which R1, R2, R3, R4 , R6 and R) are
as defined above] or their mechanical equivalents at positions 1 to 1 of the compound of formula (Va) or
vb) with a compound that serves to introduce the desired IJ f furanosyl ring in the 9-position; or (Dl) for the preparation of a compound of formula (If).
vb) with a pyrimidine nucleus of formula (■1) in which Py represents a pyrimidinyl group; and then or simultaneously carrying out one or more of the following optional transformations: (1) when a compound of formula (1) is formed, converting said compound into a pharmaceutically acceptable derivative thereof: and (1)
When a pharmaceutically acceptable derivative of a compound of formula (1) is formed, it may be combined with an acute compound of formula (1) or a compound of formula (I).
) into another pharmaceutically acceptable derivative of the compound.

In the above method according to the present invention, methods (4) to (D)
It is recognized that the selection of precursor compounds in the foregoing is primarily dictated by the particular compound desired to be prepared, and that the agents and conditions described above are selected accordingly from those known in the art of nucleoside synthesis technology. It will be good. Examples of such transformation methods are described below for guidance, and it will be understood that they will depend on the desired compound and may be modified in a conventional manner. In particular, for example, if a transformation is described which would otherwise result in an undesired reaction of a labile group, such a group may be protected in conventional manner, with subsequent removal of the protecting group after completion of the transformation.

Thus, for example, with respect to method (4), the group M in the compound of formula (la) or (11)) is, for example, a halogen (
(e.g. chlorine), hydroxy or organic sulfonyloxy (e.g. trifluorosulfonyloxy, methanesulfonyloxy or hp-toluenesulfonyloxy)
can represent a group.

For the preparation of compounds of formula (1) in which the 3'-azido group is in the threo configuration, the radical M is a hydroxy group in the erythro configuration (the 5'-hydroxy group is advantageously protected, for example with a trityl group). ) is the formula (la) or (11)
) can be treated with, for example, triphenylphosphine, carbon tetrabromide and lithium azide. Separately, M
can represent an organosulfonyloxy removed group in the erythro configuration, which can be converted to an azide group in the p-threo configuration, for example by treatment with lithium or sodium azide, and the 5'-hydroxy group can be similarly protected as above. be done. Removal of the Gotrityl protecting group may subsequently be carried out, for example, under mild acidic conditions or by treatment with zinc bromide.

For the preparation of compounds of formula (I) in which the 6'-azido group is in the erythro configuration, compounds of formula (la) in which the group M is a halogen (for example chlorine) group in the threo configuration or t! (lb.
), the 5'-hydroxy of which is advantageously protected, for example with a trityl group, can be treated with, for example, lithium or sodium azide.

The 6'-threo-halogen (e.g. chlorine) starting material is
For example, the corresponding 6'-erythrohydroxy compound can be prepared by reacting with tri7erphosphine and carbon tetrachloride or by separately treating with an organic sulfonyl halide (e.g. trifluoromethanesulfonyl chloride). -Erythro by forming an organic sulfonyloxy compound which is then halogenated, for example as described above.

Separately, the 6'-threo-hydroxy or organic sulfonyloxy compound of formula (la) or (b) may be, for example, i
Treatment with phenylphosphine, carbon tetrabromide and lithium azide can form the corresponding 3'-erythro azide compound.

Regarding process (B), the following are examples of various methods by which the precursor foundations in formula (IVa) can be converted into the desired HA, R2, R3 and R4 groups: a) R1 is alkoxy (for example methoxy or ethoxy) When indicating a group, such a compound is 2.
From the corresponding compounds of formula (lVa) exhibiting a 5'-0-anhydro bond, conveniently in the presence of potassium carbonate, it may be prepared by treatment with a suitable nucleophile, such as an alkoxide; 1)) where R1 is When representing a mercapto fund, such compounds are derived from the corresponding compounds of formula (lVa) in which Ra represents an alkoxy (e.g. ethoxy) group:
c) When R2 represents an alkyl group, such compounds can be prepared, for example, by treatment with hydrogen sulphide; c) When R2 represents an alkyl group, such compounds can be prepared, for example, from the corresponding compounds of formula (lVa) in which H represents a hydrogen atom; d) When R3 represents a mercapto group, such compounds may be prepared by treatment with N-dimethylformamide dimethyl acetal:
-) from the corresponding compound of formula (IVa) representing riazolyl,
For example, V can be prepared by treatment with an alkali metal (e.g. sodium) mercaptan: e) When R3 is an amino group, such compounds are
They may be prepared from the corresponding compounds of formula (IVa) in which Ra represents a hydroxyl group by treatment with an aminating agent such as hexamethyldisiladene and ammonium sulphate in a bomb: f) when R4 represents a halo (e.g. chloro) group; ,
Such compounds have the formula (lVa
) by treatment with a non-rodening agent such as m-roroperbenzoic acid.

Similar methods and also those described for example in the above references may be used to carry out the conversion of the precursor groups in formula (lVt)) into the desired R6 and R7 groups.

With respect to process (C), this applies, for example, to a suitable pyrimidine or purine of formula (Va) or (Vb), or a salt or protected derivative thereof, where Y is the group to be removed, for example acetoxy Or benzoyloxy or halo, for example a chloro group? and the 5' hydroxy group may be optionally protected by a p-)luenesulfonyloxy group, followed by removal of any protecting groups.

The reaction of the compounds of formula (Vl) and (Vl) with respect to the process (DJ) is conveniently carried out in the presence of a phosphorylating enzyme and, if desired, the 3'-azide anomer is separated in a conventional manner.

When a compound of formula (1) is formed, such compound may be formed by adding a phosphorylating agent such as po
cz3, or may be converted to a pharmaceutically acceptable phosphate or other ester by reaction with a suitable esterifying agent such as an acid halide or anhydride. Compounds of formula (1), including their esters, may be converted into their pharmaceutically acceptable salts in conventional manner, for example by treatment with a suitable base.

When derivatives of compounds of formula (1) are formed, such compounds can be converted into sharp compounds, for example by hydrolysis.

The following examples are intended to be illustrative only and are not intended to limit the scope of the invention in any way. The term "active base" as used in the Examples refers to a compound of formula (1) or (I)A, or a pharmaceutically acceptable derivative thereof.

Example 1 Tablet Formulation The following formulations A and B are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.

Formulation A (a) Active ingredient 25
0 250 (b) Lactose, B, P,
210 26(C) Povidone, B, P, 15
9(d) Sodium starch glycolate
20 12 Formulation B (a) Active ingredient 2
50 250(b) Lactose 150
-(c) Avicel-1016026 (d) Povidone, B, P,
15 9(e) Sodium starch glycolate) 20 12(f)
Magnesium stearate 56 Formulation C 1n9/tablet Active substance 100 Lactose
200 starch
50 povidone
5 Magnesium stearate
The fourth formulation, Formulation E, is made by direct compression of the mixed ingredients. The lactose used in formulation E is
Direct compression type [Dairy Cresz-'Zeparo:c''
)].

Formulation D ~/Capsule active ingredient 250 Pre-gelatinized starch NF15 150 Formulation E ■/Capsule active ingredient 250 Lactose
150 Avisel
100 Formulation F (Controlled Release Formulation) This formulation is prepared by wet granulation of the ingredients (described below) with a povidone solution, followed by addition of magnesium stearate and compression.

■/Tablet (a) Active ingredient
500 (b) Hydroxypropyl methylcellulose 112 (4M premium in methocel) (C) Lactose, B, P,
53(d) Povidone, B, P, 0.
28(e) Magnesium Stearate Example 2 Capsule Formulation Formulation A A capsule formulation is prepared by mixing the ingredients of the formulation of Example 1 above and filling into two-part hard gelatin capsules. Formulation B (below) is prepared similarly.

Formulation B ■/Capsule (,) Active ingredient
250(b) Lactose, B, P,
143(c) Sodium starch glycolate 25(d) Magnesium stearate 2 Formulation C In9/Capsule (a) Active ingredient
250(b) Macrogol 4000, B, P
, 350 capsules are prepared by melting Macrogol 4000BP, dispersing the active ingredient in the melt, and filling the melt into two-part hard gelatin capsules.

Formulation D ~/Capsule Active Ingredients 250 Lecithin 100 Peanut Oil
100 capsules are made by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion into soft elastic gelatin capsules.

The following controlled release capsule formulation was prepared using an extruder with component a
, b and C, followed by spheronization and drying of the extrudate.

The dried pellets are then extruded in a controlled release M (d) and filled into two-part hard gelatin capsules.

~/Capsule (a) Active ingredient 2
50(b) Microcrystalline cellulose
125(C) Lactose, B, P,
125 (al ethyl cellulose
16 cases 6 Injection formulation Formulation A Active ingredient 0.200, i
? Hydrochloric acid solution, 0.1M appropriate amount, pi (hydroxide from 4.0 to 7.0) IJum solution 0.1M
Appropriate amount of sterile water with pH 4.0 to 7.0
Appropriate amount: Total amount of 10 shochu active ingredients and most of the water (35
-40°C) and adjust the - to between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as necessary.

The batch was then brought to volume with water and filtered through a sterile microfilter into a sterile 101 volume amber vial (type 1) and sealed with a sterile stopper and overseal.

Formulation B Active ingredient 0.125 g Sterile, pyrogen-free, PL (7 phosphate buffer) Appropriate amount Total amount 251 cases 4 Weight jt (g) Active ingredient 0.20 Benzyl alcohol 0.10 Glycofurol 75 1.45 Water for injection
Appropriate amount Total amount s, oomz Dissolve the active ingredient in glycofurol. Benzyl alcohol is then added and dissolved, and water is added to 61%. The mixture was then filtered through a sterile micro-ball filter and a sterile 6μ
The brown color is sealed in a glass vial (type 1).

Example 5 Syrup Formulation A Amount (g) Active Ingredients 0.2500 Sorbitol Solution 1.5000 Glycerol 2.0000 Sodium Benzoate 0.0050 Flavor, Beach 1
7.42.3169 0.0125ff1g
Purified water Appropriate amount Total amount s, ooo
om active ingredients in a mixture of glycerol and most a ice cubes. An aqueous solution of sodium benzoate is then added to the solution, followed by a sorbitol solution and finally the perfume. Adjust volume with purified water and mix well.

When the active ingredient is difficult to dissolve, use the following formulation (B).

Formulation B 1 amount <g> Active ingredient 0.250
Sorbitol solution 1.500
Glycerol 0.005
Dispersible cellulose 0.005
Sodium benzoate o, oio
Perfume Purified Water Appropriate amount Total volume 5.000 Mix sorbitol solution, glycerol and 1 part f# ice cream. Dissolve IJum in purified water,
Add the bath liquid to the bulk. Add and disperse the dispersible cellulose and flavor.

Add active ingredient and disperse. Adjust the volume with purified water.

Example 6 Suppository ■/Suppository active ingredient (66 μM) $250 Hard fat, BP (Uitepsol H15-1770 Dynamite Nobel) 1 Active ingredient is such that at least 90% of the particles have a diameter of 66 μM
or less used as a powder.

A mass of Uitezosol H15 is melted in a steam-jacketed pan at a maximum of 45°C. Active ingredient, 200μ
sieve and add to the molten base using a Silverson with a cutting bed and stirring until a smooth dispersion is achieved. Keeping the mixture at 45° C., add the remaining Uitepsol H15 to the suspension and stir to ensure uniform mixing. The entire suspension was passed through a 250 μm stainless steel sieve with continuous stirring and
Cool to ℃. At a temperature between 38°C and 40°C, 2.02 g of the mixture are filled into suitable 21 plastic molds. Cool the suppositories at room temperature f.

Example 7 Pessary■/Pessary active ingredient (66μm) 25
0 anhydrous dextrose 680
Potato Starch 366 Magnesium Stearate 7 The above ingredients are directly mixed and the pessary is made by direct compression of the resulting mixture.

Examples 8-10 below describe the preparation of formulations containing the compound of formula (1) A (active ingredient) and other therapeutic nucleosides specified.

Example 8 Injection formulation A l Amount ~) Acyclovir 400 Active ingredient 2001M NaOH Sterile water as required Appropriate amount Total ffi10mA' Formulation B 'N Amount (~) 2-Amino-9-(2-hydroxy 400
ethoxymethyl) purine active ingredient 2001M Na
Appropriate amount of sterile water depending on the OH package Total amount: 10 ml In the above formulation, the therapeutic nucleoside is added to the IM NaOH solution,
Then stir until dissolved. Add active ingredient and dissolve. Add sterile water to 10M. Filter through a sterile filter and fill into sterile vials. Freeze dry.

Example 9 Tablet formulation A! jet acyclovir 500 active ingredients 125 povidone
14 Sodium starch glycolate 25 Magnesium stearate 6
Formulation B i Amount (In9) Active ingredient 1252-
Amino-9-(2-hydroxy 125ethoxymethyl)purinpovidone 8 Sodium starch glycolate 12 Magnesium stearate 6
In formulations A and B above, the therapeutic nucleoside and active ingredient are mixed with sodium starch glycolate and granulated with a bath of povidone.

After drying, the granules are mixed with magnesium stearate and compressed.

Example 10 Capsule Formulation A Weight (■) Acyclovir 250 Active Ingredients 62.5 Lactose
170.5 Sodium Starch Glycolate 15 Magnesium Stearate Mix the two ingredients and fill into hard gelatin capsules.

Formulation B Weight (In9) Active Ingredients 1252-amino-9-(2-hydroxy 125ethoxymethyl)purine lactose 163 Sodium starch glycolate 1
5 Magnesium stearate
The two components are mixed and filled into hard gelatin capsules.

Example 11 describes a formulation containing interferon and a compound of formula (1) A (active ingredient).

Example 11 Interferon injection 6 active ingredients 200 Sterile buffer pH 7 appropriate amount Total amount 50+11 Interferon and active ingredient are dissolved in sterile water. Filter through a sterile filter and fill into #c vials.

Examples 12 to 15 below demonstrate the preparation of formulations containing a compound of formula (1) A (active ingredient), such as 6'-azido-3'-deoxythymidine, in combination with a nucleoside transport inhibitor, such as zoviridamol. Describe it.

Example 12 Tablet weight (■) Nucleoside transport inhibitor 300 Active ingredient 200 Lactose
105 Starch 50 Polyvinylpyrrolidinone 20 Magnesium stearate 10 Total weight 685 The active compound is mixed with lactose and starch and wet granulated with a solution of polyvinylpyrrolidinone. The granules are dried, sieved and mixed with magnesium stearate and then compressed into tablet form.

