JP2523527B2 - 3'-Azido-nucleosides, a process for producing them, and an anti-virus agent comprising them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3′-azido-nucleosides, their pharmaceutically acceptable derivatives, formulations containing them,
And in their use, especially in the treatment and prevention of certain viruses and bacterial infections.

In the area of anti-virus chemotherapy there are only a few drugs that effectively outperform the virus itself, due to the difficulty of attacking the virus while leaving uninfected host cells intact. Due to the extreme parasitic nature of virus, it has long been believed that all the required ease of virus replication is provided by the host cell. Some stages of the virus life cycle that differ between species are identified by the virus itself, and those stages may prove vulnerable if they are significantly different from any corresponding host cell function. Was recently established. However, effective therapies have proven to be very difficult to identify because of the great similarity between virus and host function.

For this reason, compounds identified as suitable for the treatment of viral infections usually have some toxicity to the host. Therefore, while the ideal drug is non-toxic at anti-virulence effective concentrations, the compound should have a good therapeutic ratio in the absence of such treatment, i.e., the concentration at which the treatment is toxic has anti-virus activity. It is significantly higher than the concentration observed.

One group of viruses that have recently been estimated of special importance are the retroviruses. Retroviruses, a subgroup of RNA viruses, must first'reverse transcribe 'their genomic RNA into DNA in order to replicate [' transcription 'is usually an RN from DNA.
Describe the synthesis of A]. In the form of DNA, the viral genome can integrate into a host cell, allowing it to fully utilize the host cell's transcription / translation machinery for replication. Once coalesced, virus DNA is virtually indistinguishable from host DNA, and in this state virus can survive as long as the life of the cell. In this form,
Being virtually invulnerable to attack, any treatment must be directed to other stages of the virus' life cycle and must continue until all virus infected cells have been killed. .

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

A retrovirus was also reproductively isolated from a patient with AIDS. Although it has been characterized in detail, there is still some controversy about the internationally agreed name of Beers. It is now known as either human T-cell lymphotripic virus III (HTLV III), AIDS-conjugated retrovirus (ARV) or lymphadenopathy-associated virus (LAV), but may be internationally agreed. The name is expected to be Human Immunodeficiency Virus (HIV). This virus (hereafter referred to as HIV)
Has been shown to preferentially infect and destroy T-cells carrying the OKT4 surface marker, and is now generally accepted as the etiological agent of AIDS. Patient is this T-
It progressively loses a set of cells, loses the overall balance of the immune system, diminishes his ability to compete with other infections, and predisposes him to the more visible day than is often fatal to him. make. Therefore, the usual cause of death in AIDS victims is by day-to-day infection, eg virus-induced pneumonia or cancer, not necessarily the 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 non-blood connective tissues in the central nervous system. This central nervous system infection
It was not necessarily associated with classical AIDS and was found in patients with subclinical HIV infection. HIV infection of the CNS
Combined with progressive demyelination, it leads to wasting and symptoms such as brain disease, progressive dysarthria, ataxia and disorientation. Other conditions associated with HIV infection are asymptomatic carriage, progressive systemic lymphadenopathy (PGL) and AIDS-
It is a related syndrome (ARC).

Certain chronic nervous system infections are now believed to be caused by retroviruses. Such infections include, for example, multiple sclerosis in humans, as well as arthritic encephalitis virus infection in goats and visna-mites in sheep.
-Maedi) include infection.

The report describes the testing of compounds against various retroviruses such as friend leukemia virus (FLV), murine retrovirus. For example, Krie
g) etc. [Exp.Cell Res.], 11
6 , (1978) 21-29)] found that 3'-azido-3'-deoxythymidine was active against FLV in in vitro experiments, and Ostertag
Etc. [Proc.Nat.Acad.Sc
i.), (1974) 71 , 4980-85], is based on FLV-related antivirus activity and lack of cytotoxicity, resulting in 3'-azido-3'-dideoxythymidine being generated by "DNA virus." Bromodeoxyuridine could be suitably substituted for medical treatment of disease. " While cooling, De Clerq et al. [Biochem.Pharm., (1980) 29 , 1849-1851)
Six years later, 3'-azido-3'-dideoxythymidine was used in their trials, such as vaccinia, HSVI and Varicella soester virus.
cella zoster virus (VZV)] has no appreciable activity against any virus including DNA virus.

Bacteria also present one problem in therapy, as all organisms follow very similar life processes to each other, thus substances that are toxic to one are proven to be equally toxic to the other. I will provide a. In addition, tests have shown that bacterial strains develop resistance to commonly used antibacterial agents overnight.

Certain 3'-azidonucleosides described below include HIV infections and Gram-negative bacterial infections, and viruses that include certain strains of Gram-negative bacteria resistant to commonly used antibacterial agents. It has now been found useful in the treatment of bacterial infections, especially retrovirus infections.

Therefore, in a first aspect of the invention, a compound of formula (I) for use in human or veterinary therapy [In the formula, A is a purine or pyrimidine base other than thymine bonded at the 9- or 1-position. ], Or a pharmaceutically acceptable derivative thereof.

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

Retrovirus infection affects the central nervous system of patients, and in this connection certain advantages of the compounds according to the invention are:
As demonstrated by experiments, their ability to cross the blood-brain barrier in clinically effective amounts.

The compounds according to the invention have been found to have particularly potent activity against retrovirus and Gram-negative bacterial infections. Accordingly, (a) a compound according to the invention for use in the treatment or prevention of retrovirus or Gram-negative bacterial infection, and (b) a book in the manufacture of a medicament for the treatment or prevention of retrovirus or Gram-negative bacterial infection. Uses of the compounds according to the invention are provided.