Example 16 Capsule coulometric (~) Nucleoside transport inhibitor 600 active ingredient 100 milk l! 1
100 Sodium starch glycolate
10 polyvinyl? loridinone
10 Magnesium stearate
6 Total l volume 526 The active compound is warmed with lactose and sodium starch glycolate and wet granulated with a solution of polyvinylpyrrolidinone. The granules are dried, sieved and mixed with magnesium stearate and filled into hard gelatin capsules.

Example 14 Cream Weight C&) Nucleoside Transport Inhibitor 7.5 Active Ingredients 5.00 Glycerol 2.00 Cetostearyl Alcohol 6.75 Lauryl 4
mM Sodium 0.75 White soft paraffin 12.50 Solid paraffin 5.00 Chlorocresol 0.10 Purified water
Quantity Total amount 100.00 The active compound is bathed in a mixture of purified water and glycerol and heated to 70°C. Heat the remaining ingredients together at 70°C. Add both together and emulsify. Cool the mixture and fill containers.

Example 15 Intravenous injection needle <my) (11 active ingredients 200
Nucleoside transport inhibitor 600 Glycerol 200 Sodium hydroxide solution Appropriate amount pi (7.0-7.5 Water for injection
Appropriate amount: Add a total amount of 10% glycerol to a small amount of water for injection. Add the two active compounds and hydroxylate p[-i') from 7.0 in IJum bath solution.
Adjust to 7.5. Bring up the core solution to the specified volume with additional water for injection. Under sterile conditions, bath g is sterilized by filtration, filled into sterile ampoules, and the ampoules are sealed.

Amount (■) (2) Active ingredient 100
Nucleoside transport inhibitor 150 Mannitol 125 Sodium hydroxide solution Appropriate amount pH 8.0-9.0 Water for injection
Adequate amount Total amount 2.51 Dissolve the active compound and mannitol in one part of water for injection. - is adjusted to 8.0-9.0 with sodium hydroxide solution and made up to volume with additional water for injection. Under aseptic conditions, the solution is sterilized by tl-filtration, filled into sterile vials, and the water is removed by lyophilization. The vial is sealed under an atmosphere of nitrogen and closed with a sterile stopper and metal collar.

Examples 16-18 below contain a compound of formula (1) A (active ingredient) such as 3'-azido-3'-deoxythymidine in combination with a glucuronidation/renal excretion inhibitor, such as probenecid. Describe the manufacture of the formulation.

Example 16 Tablet weight (1n9) Active ingredient 100 Glucuronidation/renal excretion inhibitor 200
Lactose 105 Starch 50 Polyvinylpyrrolidinone 20 Magnesium stearate 10 Total weight it
485 The active compound is mixed with lactose and starch and wet granulated with a solution of polyvinyl glycolidinone. The granules are dried, sieved and mixed with magnesium stearate and then compressed into tablet form.

Example 17 Capsule 1 view (1n?) Active ingredient 100 Glucuronidation/renal excretion inhibitor 100
Lactose 100 Sodium starch glycolate 10 HoIJ vinyl glycolinone
10 Magnesium stearate
3 Total weight 323 The active compound is mixed with lactose and sodium starch glycolate and wet granulated with a solution of polyvinylpyrrolizonone. The granules are dried, sieved and mixed with magnesium stearate and filled into hard gelatin capsules.

Example 18 Amount (~) (1) Active ingredient 200
Glucuronidation/renal excretion inhibitor 600
Glycerol 200 Sodium hydroxide solution Pursuing pH 7.2-7.5 Water for injection
Add appropriate amount of 10-component glycerol to a small amount of water for injection. Add the two active compounds and adjust - to 7.0-7.5 with a sodium hydroxide bath. Make up the solution with additional water for injection. Under sterile conditions, the solution is sterilized by filtration and filled into sterile ampoules;
Then seal the ampoule.

Jt (m9) (2) Active ingredient 100
Glucuronidation/renal excretion inhibitor 150
Mannitol 125 Sodium hydroxide solution appropriate amount pH 8,0-9.0 Water for injection appropriate amount Total amount 2.5 ml Dissolve the active compound and mannitol in 1 part water for injection. Adjust the pH to 8.0-9.0 with IJum ha,
Then add additional water for injection to make up the prescribed amount. Under sterile conditions, the solution is sterilized by filtration, filled into sterile vials, and the water is removed by lyophilization. The vial is sealed under an atmosphere of nitrogen and closed with a sterile stopper and metal collar.

Example 19 Active ingredient per small animal tablet 120.0
1n9 corn starch 2
0.0■ Microcrystalline cellulose 100.0In9 Magnesium stearate 1.51
1! ! 7. Mix together the active ingredients, microcrystalline cellulose and corn starch. Add enough starch solution with continuous stirring to obtain a moist mass, which is passed through a spider to obtain granules. Pass the magnesium stearate through a sieve. Tablets are obtained by direct compression of the granules.

Example 20 Weight of granules for internal use in feed (g) Active ingredients 6.0 povidone 1.0 lactose
96.0 Hydroalcoholic Mixture Mix the appropriate amount of active ingredient with lactose. To this is added aqueous alcohol containing dissolved povidone. Sufficient aqueous alcohol is added to obtain a moist mass, which is passed through a sieve to obtain granules, which are subsequently dried.

Example 21 Oral paste N amount (g) Active ingredients 24 xanthan 0.5 Methyl hydroxybenzoate 0.1 Polysorbate 800.1 Purified water Appropriate amount Total amount 100.3
Dissolve mg polysorbate 80 and methyl hydroxybenzoate in a large amount of water. Add xanthan gum and allow to disperse and swell. The active ingredient is added and dispersed and diluted to volume.

Example 22 Amount in Ointment (9) Active Ingredients 12 White Soft Paraffin 88.0 Melt white soft paraffin at 60°C. Add the active ingredient and disperse, cool and fill into folded metal tubes.

Example 23 Sine (a) 6'-Azide- in dry t-lysine (20 passages)
By adding methanesulfonyl chloride (2,7rlLl) to a solution of 3'-deoxythymidine, 6'
-azido-6'-deoxythymidine (3.0 g, 11.
2 mmol) of the 5'-hydroxyl group was mesylated.

The reaction was allowed to proceed for 1 hour at 5°C and then poured onto ice water. The precipitate was collected by filtration. 6 obtained from the first step
'-azido-6'-deoxy-5'-mesylthymidine 1
, potassium carbonate (0.78 g, 5
．． 6 mmol) gave the desired product. The reaction mixture was heated on an oil bath at 80°C for 6 hours and then poured into ice water. The product was extracted from water with ethyl acetate. The solvent was removed in vacuo and the resulting oil was purified on silica sol with CHCJ3:MeOH(9'
Flash chromatography was performed by bathing at 1 v/v). The product was obtained in low yield. Melting point = 184~
186℃.

(b) Sodium salt of dimethyldithiocarbamic acid zohydrate (0,642 mmol) and 3.58 d of a solution of 1N tetrabutylammonium hydroxide in MeOH were added to 25M DMF. The bath was boiled to remove water and MeOH.

After cooling, the 2,5′-〇-
anhydro~6'-azido-31~deoxythymidine (
0.85 & 6.4 mmol) were added. The reaction mixture was heated in a 55°C oil bath overnight. The reaction mixture was poured into ice water and the precipitate was removed by filtration. the product,
The filtrate was extracted with ethyl acetate.

The ethyl acetate was removed in vacuo and the resulting oil was purified on silica with CHCJ3:MeOH (95:5
Purified by flash chromatography by bathing at V/V). Chromatography required a second time on silica sol. The second elution was CH(J3:
with MeOH (98:2 v/v). final ah
was performed by reverse layer chromatography on 01B, eluting with water:methanol (3N). The yield was 2.5%.

Example 24 3'-azido-3'-deoxy-5'-〇-acetyl-4-(1,2,4-triazole)thymidine [phosphorus (L
in) et al., Zoe Met Chem (JoMed.

Chem, ), 26.1691 (1983)) (1
, 41,9,3,9 mmol) was dissolved in 100μ of acetone and 30μ of water, then Na5H,XH2O0-
3911 [Sung, Jiae Geum e Sosu
Chem.Com (J, Chem, Soc, Chem, Com
m, ), 522, (1982)]. The mixture was stirred for 60 minutes, reduced in volume to 1/2, and extracted with CH (43,200 ml).

CHCJ3 was washed with 100% water and Na2SO4
Dry on top. The solvent was removed in vacuo and the resulting oil was placed on a silica sol pad (6,5 x 3 cm) and subsequently eluted with cHct 3750μ. Removal of the solvent in vacuo yielded a yellow oil, which was recrystallized from 1 to PrOH to yield 0.649 C1.9 mmol; 48.
7%) was produced; melting point = 75-78°C.

Example 25 6'-acido-61-deoxy-5'-〇-acetyl-4-thiothymidine (0.25 g; 0.76 mmol,
Example 21) was bathed in a mixture of 51 parts of dioxane and 5 parts of concentrated NH,OH and stirred for 18 hours. The solvent is removed in vacuo and the residue is applied to a silica sol column,
Subsequently, CHCj3/EZOAC (3: 1v/v)
It was eluted. Appropriate fractions were combined and the solvent was removed in vacuo to yield a yellow oil, which was dissolved in Ez20 and crystals formed upon concentration; 0.16 El (,0,5
6 mmol; 74 thymidine): melting point = 116-118°C0 Example 26 Zin-3'acido-6'-deoxythymidine (0.5 g; 1.
9 mmol) and N,N-dimethylformamide dimethyl acetal [Zemlicka, Co11.Czech.

Chem, Comm, ), 35.3572 (197
2)] (0,9rILl; 7.5 mmol), CH
The mixture was refluxed in 2011 liters of Cl3 for 48 hours. The solvent was removed in vacuo and the material was placed on a silica column. E
Elution with tOAc/CHCJ3 (1: IV/V) produced the pure material as a viscous oil; 0.26 &
(0.9 mmol, 47%).

Example 27 Synthesis of 6'-acido-2-thiothymidine was performed using 2°6'-
〇-Anhydro 5'-Tritilchi's Syn [Fox (J, J, Fax), Zoe Org Kem (
J, Org, Chem, ), 28.936 (1
Starting from 963)), it was carried out in a five-step reaction.

2.3'-0-anhydro-5'-tritylthymidine<
io, s g, 22.4 mmol) was dissolved in sodium (0.52 g, 22.4 mmol) in dry ethanol (1.2 M).
4 mlj mol) of syneresis and the reaction mixture
Refluxed for an hour. The reaction mixture was cooled and I N H
Neutralized with Cj. The solvent was removed in vacuo and the resulting oil was purified on a silica sol with CHCJ3:MeOH (94
: 6 V/v). 1-(2'-deoxy-5'-
A yield of 30% of trityl-D-lyxofuranosyl-2=ethoxythymine was obtained. The 2-ethoxythymidine derivative (3,5,!i', 16.8 milJ mol) was bathed in DMF 35mJiC containing 2.2N triethylamino. The cold bath liquid was saturated with H2S. The reaction mixture was placed in a steel tank and heated to 95°C. After 27 hours, TLC showed no starting material remaining. The reaction mixture was evacuated with N2 for several hours and poured into ice water.

The product was collected by filtration and purified on silica sol with CH
Purified by flash chromatography by eluting with CJ3/Me OH (97:3 v/v).

A 37% yield of 1-(2'-deoxy-5'-trityl-β-D-lyxofuranosyl)-2-thiothymine was obtained. UVmax in pi-11 277 nm
and 241 nm at pH 11 directed the formation of 2-thiothymidine. The 6'-hydroxyl group of the O-thiothymidine derivative was metalated as follows: methanesulfonyl chloride (665
mj, 3.5 eq.) in dry bilysin (151d) at 5°C.
J-chiru-β was added to the bath solution of 1-lyxofuranosyl)-2-thiothymidine (1,25F) in 4 portions for 6 hours. The reaction mixture was kept at 5°C overnight. The reaction mixture was poured into ice water and the product was collected by filtration. Purification was performed on silica gel using ethyl acetate:hexane (1:1
It was carried out by flash chromatography with bathing at (v/v). The yield was 50 g.

Lithium azide (0,3,!i', 6 mmol) was dissolved in 20 total dry DMF and mixed with 1 to (2'-deoxy-6'-mesyl-5'-trityl-β-D-lyxofuranosyl)- 2-Thiothymine (0.72 mmol) was added. DMF melt? & was heated at 85°C for 2.5 hours. The reaction mixture was poured into ice water and the product was collected by filtration. Purification was performed on silica gel, CHCl
3: Performed by flash chromatography with elution with MeOH (98' 2 v/v). The yield was 78 cm. A band at 2100cWL-1 in the IR indicated the presence of alkyl acid. UV is
The presence of 2-thiothymidine was confirmed.

The final product is 3'-azide-
3'-deoxy-2-thio-5'-tritylthymidine (
The 5'-human-xyl group of 0,1,li') was prepared by deprotection on a steam bath for 45 minutes.

3'-azido-3'-deoxy-2-thiothymidine (0
,021g> on silica gel, CHCl3 : Me
Chromatography by elution with OH (96:4 v/v) gave a yield of 37%.

Example 28 3'-Azide-3' in dry ethanol (251 Lt)
-deoxy-5'-mesylthymidine (2,6,9,7,
5 mmol) and 2 equivalents of potassium carbonate (1.08 g,
3'-
Azido 3'-deoxy-2-ethoxythymidine was produced. The solution was neutralized and collected in vacuo as an oil.

The oil was purified by flash chromatography on silica sol, eluting with ethyl acetate:methanol. Desired product was isolated in 39% yield; mp = 98-10
Example 29 6'-azido-6'-deoxy-2-methoxythymidine was prepared from 6'-azido-3'-deoxy-5'-mesylthymidine (1.6 g, 4.6 mmol). It was manufactured by the method No. 25. Yield was 42qb; melting point = 4
7-51℃.

Example 60 Socytidine 2.5'-0-anhydro-6'-azido-3'-deoxythymidine (0,35,!i'; 1.4 mmol) was dissolved in 15 mg of MeOH presaturated with ammonia,
and placed in a cylinder at 77°C (oil bath) for 48 hours [5karic and Mazulic-Adamic, He1v, Chim, ACta]
), 63.2179 (1980) ) o TLC (6
: 1 v/v C)T(J3/MeOH), the reaction was incomplete. The solvent was removed in vacuo and the resulting oil was placed in a silica sol column followed by CH(J
Elution was with 3/MeOH (6:1 v/v).

The appropriate fractions were combined to give the title compound 0.149 (0,5
3 mmol; 68%) was produced; melting point = 107-10
8°C0 Example 61 Lysine 6'-azido-2', 3'-dideoxyuridine (
0.259; 1 mmol) was added to 2 m# of dry dimethylacetamide (DMAC), cooled to 0°C, and 2 ml f of 0.5 M HCj in DMAC was added. m-chloroperbenzoic acid (0,227,!i';1
．． 6 mmol) was added in two portions over 10 minutes and the mixture was brought to room temperature. After 2 hours, 4 m of water
1 was added and the solution was filtered. Extract the aqueous DMAC@ solution with Ez20 (3x 3ml) and mix with Ez20
was evaporated in vacuo to an oil, which was loaded into a silica gel column. CHCJ3 diMeOH (15:1 v/v)
Elution at , combination of appropriate fractions and evaporation in vacuo produced an oil which was crystallized from Eu2O to give 58.5
Obtained 1n9 (0.2 mmol, 20%); melting point = 16
9-170°C0 UV (nm): λcoax = at pH1
276 (-= 7400) λmin: 239 (
−=500); λmax = at p)+13
274 (ε = 6400), λ. ,. = 249 (ε
= 3800) HlNMR (DMSD-d6) δ8.2
9 (S, IHXH6), 6.04 (t, 1H,
Hi', J = 5.5 Hz), 5.49-5.2
9 (m IH, 5'-○H), 4.44-4.20
(m.

IH, H3'), 3-88~6.71 (m s IH
, H4'), 3.71-3.53 (m, 2HX
H5'), 2.61-2.31 (m, 2H, H2'
); Elemental analysis value: C0H engineering. N50. (calculated as J
: C37,58H3,50N 24.35 (J 1
2.32 Measured value: c 37.67 H3,54N
24.39 ct 12.40 Example 32 Lysine 3'-azido-5-bromo-2', 3'-dideoxyuridine was converted to known 6'-azido-7,3'-dideoxyuridine [Frenilsky (T, A, Krenils
ky) et al., J. Med, Ch.
em, ), 26.891 (1983)) (0,
827,li', 3.3 mmol), the 5'-hydroxyl group was first acylated with acetic anhydride (1 strip), then the 5-position was acylated with acetic acid (o, 5 red) and bromine (0,56
6 g). The reddish-brown solution was stirred at room temperature for 2 hours. The reaction mixture was taken as an oil in vacuo and triturated with ethyl ether.

The oil was dissolved in methanolic ammonia to remove the acetyl groups. The desired product was purified on a silica sol with CH(J3:
Isolated by chromatography by elution with MeOH (95:5 V/V). Yield was 32%; melting point = 148-149°C.

Example 66 6'-Azide-2', 3'-dideoxy-5-iodourisine 6'-azido-2', 3'-dideoxy-5-iodouridine was converted to 2',3'-dideoxy-5-iodourisine (109, 28 mmol), from the literature [T, A, Krenizsky et al., J. Med, Chem, 26.89
1 (1983) E; melting point = -126-160°C.

Example 34 6'-Acid-2', 3'-dideoxy-5-trifluoromethyluridine 6'-Azide-2', 3'-Dideoxy-5-trifluoromethyluricine was produced by the following four-step reaction. did.

The 5'-hydroxyl group of 2',3'-dideoxy-5-trifluoromethyluridine (5.0 g, 16.9 mmol) was replaced with dichloromethane (1,4 m), pyridine <70rnt) and 6A molecular director (55 g). - Triphenylmethyl chloride (5
, 65 &, 20,3 mmol). The reaction mixture was stirred at room temperature for 4 days. After filtration and evaporation in vacuo, the oily product was purified on silica gel with CH
2 (J2: Chromatographed by elution with MeOH (95' 5 v/v). The product fractions were combined and the solvent was removed in vacuo.

The resulting oil was triturated with water and the solid formed was collected by filtration. Triphenylphosphine (3.27g)
The 6'-hydroxyl foundation chloride was prepared by bathing the 5'-protected uridi y (3,0,!i') in dimethylacetamide (30 ffll) containing 7 and adding carbon tetrachloride (51). It became. The reaction mixture was stirred at room temperature overnight. 1 ml of methanol was added. The reaction mixture was taken up as an oil and transferred onto silica gel with CH2Cl2:
Chromatographed by elution with EtOAC (9'1''■). The desired product was collected as an oil.

Kohli (v, Kohli
) etc. [Tetrahet o y-letters (Te
zrahedron Lezt,ers) X21.
2683, 19803, Nitromethane (80 m
Deprotection was achieved by adding zinc bromide (4,45&) dissolved in nitromethane (801d) and dissolved in nitromethane (801d). The reaction mixture was stirred at room temperature overnight. Further zinc bromide <3.0 j;l) was added the next day and the reaction mixture was left overnight at room temperature.

With mild heating, the final addition of zinc bromide (3,79) pushed the reaction to the end point. The reaction mixture was poured into 1M ammonium acetate. The product was extracted into dichloromethane. Dichloromethane was removed in vacuo and the resulting oil was purified on a silica sol with CH2Cf2:MeOH
Chromatography was carried out by elution with (95:5 v/v). The final product contains 1-(3'-chloro-cudeoxy-β-D-ribofuranosyl)-5-trifluoromethyluracil (0,48 mmol),
Obtained by treatment with lithium azide (0,1911,3,8 mmol) in dimethylacetamide (4,8 ml). The reaction mixture was heated at 90° C. for 4 hours.
Ta. The reaction mixture was taken as an oil and poured onto silica gel.
CHCJ3: MeOH (95: 5 v/v)
Chromatography was carried out by elution with . Chromatography required a second run. On silica gel, CH2C
Elution with f2:MeOH (97:3 v/v) produced substantially pure product. Crystallization from toluene led to pure product in 10% yield.

Example 35 3'-azido-7,3'-dideoxycytidine was converted into 6'
-azido-7,6'-dideoxyuridine (2,2&,
7.9 mmol) to Krenicki (T, A.

Krenitsky) et al.
J.

Mad, Chem, ), 26.891 (1983
)] as an HCj salt. Yield was 40%: melting point = 174.5-176.5°C.

Example 36 Tidine 6'-azido-7,3'-dideoxy-5-methylcytidine was converted to 3'-azido-6'-deoxythymidine<o
, s g, 6.0 mmol) according to the method of Example 35. The yield was 19%.

The synthesis of threo6'-azido-2',3'-dideoxycytidine was carried out in four steps from 2'-deoxyuridine.

Synthetic procedures for the 5'-hydroxyl group of 2'-deoxyuridine
Acid Chemistry (5ynthez1cProce)
dures in Nucleic Ac1d Che
Tritylation was carried out by the method described in J. Miszry, supra, 321, (1968).

Trityl uridine is 2'-deoxy-5'-trityl uridine (5,0 &, 10,6 mmol), triphenylphosphine (3,07 &, 11.7 mmol, 1
．． 1 equivalent) and carbon tetrabromide (3,88 &, 11.7
(mmol, 1.1 eq.) and lithium azide (5,21 mmol, 106 mmol, 10 eq.) in DMF (80d). Carbon tetrabromide was added last. The reaction was carried out overnight at room temperature.

Methanol (5 parts) was added. The solution was reduced to an oil in vacuo and flash chromatographed on silica gel, eluting with ethyl acetate.

Deprotection of the 5'-hydroxyl group was performed in 80% acetic acid by heating on a steam bath for 20 minutes. Upon cooling, trityl carbinol precipitates: '1, yo.
□1 Eh. , □, no. A, ka i□ turned into a slurry in the ether. The product, threo6'-azido-2',3'-dideoxyuridine, was used without further purification. *iP, product, HCJ, salt and
Threo-6'-azido-7,3'-dideoxycytidine as □ is derived from the uridine congener to the erythro isomer □
Exactly the same method used for production [Klenicki (T.
A, Krenizsky), et al.
J.

Med, Chem, ), 26.891, (1983
)). The power collected was 0.021.9.7 cm.

Example 68 9-(3'-azido-2', 3'-dideoxy-α
Once -ribofuranosyl) adenine, N6-ophthalyl adenine (2,09,7,7 mmol) and 6'-
Acid-3'-deoxythymidine (1,13,!i'.

4.2 mmol) to Imazaw (M, Imazaw)
a) and Eckszein (F, Eckszein
) [J. Org. Kem (J.
Org.

Chem, ), 43.6044, (1978)) in two steps; melting point = 120-122°C.

UVFJ-11λmax 258 nmλmtn 23
0 nmpH13λmax 260 nm Jm,n
229 nm elemental analysis value Calculated value as Cl0H12N802: C43,48H4,38N 40.56 1st measurement: C43,28)(4,45N 40.38Naj39-ribofuranosyl)adenine9-(3'-azido-2' , 3'-dideoxy-β-
Eurizafuranosyl) adenine'k, N6-ophthalyladenine (2,0&, 7.7 mmol) and 3'
-azido-6'-deoxythymidine (1,13&.

4.2 mmol) to Imazuwa (M, Imazawa
) and Eckszein (F, Eckszein)
The method described by J.O.
rg.

Chem, ), 46.3044 (1978)] in two steps. Melting point = 184-185°C0UVp
)11 λmax 257 nm λmin 230 n
mP' 13 'maw 260 nm 1m1n
228 nm elemental analysis value: Calculated value as Cl0H 2N802: C43,48H4,38N 40.56 Measured value: C43,33I (4,45N 40.41 Example 4
0 5'-acetyl-6'-azido-6'-deoxythymidine (0.75 &, 2.4 mmol) was added to bilicin (5 intoxicants)
and benzoyl chloride (1.4 ml,
12 mmol, 5 eq.) was added at room temperature. The reaction mixture was stirred overnight and then poured into ice water (25 ml).

The pH of the aqueous solution was adjusted to 1. The product was extracted with chloroform, the organic layer was washed with water, dried over MgSO4 and filtered. The chloroform was removed and the oil was flushed with two necks of silica sol and eluted with chloroform. The product was collected as an oil.

H”NMR (DMSO-dd): δ8.04-7.5
0 (m, 6H; 6N-benzoyl and 6H),
δ6.12 (dd %I H% J 11.2a'
=: 5.6 Hz −, J l! , 2b' = 6
, 7 Hz% 1'H), δ4.55-3.96 (
m, 4H; 3'H, 4'H, 5'H), a 2.62
~2.58 (m, 2H, 2'H), a 2.07
(S 13H, 5'acetyl CH3), 61.90
(d, 3H.

J5"! "" 1.0 H2% 50H3) Elemental analysis value' Calculated by Cx9Hx9NsO6 (directly:
C55,2D H4,63N 16.94 Measured value: C55,29H4,64N 16.96 Example 41 Threo-3'-azido-5-bromo-7,3'-dibusthreo-3'-acido-5-bromo-2' , 3'-dideoxyuridine was prepared from 2'-deoxyuridine in a five-step reaction.

5 of 2'-deoxyuridine with triphenylmethyl group
Protection of the '-hydroxyl group was carried out in a conventional manner.

The 3'-hydroxyl was metallated. 2-deoxy-3
'-Mesyl-5'-trityl uridine (22 g, 50 mmol) in dimethylformamide (38° WLA)! By adding it to syneresis of 7,84,9,120 mmol, 6 equivalents) at 8D°C, 3
The '-azido group was introduced with the correct stereochemistry. The reaction is 35
Time passed. The common liquid was poured into ice water (21) and collected by mft retention. Product on silica sol,
C') was isolated in 51% yield by chromatography with chloroform:methanol (1:1 v/v) bath. The 5'-hydroxyl position was depopulated with 80% acetic acid in a steam bath for 25 minutes. After cooling, the trityl carbinol was removed. The filtrate was concentrated in vacuo to a thick oil.

The product was transferred onto silica gel in chloroform:methanol (
Isolated by flash chromatography, eluting with 85:15 v/v). threo-3'-azido-2
The 5-position of ',3'-dideoxyuridine was brominated in exactly the same manner as outlined for the bromination of erythro 3'-azido-2',3'-dideoxyuridine.

UVPI-11λmax 280, a = 9400,
λmin 244ε= 2600 - 13λma 276, ε= 6700, box. 251
ε=3700 HlNMR(DMSO-d, ):δ1l-86(s
11Hl3-NH), a 8.02 (s, IH
, 6H), δ5.99 (dd % IHX J1',
2a'=3.0 Hz; Jl', 2b'=7.
5Hz, 1'H), δ5.1 (t% IH%
δ5. CH2 = 5'OH = 5.4 Hz,
5'○H), a 4.49 (m, IH% 3'
H), δ 4.05 (m % IH14'H),
δ Ro, 71 (m, 2H15'H), δ2-
72 (m % IH12b'), δ2.18 (
rn-.

1H12a') Elemental analysis value 9HIOBrN504-0.25H20
Calculated value as -0,1C2H402,': C32,25H3,21N 20.4
4 Br 23.32 Measured value: C32,17H3,
21N 20.33 Br 23.19 Example 42 Dinone sodium (0.4 g, 17.4 mmol, 2.6 eq.
t)'t, and reacted with dry benzyl alcohol (10a6) for 1 hour at room temperature. 2.5'-0-anhydro-31
~Azido-6'-deoxythymidine (1,65g, 6.
6 mmol) was added. The reaction continued for 1 hour.

After pouring into ice water (25 OfflA) the - was adjusted to 7 and the aqueous layer was extracted with ethyl acetate. The organic layer was extracted with water (4 times). After drying over Mg5O, the ethyl acetate was removed in vacuo. The resulting oil was chromatographed on silica sol, first bathed in ethyl acetate and then in ethyl acetate:methanol (9:IV/V). The product-containing fractions were collected and the target medium was removed in vacuo to yield an oil. The oil crystallized after covering with ethyl ether; melting point = 125-126.5°C0 UVp)li unstable X 13 umax 2561. = 10700, λ
min 2401, = 8900 HINMR (Dv5o-dd): δ7.8 (dN
IH% δ65 = 1.2Hz, 6H), a 7.4
9-7.38 (m, 5H, 2-7x = le),
a6. []δ8(dd, IH,, J1', 2a
' = 5.0Hz; J 1 'I 2 b'
= 7-OH2% 1'H), δ 5.
37 (s.

2H% 20H2), δ5.25 (t% IHXJ
s'cH25'OH=5.4 Hz, 5'OH),
64.36-4.32 (m, IH, 3'H), δ
3.85-3.81 (m-IH% 4'H), δ3
．． 7-6.58 (m, 2H, 5'H), δ2.53
~2.34 (m % 2H-, 2'H), J 1.82
(d% 3H% δ516 = 1, Q Hz,
50H3) Elemental analysis value' C17H19N! Calculated value as 504:
C57,14H5,36N 19.60 Measured value: C
57,02H5,43N 19.53 Example 46 Threoro'-azido 5'-o-mesylthymidine (1,
08 g, 3.16 mmol) [prepared from threo-6'-azidothymidine] was bathed in ET, ○H1QQmz and treated with NaHCO2 (0.26 g, 6.16 mmol) at reflux for 18 hours. Cool the reaction mixture;
And filtered. The solvent was removed in vacuo and the residue was applied to a silica gel column, followed by 9:1 (v/
v) Eluted with CHCj3/MeOH. Appropriate fractions were combined and the solvent was removed in vacuo to yield 0.7.9 (2,4
mmol, 75.7 thi) was produced; melting point = 120-1
22°C0 UV (nm) Box ax = 260 at pH 1 (
g = 9DO), λmin: 237 Ct =
5500), λ5holder = 221(,
= 7500) ; λmax = at pH 13
256 (ε=10000), λ□,. = 240 (
ε=7700).

HlNMR (DMSO-dd): δ7.58 (s
, IH, H6), a 6.0 (aa, IHX H
1', J = 2.9.4.56 Hz), δ5.06
<t, IH, 5'○H, J = 4.91 Hz
), δ4.51-4.47 (m, IH, H3
), ' 4.34 (q % 2H.

-0CH2-1J = 7.14 Hz), 84.1
0-4.05 (m.

IHX H4'), δ 3.73 (z, 2HX
H5', J = 5.62Hz), '2-82~
2-73 (m%IH%H2b'),
J 2.21-2.14 (m % IHX H2'
a), δ1.82 (s 13H%5CH3), a
1.31 ("s 3H%-CH2-"H3, J
= 6.65 Hz).

Elemental analysis value: Calculated value as C engineering, H F N504: C
48,81H5,80N 23.72 Measured value: C48
,59H5,86N 23.64 Example 44 Othymidine 3'-acido-5'-0-)dityl-3'-deoxy-4-(1,2,4-triazolo)thymidine (1,
25 g, 2.2 mmol) [W, Sung, Nucleic A
cids Research), (1981), 9
．． 6169] was dissolved in 100 ml of acetone and 60 ml of water, and then dissolved in Na5H, xH2
Treated with O0-229. The mixture was stirred for 3 hours. The volume was reduced by half and extracted with 3300 ml of CH (δ).

CH (δ3 was washed with 50!Ll of water, Na 2 SO
4 and removed in vacuo to yield an oil.

The 5'-O-) +7 thyl group was removed by bathing this oil in 10011 Ll of 80% HOAc. The solution was heated on a steam bath for 2 hours, then cooled and diluted with 100 rIL of water.
and filtered. The solvent was removed in vacuo and the oil was placed on a silica sol column. 20:1 (
elute with v/v) CH(δ3/MeOH, remove the appropriate fractions, and subsequently remove the solvent in vacuo to give a concentration of 0.1
8.9 (0.62 mmol, 28%) was produced; melting point = 65-67 ° C0 UV (nm): "max = 3 at pH 1
37 CM = 20700) λmin” 280
(g = 1200), λ5holder = 23
8 (ε=3400); p) 2max = 320 (-= 1 at 113)
8400), box □. =257 (-=1700); HlNMR(DMSO-δ6) δ7.63 (
s, 1HX H1', J=2.93, 4.89 Hz
), δ 5-06 (s 11H% 5'OH)
, δ 4.50-4.46 (to, IH, H
3'), 8 4.10-4.04 (m, IH, H4
'), δ 3.73 (d, 2HX H5',
J=5.61 Hz), J2.78~2.68
(m % IH% H2b'), a 2.2
0 to 2-14 (m% IH% H2'a),
δ 2.00 (s.

3H,5CH3) Elemental analysis value: C1oH13N503S0. IC2H,
Calculated value as O-0, 25H20: (14), 90H4, 86N 23.95
S 10.97 measurement value: (14), 99H4, 73
N 23.88 310.91 Example 45 3'-Acid-2', 3'-dideoxyuridine was prepared by the method of Visser
Chemistry - (5ynthetic P
rocedures 1nNucleic Ac1d
5'-acetyl-3'
-azido-5-bromo-2',3'-dideoxyuridine was obtained. This material was dissolved in 1.5 equivalents of 5 equivalents in dry pyridine.
2.4-) lyazole and 2JiL17) Reacted with 4-chlorophenyldichlorophosphate at room temperature for 7 days to give 5'-acetyl-3'-azido-5-bromo-
4-(1,2,4-triazolyl)-2', 3'
-Dideoxyuridine was obtained as a yellow oil in moderate yield. Treatment with ammonia-saturated methanol at room temperature for 0.60118 hours, after recrystallization of the resulting crystals in ethyl acetate and filtration, 4-amino-6'-azido-5-
promorph, 6'-dideoxyuridine 176 da(0,
5 mmol, 6.3%); mp = 162-16
5°C (decomposition).

UV (nm): λmax = 300 at p) 11
．． 215 (ε=10700.12100), λmin
"253 (g = 1500) ; λma = 288 C! = 7300) at -16), λ, □.

=260(ε=3900) HINlviR(DMSO-δ6) J8-3(
19% IH-, H6), a 7,85 (broad s, IH% 4-NH2), a 7.05 (broad s, IH% 4-NHz), δ6.0 (ts
1HsH1', J'' 5.94 Hz), a
5.33 (t% iH, 5'-OH.

J = 5.01 Hz), δ 4.4-4.3
(m, IH, H3'), δ 3-9 to 3-5
(m-, 3H, H4', H5'), a2
．． 31 Kunoso D, 2HS H2', 6.27 Hz).

Elemental analysis value: Calculated value as CgH11N603Br:
C32,64H3,35N 25.38 Br 2
4.13 Measured value: C32,52H3,41N 25.
32 Br 24.04 Example 46 5-bromovinyl-coudeoxyuricine (BVDU
), using the method of Jones et al. [Tezrahedron I, 9Z
terS), 45.4415 (1979)) in a similar yield. BVDU is Horwitz (
Horwizz) et al.
, Org, Chem, ), 31.205 (196
6) Tritylation and mesylation by l). This product was treated with an equimolar amount of sodium monocarbonate in refluxing methanol to produce 3',2-0-anhydro-5-bromovinyl-2-deoxyuridine. This product was treated with 6 equivalents of lithium azide in 1 water/dimethylformamide at 160°C. The crude material was chromatographed on silica gel, followed by the appropriate fractions being combined and evaporated to yield 3'-azido-5-bromovinyl-2',3'-dideoxyuridine as a golden oil; UV (nm ) s fJ (at 1, λmax = 292.247, λmin = 270.
238; λmax = 253.2m at pH 13
1n=238, λsh=284; HlNMR(D
MSO-ci, )δdan, 06 (s, 1HXH6),
δ7.25 (d, IH, -CH==CHBr,
J = 13.4 Hz), a 6.85 (a,
IH, = CHBr XJ = 13.7 H2), a
6.07 (ts IH% H1/, J = 6.3
Hz), a 5.30 (broad 8% IH%
5'-0H), δ4-42 (q% IH1H3
', J=6.3.6.1 Hz), a 3.86-3.
82 (m.

1HXH,'), a 3.68-3.59 (m %
2H% H5'), δ2.47-2.32 (m,
2H, H2').

Elemental analysis value: Calculated value as C11H12N504Br: c 36.89 H3,38N 19.55 Measured value: C3(ri,86 H3,41N 19.51 Example 47 hh compound is 3'-azido-5-chloro-7° 6'-
Prepared in a similar manner to dideoxyuridine (Example 61) to yield 0.15.9 (0.5 mmol, 25 thi); melting point = 65°C.

UV (nm); λmax = 278 at -1
．． 212 Ce =8900), λ□. = 240 (
, = 1600);, in H2S, λrnax =
275 (ε=6600), λ. ,. =248(ε
= 3300); H”NMR (DMSO-d6) δ11.89 (S,
IHlNH), δ7.94 (s 11HXH6),
δ6-00 (dd% IHXH1', J = 2.9
3.4.64 Hz), 85.1 (t% IH%
5'OH%J = 5.1H2), δ4-5[] ~4
-46 (m% 1HXH3'), δ4.08~
4.03 (m, IH, H4'), a 3.71
(tN2H,H5', J = 5.32 Hz),
δ2.77-2.67 (m.

1HXH2'b), δ2-23~2.16 (m %
IHXH2'a).

Elemental analysis value: C9H1oN504cj, 0, lH2O
-0, Calculated value as IC4H802: c 37.85 H3,72N 23.4
8 Cf1Ls9 measurement value: C37,94H3,91N
23.23 Cf11.86 Example 48 Dinone 1~ (3'-azido-2', 3'-dideoxy-β-
Riichi erythrobento 7lanosyl)-5-methyl-2-
(pentyloquine)-4-(IH)-pyrimidinone,
1-(3'-azido-2', 3'-dideoxy-
[beta]-nierythropentofuranosyl)-2-(pendyluoquine)-5-methyl-4-(1H) Zarimizonone was prepared by the method used to make it (Example 42). The final product made by i is Cyu. Above, by HPLC with water:methanol (Lonia) bathing. The bath medium was evaporated and the product was collected as an oil.

UVp) 11 λmax 258 nm ε=
9400, λmin 232 nmε = 5900 pH13λmax 256 nm t = 1060
0, λmtn 239 nm -%8200 The sample was taken in DMSO-a.

NMR: δ 7.81 (s, IH, 6H)
, δ lls, 04 (Z, IH.

Jl'+2'=6.7 Hz, 1'H), δ
5.2B (t,,1H,J5'CH2,5'OH=
5. IHz, 5'OH), a 4.43~
4.37 (&IH, 3H), z 4.27 (b
2HXJ2-0 (10H2, 2CH2) ~6.6Hz
%2-〇(CH2)l), δ 3.88-3.84
(m.

1H, 4'H), δ 5.70~3-50 (m
% 2H% 5'CH2), a 2.50-2.
34 (m 12H-, 2'H), δ 1.80 (
s.

3H15CH3), δ 1.72~1~68 (m
%2H12-0(CH2)2), δ1.
38-1.30 (m, 4)(, 2-0(CH
2) 3 and 4), δ0.92-0.87 (m, 3
H, 2-0(CH3) 5).

Elemental analysis value ' C15H23N504 "Calculated value as 4H20: 052.70 H6,93N 20.4
8 Measured value: C52,63H6゜92N 20.4
8 Example 49 3'-azido-6-penzoyl-6'-deoxy-5'
- medylthymisine similar to that used in Example 40 for the preparation of 5'-acetyl-6'-azido-3-benzoyl-3'-deoxythymidine from 5'-acetyl-6'-azido-6'-deoxythymidine. Depending on the method, 6'-azido 3-
Benzoyl-3'-deoxy-51-mesylthymidine was prepared from 3'-azido-6'-deoxy-5'-mesylthymidine; melting point = 86-88°C.

UVpH1λTnax 259 nmε=21200,
λmin 230nmζ = 6400 - 16 boxes Uni 265 nmε = 9600, λ1□n
248 nmε=8000 HINMR (DMSO-d6) δ8-00 to 7-58
(m-, 6H16H and phenyl), δ6.15
(Z% IH% J1'J2' ~6, IHz%
1'H), a 4.55-4.47 (m, 3H
; 3'H and 5' CH2), a 4.12-4.
10 (m, IH, 4'H), J 3-28 (S
N3HN5'-5o2CH3), a 2.65~2
．． 4 (m% 2H% 2'H), J 1-89 (
dX 3HN tT516 == 1~3Hz,
50H3) Elemental analysis value Calculated value as 18H19N50WS:
c 48.10 H4,26N 15.58 s
7.13 Measured value: C48, QOH4, 25N 15.
59 87.10 Example 50 5-Yobi 21~Deoxyuridine was added to Horvitz (
Horwizz) et al. [Zoe Org Kemm (J.

Org, Chem, ), 61, (1966), 2
05], tritylation and mesylation were carried out. This product was heated with 6 equivalents of lithium azide in anhydrous dimethylformamide at 74°C for 48 hours.

Silica sol chromatography of the reaction mixture with 20:1 CH(J3:MeOH (v/v), followed by combination and evaporation of the compatible components gives the threo6'-azido-
7,6'-zodeoquine-5-iobi-5'-trityluridine was given. The 5'-hydroxyl was deprotected with a saturated zinc bromide/nitromethane bath at 0°C.

Silica gel chromatography of the crude product using 9:I CHCJ3/MeOH (v/v), followed by combination and evaporation of the appropriate fractions gives threo6'-azido-2
゜6'-dideoxy-5-yolaP uridine was produced as a solid; melting point = 80°C0 UV (nm); p) λmin at l 1
= 247; λmaw = 277 at pH 13
;λ□,. =252; HINMR (DMSO-d6) δ8-37 (8% I
H% H6), a 6.00 (t% IH% H1
', J = 6.17 Hz), 65.4-5.6 (m
, 1H15'OH), 64.4-4.3 (m, 1
B.

H6′), J 3.9-3.8 (m, IH, H4
), a3.7-3.6 (m % 2H% H5'
).

Elemental analysis value: C9H1ON504IO, 4C4H80
Calculated value as 2: C30,73H3,21N 16.
90 I 30.63 Measured value: C30,93I (3
,09N 16.61 I 30.94 Example 51 1~(5'-0-acetel-6'-azido-2',3'
-dideoxy-β-ri-erythrobentofuranosyl)
-5-methyl-4-(1,2,4-triazole-1~
yl)-2-(IH)-virimizonone 5'-acetyl-
6'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and 2 equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine for 10 days at room temperature. 1:1 EzOAc/
Silica sol column chromatography of the crude product using hexane (v/v) followed by combination and evaporation of the appropriate fractions produced an oil. Crystallization from EtOAC yields 2.7 g (7.5 mmol: 60%) of the hexasetite compound solid.
produced as; melting point = 146-145°C.

UV (nm) P) Jmax = 32 at 11
4.245.215 (ε= 9300.10000.2
0500), λ. , U = 282.233 (, = 2
100.8200) ; λmaw at pH 13
=276(ε=6000), λ0,. = 242 (
g = 2000) HINMR (DMSO-δ6) J
9.34.8.40 (2s, 2H% triazolyl), δ8.23 (s, IHXH6), δ6
．． 12 (t,, 1HXH1', J = 6.16
Hz), a 4.48~4A7 (m -, 4HXH3
', H4/, H5'), a 2.35 (8%3H,5
'-acetyl), δ2.07 (S, 3H, 5CH
3) Elemental analysis value Calculated value as 014H16N804: c 46.67 H4,48N 31.10 Measured value: C46,58H4,51N 31.02 Example 52 -Erythrobenfuranosyl)-4-dimethylamino-5-methyl -2-(IH)-gyrimidinone 5'-acetyl-6'-azido-3'-deoxy-4-
(1,2,4-triazolyl)thymidine was dissolved in dry acetonitrile at room temperature under nitrogen atmosphere. Add 20 ml of dimethylamino at once and add 60 ml of dimethylamino to the reaction mixture.
Stir for a minute. The solvent was removed, the residue was bathed in ammonia-saturated methanol, and the solution was stirred for 30 minutes. The solvent was removed and the residue was dissolved in EZOACK. The title compound slowly precipitated from the bath solution and was filtered to give a white solid; mp = 157-159°C0 UV (nm
): p) 11 in λmax = 299.224(
ε=14900.7900), λ Engineering,. = 254
(, = 2500); λma at pi-11,3
x = 287 (ε = 14000), λ0,. =2
46 (ε=6800).

HINMR (DMSO-δ6) δ 7-63 (
s % IH, H6), a 6.06 (t %
IHXH1', J = 6.53 Hz), 65.
22(Z, 1H, 5'OH, J = 5.2H
z), 24.37~4.34 (m, 1H, H3
'), δ 3.83-3.80 Cm, IH.

H4'), a 3.65-3.60 (m %
2H% H5'), δ 3.06 (s,
6H, N(C)i3)2), δ 2.29-2.23
(m 12HX H2'), ' 2-11 (
s % 3Hs 5-CH5).

Elemental analysis value Calculated as Cl2H1BN603 Irosi L: C48,97H6,16N 28.56 Measured value: C49,06H6,20N 28.50 Example 56 Rimicinone The title compound was prepared from 1 to (3'-acid-2', 3'
-dideoxy-β-ri-erythrobentofuranosinolyne-2-(benzyloxo)-5-methyl-4(1H)-
It was prepared in a manner similar to that in which virimizonone was prepared (Example 42).

UV P)l 1 (nm) Jmax 258 g
= 9000, box, n237 g = 6000, pH 13 (nm) λmax 255 g = 100
00, λ. in 239 g = 8000H1NM
R(DMSO-δ6): δ7.79 (s, I
H, 6H), δ6.02 (t % IHXJl', 2
'~6-3 Hz% 1'H), δ5-23D
s IH% J5'0H15￥ (=5-2 Hz %
5'OH), δ4.4-4.3 (m, 3'H and 2-O-CH2-CH2CH(CH3)2), a3
-9 to 3-8 (m-, IH, 4'H), a 3.7
~3-5 (m 12H% 5'H), δ2.5~2
．． 3 (ms2'l, δ1~78 (S% 3H%
5 CH3), δ1.7-1.5 (m 13H, 2
-OCH2-CH2-CH(CH3)2), 60.92
and 0.89 (d, 6HXJ = 6.3H
z.

2-0(CH2)2CH(CH3)2).

Elemental analysis value: Calculated as C engineering 5H23N504 if
: C53,4D H6,87N 20.7
6 Measured value: C53,14H6,92N 20.62 Example 54 Lobenzoyl)-6'-deoxythymidinebenzene 20
6'-azido-5'-0-(4-chlorobenzoyl)-61-deoxythymidine (0.3 g, 0.74
mmol) and silver cyanide (04,!i', 3.0
to a mixture of acetyl chloride (IJ mol) in excess of acetyl chloride (
2, tl, 33 mmol) was added in several portions. T.L.
The mixture was stirred at room temperature until the disappearance of the starting material (4 h) as confirmed by CCHCf3/MeOH20' 1 (v/v). The reaction mixture was filtered, filtered and the filtrate was evaporated to dryness under reduced pressure.

The resulting oily residue was chromatographed on silica gel and bathed with chloroform/hexane 1:1 (v/v) followed by chloroform to give 0.21 g of the desired product.
(64 g) was obtained as an oil.

UV (nm): λmax 27 at pH 1
3 (ε = 9000), 'min 251 (# =
6200); λmax 266 at pH 13
(g = 8800), λmin 247 (-= 7
000) H”NMR (DMSO-d6) J 1-6
8 (5% 3HN 5-CR2), a 2.47
(s, 3-COCH5), δ2.3-2.5 (
m, 2M), a 4.1-4.2 and 4.4-
4.7 (m, 4H, 3'H.

41u and 5'H), δ6-1 (Z N IHXJ
l'-2'=6.3Hz, 1'H), δ7.5-8.
0 (m, 5H, 6H and phenyl) Elemental analysis value: C19H18N50. Cf-Q, 2CH
(Calculated value as J3: C48, 89H3, 89N 1
4.85 (J 12.03 measurement value: C49.05H
3,94N 14.79 (J 12.5 < 5 Example 55 Lysine 5-iodo 7,6'-dideoxyuridine was dissolved with acetic anhydride (2,1 eq.) in pyridine for 2 hours at room temperature with exclusion of moisture. React with t21, 3/-dideoxy-3
', 5'-diacetyl-5-iodourisine was obtained. Nucleoside (1 equivalent fjk), potassium cyanide (1
, 6 eq.) and potassium acetate (1,3 eq.) in dry D
Combined in MS O and heated at 97°C for 2 hours under nitrogen. The solvent was removed in vacuo and the residual oil was applied to a silica sol column followed by 1:I CHCJ3/
Bathe with EZOAC (V/v). Appropriate fractions were collected, combined and evaporated to yield 5-cyano-2°3'-dideoxy-3',5'-diacetyluridine. The compound was dissolved in ammonia-saturated methanol and O
Stirred at oC for 18 hours. The solvent was removed in vacuo at room temperature to give crystals of the title compound; mp = 160-1
62°C0 U■ (nm): λmax = 27 at pH1
6.215(,~13500.11200),λ□,.

= 238 (g = 1700); λmax = 276 (g = 10100) at pi-113
,λ. ,.

= 240 (, = 3400) H'NMR (DMSO-d6): δ8.81 (s,
1H, H6), J 6.00 (z, 1HXH1',
J = 5.94 Hz), 65.6-5.21 (m
12H% 5'0H13'OH), a 4.28-4
．． 15 (m, IHX H3'), δ Ro, 8
2-3.77 (m, IH.

H4'), δ Ro-7~5-5 (m % 2H
%H5'), 8 2.18(t% 2HSH
2', J = 5.75 Hz).

Elemental analysis value Calculated value as Cl0H11N3050-25H20: C46,61H4,50N 16.31
Measured value: C46,67H4,71N 16.54 Example 5
6-threopentofuranosyl)-5-71thyl-2-pentyloxy-4-(IH)! "Limidinone 2.5'-
0-anhydro-1~<3'-azido-2', 3
'-dideoxy-β-D-threo-pentofuranosyl)
Thymine was added to a solution of potassium t-butoxide (0.5 eq.) in pentan-1-ol. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The solvent was removed in vacuo and the residue was applied to a silica sol column. 20
'I Elution with CHCf3/MeOH (v/v),
Subsequent combination and evaporation of the appropriate fractions produced a clear oil that gradually formed crystals of the title compound on standing; mp = 110-111<0>C.

UV, (nm): 'maw = at pH 1
255 (t = 10200), Fuku 0. = 237
C1=6200), λsh=222 (g=9
000); λmax = 251. at pH 13.
226 (,=116009600),λ□,. =2
38 (ε=8600)H”NMR (DMSO-d6)
δ7.58 (s, 1H, H6), a 5.98 (a
a, IH, H1', J = 2.98.4.88
Hz), a 5.07 (T,, IH15'OH% J
= 5-42 Hz), a 4.5-4.47 (
m, IH, H3'), a 4.31-4.2
5 (m.

2H%-0CH2-), a 4.1-4.06 (m
% IH% H4'), δ3.73 (Z, 2H
% H5', J = 5.62 Hden), a 2.82
~2-72 (m 11H% H2'), a
2.2-2.14 (m.

1Hsa2'), δ1~82 (s% 3H%
5-CH5), δ1.75-1.65 (m, 2
H, pentyl), 61.4-1.3 (m, 4H, pentyl), -0,92-0.87 (m.

3H, pentyl) Elemental analysis value' Calculated value as C15H23N404:
C53,40H6,87N 20.76 Measured value: C5
3,31H6,90N 20.74 Example 57 The title compound was converted into 1-(3'-azitok,3'-dideoxy-β-D-threo-pentofuranosyl)-5-methyl-2-pentyloxy-4- Prepared in a similar manner to that described below for (1 and)-pyrimisonone (41156), using benzyl alcohol instead of pentan-1-ol; melting point = 167-169° C0 UV (nm): at pH 1 Box a! = 266
C1=9100), λmin” 235 (s
= 3000) ; λmax = 2 at pH 13
56 (, = 11500), λ. ,. = 240 (
, = 9600).

H1 collection R (DMSO-δ6) δ7.6 (s % I
H, H6), a 7.49-7.37 (m s 5H
% phenyl), δ6.01(dd, IH,81',
J = 2.52.5. [l Hz), a 5.35 (
S% 2Hs benzyl), 85.1~5-0 (ox
IH%5'OH), δ4.5-4.4 (m% I
H% H3'), a 4.1-4.0 (m, IH
, H4'), a 3.77-3.67 (m % 2H
%H5'), 82.85-2.70 (m, IHX
H2'), δ2.25-2.15 (m, IH,
182'), a 1.83 (s.

3H: 5-CH5).

Elemental analysis value: Calculated value as C17H19N5040.25H20: C56,43H5,43N 19.35
Measured value: C56,51H5,37N 19.36 Example 5
8 5-Methyl-2(I H)-pyrimizonone 5'-acetyl-3'-azododadeoxy-4-(1,2,4-
) riazolyl) thymidine was treated with 0.5 N sodium methoxide in methanol for 24 hours at room temperature. The solution was neutralized to −7 with Sulfone M resin (DOW50W, H"), the sulfur was filtered off, and the mixture was evaporated in vacuo to a solid. The solid was poured into aqueous CHCl, It was applied to a silica gel column and extracted with (7) 2% MeOH in CHCl. Appropriate fractions were collected, combined and evaporated to dryness to yield a white solid; mp 119 ~123℃.

UV (nm): λmax = 276 in ptii
(ε=7500), 2m1n=239 (t=1700
); P) 113, λmax=276 (e=6
400), 2m1n-=245 (ε=1300)
.

HlNMR (DMso-δ6) δ8.02 (8% I
HXH6), δ6.08 (t, I H, H1'
, J=5.86Hz), δ5.29 (t,
IM, 5'0HXJ=5.48 Hz),
δ4.41~4.55 (m, IHXHda), δro, 9~3-86 (m, IH%H4'), δ
5.86 (s, 5H24-OCH3), δ 3-7
5-3-58 (m, 2H, H5'), δ2.
4-2.5 (m% 2HXH2'), δ1.
89 (8,3H% 5-CH3).

Elemental analysis [: Calculated as C11Hz5N50a 1@
: C46,97H5,58N 24.90 measurement constant:
C47,06H5,40N 24.86 Example 59 Mizonone 5'-acetel-5'-azido-6'-deoxy-4-
(1,2,4-)Thymidine was dissolved in dry acetonitrile at room temperature under a nitrogen atmosphere. Pyrrolidine was added dropwise over 5 minutes and the reaction mixture was incubated for 2 hours. 6 medium is removed in vacuum,
oil was produced. This oil was poured into ammonia-saturated methanol at room temperature and stirred for 4 hours. Each section was removed in vacuo and the residue applied to a silica column. 2
0:I CHC4/MeOH (v/v) followed by appropriate combination of both fractions and evaporation gave the title compound as a white solid; M point = 168-171 °C
.

Uv (nm): p) (at 1 λmaX = 295.
253 (!=15700.9500), 1m1n=25
5 (ε=2600); p) 115, λmax=
285 (ff=15300), λmin=241
(t = 7900).

HINMR (DMSO-d, )δ7-57 (S %
I H1H6), δ69ro2 (ts I
H% H1', J=6.5 Hz), δ5.2
2 (tll H15'OH% J = s, i 5 H
z), δ4.4-4.3 (m, I H, H3
'), δ3.84-3.77 (m, IHX H4'),
δ5.67-5.51 (ms 6 H% H5', 4
pyrrolysine H's), δ2.24(t -2H, H2'
, J = 6-08 Hz), δ2.14 (S, , 5
H,5-C'H3), δ1-87-1.78 (m.

4H, pyrrolysine).

Elemental analysis [direct' Calculated as C14H20N603 (direct: c 52.49 H6,29N 26
．． 25 measuring box: C52, 57H6, 55N 26.1
Example 7 60 5'-acetyl-3'- dissolved in dry acetonitrile
Azi-3'-deoxy-4-(1,2,4-triazolyl)thymidine was prepared by combining benzyl alcohol (5 points) and potassium t-butoxide (
2 equivalents) dropwise at room temperature for 5 minutes under nitrogen. The reaction mixture was stirred for 1 hour and the solvent was removed in vacuo.

The residue was placed in an all-silica sol column and 3:1 CHC2
6 with 3/EtOAc (v/v). Appropriate fractions were taken, combined and evaporated to give a solid. Solid fi: I CHCl3/gtOAc (v
Recrystallization from /v) and filtration of the resulting solid yielded the title compound; mp = 153-134'
C.

UV (nm): p) 11 at λmax=276 (
t=8000), λm1H=257 (ε=20
00); λmax=281 (ε=8
100), λm1n-237 (ε=1600).

H”NMR (DMSO-d,) δ8.05 (s,
IH, H6), δ7.45-7.55 (m, 5H
% phenyl), δ6, mouth 7 (t, I H
, H1', J=5.94H2), δ5.55(
8% 2H, pencil), δ5.27 (t.

1 H,5'0HXJ = 5.20 Hz),
δ 4.41-4.31 (m11 H% H5'
), δ 5.91-3.83 (m, IH, H4')
, δ 5-7~3.6 (m% 2 H% H
5'), δ 2-4~2.5 (m, 2H,
H2'), δ 1.9 (s.

3H,5-CH3).

Elemental analysis 1st shift: C engineering 9H2□N50. Measurement - Paralysis 1st shift: C57, 14H5, 56N 19.60 Measurement 1st shift: C57, 06H5, 57N 19.58 Press j6
1 5'-Azo l-''-2',3'-zodeoxyuridine was prepared by the method of Visser [Synthetic Procedures in Nuclear Acid Chemistry].
Story - (5ynthetic Proceded
ures in Nucleic Acid Che
1.410] to give the title compound; mp = 112-11
4℃.

UV (nm) λmax = 279 at pH 1,
210 (ε=9500.10600), 2m1n=24
3(ff=2000); p[(λrr in 15, a
x=276 (ε=700), 2m1n=250 (ε=4
01]0).

H”NMR (DMSO-d, )δ11~88 (s,
1 H, NH), δ8.02 (S, IH, H6), δ
6.08-6.01 (m% I HlH1'), δ4
．． 47~4.40 (m, IH, H3'), δ4.27~
4.24 (m, 2HXH5'), δ4.05~4
．． 00 (m, 1) (, H4'), δ2.41 ~
2.54 (m, 2HXH2'), δ2.09 (SX
3H1 acetyl).

Elemental analysis 11i: Total $11 as C11Hx2Ny, 03Br 2 C35, 31H3, 23N 1
8.72 Br 21.36 Measurement III:
C35-29H5, 25N 1B, 66 Br 2
1.45 Example 62 -Threo-pentofuranosyl)-5-()riple The 5'-hydroxyl group of 5-trifluoromethyl-2'-deoxyuridine is protected with a triphenylmethyl group, and the 5'-hydroxyl group was mesylated. Product (3,0
g, 4.9 mmol) in DMF at 70°C.
LiN3Q,79 in 5Q ml and allowed to warp for approximately 26 hours. The cooled warping mixture was poured into ice with stirring. The solid was isolated, washed with water, and purified by flash chromatography using hexane/ethyl acetate (2:1 v/v). Combining the appropriate fractions and removing the solvent yields a tritylated product of 0.83,! i' was given. This was poured into a solution of zinc bromide in an acetonate IJ sil, stirred overnight at 0°C. After adding 100 g of ammonium acetate (1M), the organic layer was separated,
Then, it was dried in vacuo. The residue, CHC4/CH30
Purified by flash chromatography using 'H (20:lv/v). Both parts were combined and dried in vacuo. Yield of the title compound was 0.259 (0.8 mmol, 5.3%); mp 118-120°C.

Elemental analysis II; Calculated as Cl0H10F3N504 [Nao 2 c 37.39 H3,14N
21.80 F 17.74fill constant 101
[2 C Yoi7.31 H5-25N 21.7
5 F 17.60 Example 63 1~ (3'-7soh-2', 5'-diteo*cy
The 57-hydroxyl group of /J-D2'-deoxyuridine was protected and the 3'-hydroxy A/ group was mesylated. 3'-Mesyl foundation was substituted with configuration reversal by heating with lithium azide (5%) at 80° C. in dimethylformamyl sulfate for 24 hours.

The reaction mixture was poured into ice water and the product precipitated.

After filtration, the wet product was deprotected@final purification was by chromatography on silica sol, eluting with chloroform/methanol/' (95:5). ! The appropriate portions were combined and the solvent removed to yield the title compound as a solid; mp 142-145°C.

Example 64 5'-hydroxyl foundation of 2'-deoxyuridine (30,9,0,13 mol), FTorwit
z) method [Zoe Org Kem (J, Org, C
hem, ), 31.205 (1966) E. 3'-hydroxyl group (12,6F,
0.027 mol) was chlorinated by the method of Example 62. The dimethylacetamide was removed in vacuo and the concentrated oil was poured into total water (50 (1 ml)). The 0 product fractions, chromatographed above and eluted first with dichloromethane and then with 1% methanol in dichlorothane, were combined and the solvent removed in full vacuum. 5'- by heating on a steam bath in % acetic acid for 20 min.
The Hydroxyl Fund theory was supported. Ditrityl carbinol precipitated on cooling and was filtered. The filtrate was condensed in vacuo and chromatographed on silica sol, eluting with ethyl acetate. The dark chloro was replaced by heating with lithium azide (5 equiv. t) in HMPA at 90°C overnight. The reaction mixture was poured with water and extracted with chloroform. Chloroform was added to the product 9j and dried with MgSO4. Removal of the chloroform produced a solid, which was first recrystallized from water with ethyl acetate/methanol.

The recrystallized solid was dissolved in water and applied to a column of XAO. After washing with water, the title compound vJ was eluted with ethanol. Ethanol was removed in vacuo to form a ~solid; mp = 166.5-168.5°C0 Example 65 0-β-D-pentofuranosyl-5-ethyl)uracil 5-chloroformyl-2'-thi oxyuridine gold,
From 2'-deoxyuricine (10 g, 0.044 mol), the method of Bergstron and Ruth, J., Cark, Nucl, and
NucL, ), 4.257 (1977)). 2'-deoxy-5-ethyluricine was prepared by the method of Bergst, ROM et al.
Soc, ), 100.8106, (1978)). The 5'-hydroxyl group was protected by the method of Example 62. The 3'-hydroxyl group was chlorinated and the 5'-hydroxyl group was deprotected by the method of Example 64. 55”
Threodarchloro-2' by heating at C for 1 hour.

Derzodeoxyuridine was replaced by a configuration inversion. The title compound was purified by chromatography on silica gel, bathing with ethyl acetate.

Removal of the appropriate fractions or solvent gave the desired compound;
Melting point = 112.5-115"C0 Example 66 5-bromovinyl-2'-deoxyuridine (BVD
U) by the method of Jones et al. [Tetrahedron L
etters).

45.4415 (1979)) in a similar yield. BvDU i, Horwitz
[Zoe Org Chem (J, Org, Ch.
tritylation and mesylation according to Em), 61.205 (1966)). This product (4,25,!i'
, 6.5 mmol) total, L
iN5 O,995,! i' (19,5 mi
Dissolve the liquid in 100% DMF,
It was then heated at 74°C for 24 hours. Place the reaction mixture on ice 6
The mixture was injected to 0.00 g while stirring. isolating the solid formed;
Then, by chromatography, a rubber-like substance (2,48,9
). Treatment by dissolution in 100 ml of 80% acetic acid and heating on a steam bath for 5 hours deprotected the compound. The cooled reaction mixture was diluted with water and filtered to remove trityl carbinol. The volume of the filtrate was reduced to an oil and it was diluted with CHCt3/CH30H (9:
It was purified by flash chromatography in 1 y/v). Combining the appropriate fractions and removing the solvent gave a solid that was crystallized twice from aqueous methanol.

Yield 0.66 g, 1.8 mmol, 27.7%; melting point 165-166°C.

Elemental analysis value: C11H12BrN504-0-5H
Calculated as 2O fi[: C35,98H5,57N
19.07 Br 21.85 feet 11 hours 1 shift:
C35,98H3,57N 19.07 Br
21.76 row 67 cytosine 1~ (3'-azido-2', 5'-zodeoxy-β-
D-threo-pentofuranosyl)-2-methoxy-5-
Methyl-4(H)-pyrimidinone (0,5,F.

2 mmol) t-, combined in a bomb with methanol saturated with ammonia. After 6 days at room temperature, the zebra was heated in an oil bath at 65°C for 4 days. Reaction mixture, conversion to dryness,
So L Te CHC23/ CH30H (921 v/v)
It was purified by crystal ratio from . Wash with solid txt3,
and air dried to yield 0.161.0.6 mmol (50%) of product; melting point 158-160<0>C.

Calculated as elemental analysis value 201oH14N6031/4H20: C44,36H5,40N 31.04Measurement: C44,42H5,36N 31.04Example 68 (1threopentofuranosyl)-3-methylthymine 5'-trityl-6 '-threo-6'-azo)F-3'
-deoxythymidine (1.0 g, 1.95 mmol) and N,N-zomethylformamylzomethylacetal [Zemlicka, Co11. Czech, Chem,
Comm-) , 55.6 5 7 2 , (
1972) ) (0.93g, 7.
8 mmol) in CHCt, 50 d
It was refluxed for 6 hours.

Removal of the solvent gave an oil which was purified by flash chromatography using CHCl3.

Removal of the M medium gave a foam of 0.54 F. Deprotection was performed by heating the foam in 80% acetic acid 50 on a steam bath for 2 hours. Filter trityl carbinol! After removing 1 ml, the reaction mixture was diluted with water. The filtrate is drained as an oil in a full vacuum and the oil is reduced to c”Hcz3.
/EtOAC (2:1 v/v) e using flash chromatography! 7 was purified.

Removal of the solvent gave the compound as an oil [1,20,F.

UVmax (nm) p[(λmax=26 in 1
7 (ε=8100), λ5h=209 (ε=8500
); λmax = 267 (ε = 8 [
]0[1).

H1NMR (DMSO-d 6) 2 δ 7-5
6 (s −I H,, H6), δ6.07
(dd, 1H, H1/), δ5.17 (SX 3H
, N-CH3), δL86 (sX 3H% 5-C
H3).

Elemental analysis 1st shift"C1IH1sN5C)4-1], 4H
Calculated as OAc-Q, 3H20 If: C45,
62H5,58N 22.54 sub-determined value: C45,67
H5,60N 22.57 Shiori69 2'-deoxyuridine was converted to the t''s5-chloromercury derivative in 96% yield according to literature methods [BergStrom and Rus (R
uth), Zoe Carb-Nukl (J, Carb.

NucL,'), 4.2 (57 (1977)).:
50 g of the main product; 1.04 mol), 800 m of dry methanol containing ethyl acrylate (104 g; 1.04 mol), and L in MeOH (10 QInl).
Dissolved in a 0.1 N solution of i2PdC64. 4 of the solution
Stir for 1 hour and then treat with H2S for 2 minutes. The suspension was filtered through a pad of Celite and the filtrate was evaporated to dryness in vacuo. Trituration of the residue with methanol produced a solid, which was filtered and dried to yield white solid 22F. This generation* is described by Horowitz
) Specialized method [J.
Chem, ), 61.205 (1966)] and mesylated. A portion of this substance (7,
06 g, 10.9 mmol) f, NaHCO3 (0
, 92 g; 10.9 mmol) t-containing dry Me
The mixture was poured over 100 OH and refluxed for 6 hours.

宕'Is was removed in vacuo, the residue was stirred with water, filtered through a sieve, and air dried to yield 6.1 g as a white solid. This product was expressed as LiN5(1,65,!i'
;33.2 mmol) containing DMF 5 Q H
i/dissolved in 1 ml of water and heated at 125°C for 4 hours. The reaction mixture was poured into 2[N] ice cubes to evaporate the precipitate and washed with water. On this material, 80% H
OA0100 and heated at 100° C. for 4 hours. The reaction mixture was diluted with water and the precipitate was filtered off. The filtrate was evaporated to dryness to yield 8001 ng of gold as an oil.

Cover this oil with 20.5N NaOH20rttl,
The mixture was stirred at room temperature for 2 hours. Adjust the bath solution to pH 5,
The precipitate was filtered and air dried to give the title compound 550
mg (1.7 mmol) was obtained: melting point>250°C0U
V (nm): λmax = 500 (
ε=20400), λm1n=-230(ε=4900
), λ=262 (ε=16100) λmax=297.266 (t=1
5600.14800), λmin = 281.28
8 (εMi1560D, 8600); HlNMR (DMSO-d, )δB-37(s, I
HX H6), δ 7゜30 (S, i H,
-CH=, J= 15.5 Hz), δ 6-7
s (a, 1 H,=cH-cooHX J
=16.95Hz), δ6-1~6. o 6(m
11 H% H1'), δ5.41~5°5 7
(m 11 H% 5' OH), δ 4.4
7-4.39 (m, 1 H, Hro')
, δ 3.8 7 ~ 3.8 3 (m, 1HX
H4), δ 3.74 5.58 (m, 2HX
H5'), δ2.54~2-81 (m, 2
H, E (2').

Elemental analysis 1st shift” Calculated as Cl2H13N506:
c 44.59 H4-05N 2L67ffll
J constant f[: c 44.45 H4,06N
21.60 Example 70 2.3.4-Tetrahyr-2,4-zooquine-5-pyrimidinyl]-2-propenoic acid 2'-deoxyuridine was converted into a 5-chloromercury derivative by reversing the literature method. [Bergstrom and Ru] were converted with 96% yield.
th), sie karsi nyukur nyuk/l/ (J
, Carb, Nucl, Nucl, ), 4.2
57, (1977)]. This product (50g, 1.04
mol) to ethyl acrylate (10.4, SF, 1.
800 rttl of dry MeOH containing 0.04 mol) and a 0.1 N solution of Li2PdCt4 in MeOH (10.40 mol). The solution was stirred for 4 hours and then treated with H2S for 2 minutes. Suspension with Celite Parar
and the filtrate was evaporated to dryness in vacuo.

The residue was triturated with MeOH to produce a solid, which was filtered and air dried to yield white solid 229.

This product was prepared by the method of Horowitz et al.
Chem), Li 1.205 (1966)) tritylation and mesylation. A part of this substance (
2,79; 4.2 mmol), LiN3 (0,6
dry DMF (2 g; 12-7 mmol)
Dissolve the solution in 55℃, stir, and heat at 70℃ for 24 hours under N2. Pour the reaction mixture onto 400 g of ice and let it settle. II
'c'42! 7% and by flash chromatography) rft! l! ! Shita@50: I CH
Elution with Cl5/MeOH (v/v) gives the azo r intermediate 1.48,! ii' was given. This material was treated with 50% acetic acid (100ml) at 100°C for 3 hours. Dilution with water, filtration of the resulting suspension and evaporation of the filtrate in vacuo gave oil 7107Ve.

Dissolve this oil in 50 ml of NaOH, and at room temperature
Stir for hours. Solution P) (gold 3, filter the precipitate,
and air-dried to obtain 240m9 (0.7 mmol, 50%) of the title compound; melting point = 250 °C OUV (nm
): p) (at 1, λmax=301 (t=195
00), 2m1H=230 (ε=3600), λ5
h-249 (ε = 12700) p) (λmax = 299.267 (ε
= 1400.13200), 1m1n = 232.23
9 (ε=1200.7560).

H”NMR (DMSO-d6) δ3-15 (s, 7
H, H6), δ to 32 (d, 1 H, -C) (=
, J = 15.87 Hz), δ6.78 (d,
1H,=CH-C0OH,J=15.62Hz),
δ6.01-5.98 (m, I HXH1'),
δ5.11~b-98 (mz I Hs 5'OH
), δ4.50~4.45 (m% I HXH!l
'), δ4.13-4.08 (ms 1HXH4'
), δ3.80-3.75 (m, 2H, H5'
), δ 2-7 7 ~ Ri-67 (m 1
1 HX H3, δ2-30~2.20 (m
, I HXH2') Elemental analysis 匝' Cx+Hx3
Calculated as NsOv-1,5H20: (14),1
5H4, 60N 19.99 jaws 1j constant 1 shift: C4
L58 H4,50N 20.01 Shio 1171 (E) -5-[I 1~ (3'-acid-2',!
l'-Dide 5'-trityl-6'-mesyl-5-propanoate-2'-deoxyuridine was prepared according to the method of Example 69. This material was prepared using 10% Pd in EtoH.
Hydrogenation with /C gave the propanoate derivative.

This product was then treated analogously as described in the above method to obtain the title compound; melting point: 118-120°C.
(t=9900), 2m1n=235(ε=5100
); p) 115 and λmax = 265 (t
= 7400), λm1n=247 (ε=5400)
; H'NMR (DMSO-d6) δ 7.6B(s,
IHX H6), δ6.1 1~6-06 (m
, I H, H1'), δ 4.45-4.6 5
(m, i H, H3'), δ 3.85-3
．． 80 (m% I HX H4'), δ 5.6
8-3.55 (m, IH% H5') Elemental analysis: Calculated as Cl2H15N506 [:
c 44.31・H4,65N 21.5+41J constant 1
Direct: C44,26H4,68N 21.49 cases 72 Clinical trial 6'-azido-6'-deoxythymidine (AZT) was administered to 2 AIDS patients at 1 and 28 of treatment 11 at 8
It was administered orally at a dose of 2/kg every hour. 2 and 6
On Sun and Moon, the patient was given 500 mg of Zorobeneci F' again at 6 o'clock.
A single dose of AZT was given on the 38th day. Maximum of AZT (C
max ) and course (Cm1n ) levels were associated with a 3-fold decrease in total clearance (ct/F'), and P
Average half-life (tt/2) of AZT during B treatment (0,8
This was significantly higher than the level of response on the first day, which resulted in a prolongation (from 8 to 1.76 hours).

The average ratio of AZT glucuronide/AZT in urine is
After PB treatment, it decreased significantly from 7.5 to 2.4.

The main miskinematic parameters of AZT before and after concomitant administration of PB are summarized in Table 1.

Table 1 tAZT/PB 10.416.130°150.25
829.501.842, AZT/FB10.006.
460.270.50921.001.61wwAN1
0-216.500.210.58875-251.7
+±SD O, 290, 251F, 080.1864
,700.16+,AZT 3.705.740.0
00.502333.800.872, AZT 3.
042.510. []00.51 ri027-DOO,
89MEAN 3. ro73.130.000.4126
80.400.88±SD O,470,870,1
100-15480-170,01 Example 73 Nucleoside transport inhibitors dipyridamole, dirazep and 6-((4-nitropencyl)thio]-9-β-D-
Anti-Friend Leukemia Virus of 5'-azidoderdeoxythymicin (AZT) by lye7lanosyl)zolin
s (FLV) ] activity was shown in Table 2.
-10 cells were plated one day before they were infected with FLY. One day after infection, incubate Robreto with known concentrations of the test compound or formulation for 6 days and transfer the medium to fresh carp (MCC0Y).
5. Transfer to A medium and incubate for another 3 days. The concentration of test compound/formulation that gave 50% inhibition of plaque was determined as shown in Table 2. No significant antiviral effects were observed with either zopyridamole (10 μM) or dirazep (5 μM) alone.

Table 2 AZT 5 AZT+iμM dipyridamole 1A 7. T
+ 5 ti M dipyridal-r=-ruQ, 5AZT+
10 μM Zoviridamol 0.2 AZT + 5 μM Dirazep 0.5 AZT + 5 μM 6-((4
-Nitrobenzyl)'5thio]-9-β-D-rizafuranosyl)purine Example 74 - The number of ITP-activated platelets was 58.000111 m-3. The patient
Thrombocytopenic plaque disease (platelet count <100,000+ηl
! -3) diagnosed with ft and every 6 hours A2
He was treated with 75m9/Yushei for 6 weeks, during which time his platelet count rose to H140,[]00)1-3. Treatment was then changed to oral for 4 weeks 5/4 hours and discontinued for 4 weeks, at which time the platelet count decreased to 95.000 vrw-'' after 2 weeks and to 70.000 mm-3 after 4 weeks. A treatment of 5 m97 kg/4 hours orally for 5 weeks was recommended, and the platelet count rose to 194,000 e-3. Reducing the dose to 2.5 da/9 e-4 hours orally reduced the platelet count. This resulted in an indistinct spurious decrease in the number of patients, but was not within the diagnostic range of ITP.

EXAMPLE 75 In this study, 9 patients diagnosed with sensitogenic sarcoma (KS) were treated with AZT and the following effects were observed.

Complete healing occurred in one patient.

Five patients showed regression of the lesions.

KS remained stable in 2 patients.

In 5 patients, lesions progressed @ 250% response is the preferred current treatment for KS, recombinant α
- Comparable OK obtained with treatment with interferon.

Example 76 Using a method similar to that in Bill Formulation Example 79, the in vitro effect of a combination of AZT and acyclovir (ACV) on HIV was tested.

ACV alone showed oyster activity, with a concentration of 16 μy/g (
maximum tested) showed less than 50% protection, -10,000 A
Use this method when ZT is 8 μM! It showed 710[]% protection.

Table 3 shows the combination of these two drugs required to achieve 100% retention.

Table 5 - 80.5 These results show that ACV enhances the antiviral activity of AZT by a total of about 6 times.

Example 77 Peripheral blood mononuclear A cells (PBMCs) from healthy HIV I'11 serum negative volunteer donors were collected using heparinized blood Ficoll-Hypaqve.
Obtained by sedimentation. cells with phytoagglutinin (PHA)
) treated with 10 μy/ml and 20% fetus [I
II supernatant (Fe2), antibiotics, t-glutamine and 10% interoyl-2 (IL-2) (Electronucleonix).
onics), Bethesda, MD] in RPMT 1640 medium. 4 to 6 days after exposure to PHA K, 5 ml of the medium is injected into the stomach.
Cells were grown at 4 x 105 cells/in a 3' strain flask.
nl immersion and then exposed to drug and virus as detailed below.

The day of virus inoculation is indicated as day 0. Fresh medium was added to the fourth quarter. Every 5 to 4 days thereafter, a portion of the cell suspension was incubated for analysis and replaced with cell-free medium.

Experiments 2 and 4 were terminated after 14 days and experiments 1 and 3 after 16 days.

The virus stock was partially frozen at -70°C.
was a cell-free supernatant of IV-infected H9 cells.

Save beer! - 50% m tissue culture hair infection @ (TCT
D50) was 105/ml.

Four separate experiments were performed using all PBMC from raised blood donors. Part of the 40 ^, cell α
Incubate for 24 hours in medium with or without interferon (rrFN'xA) and incubate with AZT.
and exposed to viruses. The virus was added directly to the culture in a small amount of medium and was not washed. Virus inoculation was carried out in experiments 2, 6 and 4 cases, respectively.
The temperature was 2×103.

In all experimental examples, r I FN (IA and AZ
A 42-fold dilution of a fixed formulation of T was tested. Each of rIFNαA and AZT I used in the formulation
The Ik degree was also tested only to provide a reference point.

In all experiments replicate cultures were collected at each immersion level.
and maintained for infected and uninfected controls. In experiment 1, AZT 3.2 μM and rIFNαA
Five 2-fold dilutions of this formulation were tested.

In Experiments 2 and 6, AZT [1,16 μM and 3-4 2-fold dilutions of the FNαA 128 U/m1XyK formulation were used. In experiment 4, AZT Ooo 8 aM and rIFNαA1
2.81 J/7nl, as well as two doses of this formulation.
1 straddle Kanazawa was used.

After approximately one week, cultures were evaluated every 4 days for the presence of viruses. J cells were assayed for di-HIV antigen by indirect fluorescence; supernatants were assayed for HIV p24 antigen by reverse 1 transfer (RT), viral assay, and radioimmunoassay. evaluated.

In order to calculate the combination drug effect, the multiple drug effect analysis of Chou and Talalay [Advances in Enzyme Regul
ation), (1984), 22.27-55] was used.

The data can also be analyzed using isobologram techniques to assess drug interactions.
chni-que), and was evaluated by the boundary method. The desired effect (for example, 5G% inhibition) is plotted on the horizontal axis, and the same degree of effect is derived.
The concentration of FNαA is plotted on the basal axis. Draw a line in relation to those points and plot the concentration of drug in the configuration that leads to the same effect. If this point falls below -, the formulation is considered synergistic.

In Experiment 1, AZT envy was completely inhibiting, making it impossible to determine the combination effect.

In experiments 2-4, a synergistic interaction of the two drugs was consistently observed (Tables 4-9). A synergistic effect was evidenced in all assays of viral replication employed, and persisted even when the effects of rTFNaA alone were absent. Synergistic effect calculation, RT data from experiments 2 to 4, virus production data from experiments 2 and 3,
This was accomplished by applying multiple drug effect analysis to the RIA data from Experiment 4 as well. Isozalogram analysis also indicated synergism.

Table 4 1 A 1050 0 2 B Between 4x10" and 244
05 B '103-24 hours 04
B 2X103-24 hours 0fal LA:
40 x 10'J cells, TCID5oHrV 1Q
Make 2Qml of medium with 5 ml! Suspended for 1 hour at +7-C, then washed and resuspended.

Method B: The indicated amount of virus was 2 x 10'; cells were not washed by subtraction.

Table 5 Experimental Day 2-10 Reverse transcriptase f [(cpm/10', a-cell X 103
Effects of rIFNαA and AZT on rtFNα
A (U/m) AZT (μM) 0 8 16 52 64 12
80.01 159 85 0.02 110 42 0.04 71 10 0.08 314 0.16 7 1 Table 6 - Effects of rIFNαA t6 and AZT on F average RTI direct (cpm/106 cells X103) 07m1) 0.02 51 10 0.04 10 00.08
2 00.16
5 0 Table 7 Effects of rrFNαA and AZT on lateral RTI directivity (cpm/10′a cells rI against virus production (TCID5o/ml)
Effect of FNaA AZT rIFNaA (U/d) 0105・7105・6105・3105・1105・
0.0410'<101・9shi1→
Knee → Table 9 Experimental Days 4-14 rIFNaA against HIV p24a Oh! BiAZ
'r 17) Effect IFNαA (U/Go) 0.02 100-200 2.2 0.04 25-50 1.00.08
11.2 0.8aHrV p
24 levels are presented as ng protein/''nl.
Various percentages of RT inhibition 2 7 2.14 L], 34 0.232
10 0.37 0.30 0.283 6
0.26 0.75 1.595 15 0
．． 12 0-15 0-175 16 <
0.01 0.02 0.054 8 0
．． 01 0.03 0.044 14 0.02
The 0.07 0.12 blending factor is determined by solving the equation for various degrees of RT inhibition. A combination factor of 1 indicates a synergistic strategy. The blending factors shown were obtained using the equation 0:1 shift obtained using the mutually exclusive form were always slightly lower.

Example 78 Pseudo Fetal Fetal Lung Fibroblasts (Fr=F-5), Dulbetsko-Modified Eagle Media Pond (DME)
(105a gun/m/, O-05m/well) and incubated overnight at 37°C.

Feline leukemia virus (FeLV) was added to each of the 62 holes.
) with 40 to 60 foci-forming units (ffu) for 1 h, and then the medium was infected with fresh ME with various degrees of 5'-acid-2',3'-dideoxycytidine per 4 wells. I called out. After 6 days of incubation at 67°C, the cultures were assayed for production of kFeLV by an indirect fluorescent antigen test.

By this method, di,5'-2',5'-dideoxycytidine yielded TD5o values of between 10 and 50 μM.

Example 79 In Vitro Antimicrobial Synergy Test 3'-azido-6'-deoxythymidine and eight known antimicrobial agents (listed in Table 11) were each treated with N,N-dimethylformamide for 60 minutes. Microtiter dilutions were made using WeLlcotest broth.

Synergistic test example Previously, test microorganisms (E, Co11 CN
MIC determinations for 314) were performed for each compound. Table 11 shows the MIC endpoints of each drug against L CoLi CN 514.

Two-fold serial dilutions of test drug or 5'-acido-3'-deoxythymidine were
” or “multiple transfer” in microtiter plates. By combining the plates with appropriate dilutions, a series of 192 selections/formulations was produced consisting only of compounds. A control was also included. The highest concentration of drug used was twice that of the MICi (Table 11).

Test plates were inoculated with 4 cultures of bacteria containing approximately 5 X 1' 05 CFU/go and then incubated for 18 hours at 27°C. Wells were scored for bacterial growth or non-growth and the MIC was determined.

Fractional Inhibitory Concentration
tory con-cenzration)' (
FIC) was calculated directly from the MIC by dividing the MICi of the formulation by the MTC of each single drug. Total separation (
The sum of fraction 1 and harmful concentration) was then calculated. Approximately 0.5
Results above or below are indicative of synergy.

Table 11 Dopramycin 0.4 Fusicic acid 1000 Chloramphenicol 3.1 Clindamycin
100 erythromycin
25 rifanpicin 6
．． 26'-acido-5'-deoxythymidine 1
．． 0 trimetozolim 0.
125 Sulfacimidine 62 The results of the synergistic experiments are shown in Table 12.

Table 12 Optimal MIC (μg/go) Dopramycin/AZT 0.210.125
0.257 Schizonic Acid/AZT 25010.
05 0.28 Chloranephenicol/AZT
1.610.06 0-31 Clindamycin/AZ
T 12.510.25 0.575 t+)xo
-cr Isin/AZT 6-210-25 0-
5 Rifamycin/AZT 3.110.06
0.56 trimester A/AZT 0-0
0410.5 0-504su/I/ 7azomidine/
AZT 0.2510.125 0-575 Examples 80 I (Iv activity The in vitro activity of 5'-azido nucleosides (medicines) was assayed in two cell lines; H9 (permissive for HIV replication but cytopathic of HIV) OKT 4” T-cell line) and TM, which are partially resistant to the effect
5 (lethally irradiated T-cell clone specific for tetanus toxoid, immortalized by TLV-1 and selected for rapid growth and susceptibility to the cytopathic effects of HIV).

Inhibition assays were performed as follows: TM3 cells were stimulated with antigen + irradiation (4000 rad; 40 ()y) freshly autologous peripheral blood mononuclear cells (PBM), and 6 days before the assay, interleoxy2 [IL-2, lecithin removal; Cellular Products (CelularPro
ducts), Buffalo, New York] 15%
(V/V).

ATH8 cells were used without antigen stimulation. After a 30 min pre-injection against 2 μg/trtl of polyprene,
Target T-+! fl follicles (2X 105) k pelleted j,
, exposed to HIV for 45 min, fresh medium 2rILIV
c resuspended and incubated at 57° C. in medium Iz.α in humidified air containing 5% CO2. The control fine J foam was treated in the same way, but was careful not to expose it to viruses. Cells were exposed to L-2 and drug sequentially. When ATH8 cells were used in this assay system, v5 viral particles per cell was the minimal cytopathic dose of the virus. In cell culture experiments, lethal irradiation (10,000r
ad) Targeting T cells 2X to HIV RF-1i-induced H9mA cells or uninfected H9 cells 5X10'
Added to 10'. At various time points, 4 viable cells were counted using a hemocytometer under a microscope using the Trivan blue dye exclusion method. The results are shown in Table 13.

Table 15 5'-azido-2',3'-dideoxycytidine
10 daso 1-5-bromo 2', 3'-
dideoxyuridine
55'-azido-5-bromo-2',5'-dideoxycytidine
5(E)-5-(1-(3'-acid-2',
3'-zodeoxy-β-nierythropentofuranosyl)-1,2,3,4-tetrahyro2,4-dioxo-5-pyrimidinylcou-2-propenoic acid 10
Example 81 Table 14 demonstrates the in vitro anti-1 activity of 3'-azido nucleosides against various bacteria in small inhibitory concentrations (MICs).

The standard used was trimethoprim (TMP) and the medium used was WeLLcotestsen susceptibility test agar with 7% molten mother's blood.
sitivityTe5tAgar).

#Ta1. ÷ (K is the first order of the equation: to ?-?
? --? − △ Δ ) ＾■ gussho 2) 5'-azido-5'-deoxy-5'-〇-acetyl-4-thiothymidine 5) 5'-acido-5'-deoxy-2-deoxy-2
-Thiothymidine 4) 5'-acetel-3'-acido-3-benzoyl-
3'-deoxythymidine 5) 1-(5'-0-acetyl-3'-azogen-12').

sil)-5-methyl-4-(1,2,4-triazol-1-yl)-2(IH)-pyrimidinone 6>1-(5
'-Acy group-2', 3'-dideoxy-β-ri-erythrobentofuranosyl)-2-(benzyloxo)-5
-methyl-4-(IH)-pyrimidinone 7) 3'-acido-5'-deoxy-2-methoxythymidine 8) 3'-azido-5-zolomo 2',3'-dideoxy'warinno

Claims (1)

[Claims] (1) The active ingredients include formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, A is a purine other than thymine bonded at the 9- or 1-position. or a pyrimidine base] or a pharmaceutically acceptable derivative thereof. (2) A therapeutic agent according to claim 1, wherein A is a cytidine derivative, a thymine derivative or a uridine derivative, and the azide group is in the \erythro\ configuration. (3) A is a thymine derivative or a uridine derivative,
and the azide group is in the \threo\ configuration,
A therapeutic agent according to claim 1. (4) The compound has the formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^1 is hydroxy, mercapto, amino,
alkylthio, aralkoxy, alkoxy, cyano, alkylamino, dialkylamino, where the alkyl groups can be optionally combined to form a heterocycle; R^2 is hydrogen, acyl, alkyl, aroyl or sulfonate; R^2 3 is hydroxy, mercapto, amino, triazolyl, alkylamino, dialkylamino, aralkoxy, alkoxy or alkylthio in which an alkyl group can be optionally combined to form a heterocycle; R^4 is alkyl, substituted alkyl, halo , perhalomethyl, hydroxy, alkoxy, cyano, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or hydrogen, or a pharmaceutically acceptable derivative thereof. A therapeutic agent according to any of paragraphs up to 3. (5) R^1 is hydroxy, mercapto, C_1_～_
4 alkoxy or amino; R^2 is hydrogen, methyl, C_1_-_2 alkoxy or benzoyl; R^3 is hydrogen, mercapto, amino or substituted amino; and R^4 is R^3 is amino or substituted amino, hydrogen, and when R^3 is other than amino or substituted amino, hydrogen, perhalomethyl, C_1_~
4. The therapeutic agent according to claim 4, which is _3 alkyl, C_2_-_3 alkenyl or substituted ethenyl. (6) A therapeutic agent according to claim 1, wherein A is an adenine derivative or a guanine derivative. (7) The compound has the formula (II)A ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)A [wherein R^6 and R^7 may be equal or different, and amino, hydrogen, hydroxy, mercapto, alkylthio, alkoxy, aralkoxy, cyano or alkylamino] or a pharmaceutically acceptable derivative thereof;
A therapeutic agent according to any of claims 1 and 6. (8) R^6 is amino, C_1_-_4 alkylamino, mercapto, hydroxy, or C_1_-_4 alkoxy; and R^7 is amino, C_1_-_4 alkylamino or hydrogen, Claim 7 Therapeutic agents according to Section. (9) An anti-gram negative bacterial agent according to any one of claims 1 to 8. (10) An antiretroviral agent according to any one of claims 1 to 8. (11) An anti-human retrovirus agent according to claim 10. (12) An anti-animal retrovirus agent according to claim 10. (13) An anti-lentivirus agent according to claim 10. (14) Claims 10, 11 and 1
An anti-HTLV, -hepatitis B or -EBV agent according to any of clause 3. (15), anti-HTL according to claim 14
VI or HTLV-II agents. (16) Claims 10, 11 and 1
An anti-HIV agent according to any of Item 3. (17) An anti-AIDS agent according to any one of claims 1 to 8. (18) An anti-ARC agent according to any one of claims 1 to 8. (19) An anti-PGL agent according to any one of claims 1 to 8. (20) An anti-AIDS loading agent according to any one of claims 1 to 8. (21) As the first active ingredient, the formula (I) A▲ formula,
Chemical formulas, tables, etc. ▼ (I) Compounds of A [wherein B is a purine or pyrimidine base bonded at the 9- or 1-position, respectively], or pharmaceutically acceptable derivatives thereof, and A therapeutic agent comprising at least one other therapeutic agent as a second active ingredient. (22) A therapeutic agent according to claim 21, wherein the two active ingredients are present in a synergistic proportion. (23) The therapeutic agent according to any one of claims 21 and 22, wherein the second active ingredient is a glucuronidation inhibitor and/or a renal excretion inhibitor. (24) The second active ingredient is probenecid, aspirin,
The therapeutic agent according to claim 23, which is acetaminophen, lorazepam, cimetidine, ranitidine, zomepirac, clofibrate, indomethacin, ketoprofen or naproxen. (25) The therapeutic agent according to any one of claims 21 and 22, wherein the second active ingredient is a nucleoside transport inhibitor. (26) The second active ingredient is dirazep, dipyridamole,
6-[(4-nitrobenzoyl)thio]-9-(β-￥
The therapeutic agent according to claim 25, which is D\-ribofuranosyl) purine, papaverine, myoflazine, hexobendine, lidoflazine or an acid addition salt thereof. (27) The therapeutic agent according to any of claims 21 and 22, wherein the second active ingredient is another therapeutic nucleoside. (28) The second therapeutic nucleoside has the formula (A) ▲ has a mathematical formula, chemical formula, table, etc. ▼ (A) [wherein Z is hydrogen, hydroxy, or amino;
and, X is (a) an oxygen or sulfur atom, or a methylene group, and Y is a hydrogen atom or a hydroxymethylene group; or (b) a methyleneoxy group (-OCH_2), and Y is a hydroxy or a pharmaceutically acceptable derivative thereof.
Therapeutic agents according to Section. (29) The second active ingredient is 9-[(2-hydroxy-1
-hydroxymethylethoxy)methyl]guanine, 2-
The therapeutic agent according to claim 28, which is amino-9-(2-hydroxyethoxymethyl)purine or 9-(2-hydroxyethoxymethyl)guanine. (30) The therapeutic agent according to any one of claims 21 and 22, wherein the second active ingredient is an antibacterial agent. (2) The second active ingredient is 2,4-diamino-5-(3'
, 4',5'-trimethoxybenzyl)pyrimidine or a homolog thereof, sulfadimidine, rifampicin, tobramycin, fusidic acid, chloramphenicol, clindamycin or erythromycin. (32) A therapeutic agent according to any of claims 21 and 22, wherein B in the compound of formula (I) A or a pharmaceutically acceptable derivative thereof is a thymine residue. (33) The compound of formula (I)B is 3'-azido-3'-
33. The therapeutic agent according to claim 32, which is deoxythymidine. (34) The therapeutic agent according to claim 33, wherein the second active ingredient is 9-(2-hydroxyethoxymethyl)guanine. (35) Claims 21 to 3 for use in the treatment or prevention of any of the human or animal diseases described in Claims 9 to 20.
A therapeutic agent according to any of items up to 4. (36) Any of claims 21 to 34 for use in the treatment or prevention of Kaposi's sarcoma, goat arthritic encephalitis, feline leukemia, multiple sclerosis, or thrombocytopenic purpura. Therapeutic agents according to. (37) Formulas other than those below (I)B ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)B [In the formula, C is a purine or pyrimidine base bonded at the 9- or 1-position, respectively. ], and their pharmaceutically acceptable derivatives: (a) Compounds of formula (I)B, wherein C is an adenine, guanine, uridine, cytidine or thymine base, and their 5'-mono- or 5'- (b) 5'-O-acetate, 5'- of a compound of formula (I) B in which C is a uridine base and the 3'-azido group is in the \erythro\ configuration; O-trityl and 5'-O-(4-methylbenzenesulfonate) derivatives; (C) C is (i) a 5-bromovinyluridine or 5-trifluoromethyluridine residue, and 3
′-azido group is in the \erythro\ configuration;
(ii) is a uridine residue and the 3'-azido group is in the \threo\ configuration; and (iii)
Compounds of formula (I)B which are 5-iodo or 5-fluorouridine residues and the 3'-azido group is in the \erythro\ or \threo\ configuration, as well as the 5'-O-trityl of said compounds. derivatives; (d) C is (i) a 5-bromovinyluridine or cytidine residue and the 3'-azido group is in the \threo\ configuration; (ii) a 5-fluorocytidine residue; , and the 3'-azido group is ￥erythro￥
or (iii) is a 5-methylcytidine residue and the 3'-azido group is in the \threo\ or \erythro\ configuration;
I) Compound B; (e) C is 4-chloro-2(1H)pyrimidinone or 4-(1H-1,2,4-triazol-1-yl)-
5 of a compound of formula (I)B which is a 2(1H)pyrimidinone (optionally substituted by fluorine or methyl in the 5-position) and the 3'-azido group is in the \erythro\ configuration. '-O-acetate ester (f) 5'-O-[(4-methoxy phenyl)diphenylmethyl] derivatives; and (g) 5'-O-trityl derivatives of compounds of formula (I)B, wherein C is an adenine residue and the 3'-azido group is in the \threo\ configuration. . (38) Formula (I) claimed in claim 37 as described in any of claims 1 to 8
A compound of B, or a pharmaceutically acceptable derivative thereof. (39) In the method for producing the compound described in any of claims 1 to 8, (A) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula , A is as defined in claim 1, and M represents a precursor group for a 3'-azido group], by converting the precursor group into a desired azide group. React with an agent or under conditions that help to convert; or (B) Formula (IVa) or (IVb) ▼(IVb) [In the formula, R^1_a, R^2_a, R^3_a, R^4
_a, R^5_a and R^7_a are groups R^1, as defined in claims 4 and 7, respectively;
R^2, R^3, R^4, R^6 and R^7 or precursor groups therefor, with the proviso that R^1_a, R^2_a, R^3_a and R^3_a in formula (IVa) R^4_
at least one of a or the group R^6_a in formula (IVb)
and at least one of R^7_a represents a precursor group] with an agent or under conditions that serve to convert said precursor group into the corresponding desired group; or ) Formula (Va) or (Vb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Va) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Vb) [In the formula, R^1, R^2, R^ 3, R^4, R^6 and R^7 are as defined in Claims 4 and 7] or their functional equivalents as a compound of formula (IVa) or (D) A of the compound of formula (I) is a purine residue; When a purine of formula (Vb) is reacted with a pyrimidine nucleus of formula (VI) ▲Mathematical formula, chemical formula, table, etc.▼(VI) [wherein Py represents a 1-pyrimidinyl group] and subsequently or simultaneously carrying out one or more of the following optional transformations: (i) when the compounds of formula (I) are formed, the compounds are (ii) when a pharmaceutically acceptable derivative of a compound of formula (I) is formed, converting said derivative into a parent compound of formula (I) or a compound of formula (I); Convert to a separate pharmaceutically acceptable derivative. (40) together with a pharmaceutically acceptable carrier therefor;
A pharmaceutical preparation consisting of a drug according to any of claims 1 to 36 as an active ingredient. (41) The formulation according to claim 40, which is sterile. (42) A formulation according to claim 41, which is adapted for administration by injection. (43) A formulation according to claim 40, which is adapted for oral administration. (44) A formulation according to claim 43 in the form of a tablet or capsule. (45) A process for producing a formulation according to any of claims 40 to 44, which comprises bringing into association an active ingredient with a pharmaceutically acceptable carrier therefor. (46) Claims 40 to 44 for use in the treatment or prevention of any of the conditions set forth in claims 9 to 20 and 35. Preparations according to any.