The term "retrovirus infection" as used herein refers to any virus that uses reverse transcriptase for the integral part of its life cycle.

The specific bacteria for which good activity was observed are as follows.

Escherichia coli, Salmonella dublin, Salmonella
Salmonella typhosa, Salmonella typhimurium, Shigella flexneri, Citrobacter freundii, Klebsiella pneumoniareae, Klebsiella pneumoniareae, Klebsiella pneumoniaeae (V
ibrio anquillarum), Enterobacter aerogenes, Pasteurella multocida, Haemophilus influenzae, Yersinia enterocolitica, Paste haurella paste haemorica.
a), Proteus mirabilis and Proteus vulgaris, such as traveler's diarrhea in humans, urinary tract infections, shigellosis,
Organisms such as typhoid fever and cholera, and also animal diseases such as neonatal enteritis of cattle, post-weaning enteritis of pigs and colisepticaemia of chickens.

The compounds according to the invention had particularly good activity against the following viruses: human T-cell lymphotropic virus (HTL).
V), especially HTLV-I, HTLV-II and HTLV-III (HI
V); cat leukemia virus, equine infectious anemia virus, goat arthritis virus and other lentiviruses,
And also other human viruses such as hepatitis B virus, Epstein-Barr-v
irus (EBV)] and multiple sclerosis (MS). The compounds according to the invention have also been found to be effective in the treatment of Kaposi's sarcoma (KS) and thrombocytopenic purpura (TP). With respect to their last indication (MS, KS and TP) and goat arthritis virus, the present invention relates to compounds of formula (I) in which A is thymine for use in their treatment and prophylaxis, and also for their treatment or prophylaxis. Use of the 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 benefit in medicine, and the novel mode of action is that of the compounds in combination therapy to reduce the chance of developing resistance. Allow the use of. However, such formulations are particularly useful because the 3'-azidonucleosides have a surprising ability for the potentiating effect of other therapeutic agents as described below.

3'-Azidonucleosides synergistically synergize with a wide range of other therapeutic agents, thereby disproportionately enhancing the therapeutic potential of both agents. Significantly lesser amounts of each compound are required for treatment, the therapeutic rate is increased and thus the toxicity from either compound is reduced.

Therefore, in accordance with yet another aspect of the present invention, at least 1
Formula (I) A for use in combination therapy with two other therapeutic agents Provided are compounds of the formula: wherein B is a purine or pyrimidine base attached at the 9- or 1-position, respectively, or a pharmaceutically acceptable derivative thereof.

In particular, there are provided compounds of formula (I) A, or pharmaceutically acceptable derivatives thereof, for use in combination therapy as described above, wherein the two active agents are present in a potentiating ratio.

“Enhanced ratio” refers to a compound of formula (I) A, or a pharmaceutically acceptable derivative thereof, to a second therapeutic agent that provides a greater therapeutic effect relative to the sum of the therapeutic effects of the individual components. It is a ratio.

Although an optimal ratio will usually be present to ensure maximal potentiation, even very small amounts of one drug may be sufficient to potentiate the effects of the other to some extent, and thus the optional of the two potentiating drugs. It will be appreciated that a ratio of 1 can still possess the required synergistic effect. However,
The maximum synergistic effect is that the two drugs range from 500: 1 to 1: 500,
Preferably 100: 1 to 1: 100, specifically 20: 1 to 1:
Observed when present up to 20, and especially between 10: 1 and 1:10.

Therefore, the present invention specifically relates to 3'- as an active ingredient.
A glucuronidation inhibitor and / or renal excretion inhibitor containing azido-3′-deoxythymidine,
Provided is an effect enhancer for at least one therapeutic agent selected from nucleoside transport inhibitors, other therapeutic nucleosides and antibacterial agents. In the following description, this type of toughening agent is referred to as a compounding agent according to the present invention.

Accordingly, a formulation according to the invention for use in the treatment or prevention of any of the above infections or indications, or such a formulation in the manufacture of a medicament for the treatment or prevention of any of the above infections or indications. Further use is provided.

The formulations according to the invention are expedient in order to achieve the required therapeutic effect, either as a combination of tablets and injections, which are administered together, for example in a single pharmaceutical preparation, or separately, at the same time or at different times. Can be administered to

In the anti-virus test, for example, azidonucleosides can be treated with various agents such as interferon, nucleoside transport inhibitor, glucuronidation inhibitor, renal excretion inhibitor, and to the same organism in the formula (I) A
It has been found to be potentiated even by other therapeutic nucleosides that may not have the required activity, such as the compounds of.

Particularly preferred forms of interferon are α, β and γ
While the nucleoside transport inhibitors are dilazep, dipyridamole, 6-[(4-nitrobenzoyl) thio]-
9- (β- D -ribofuranosyl) purine, papaverine,
It includes agents such as miofrazine, hexobendine, lidofrazine and their acid addition salts.

Probenecid is particularly useful in combination with the 3'-azidonucleosides of formula (I) A because it possesses both renal excretion inhibiting activity and glucuronidation blocking activity. Examples of other compounds useful in this embodiment are competing for acetaminophen, lorazepam, cimetidine, ranitidine, zomepiraz, clofibrate, indomethacin, ketoprofen, naproxen, and glucuronidation, or otherwise significant glucuronide. Includes other compounds that undergo sterilization.

3'-Azidonucleosides of formula I (A) and their pharmaceutically acceptable derivatives are described, for example, in British Patent Specification No. 1,523,865, US Patent Specification No. 4,360,522, European Patent Specification No. 74 306,55. No. 239 and 146 516 and European Patent Application Nos. 434 393 and 434 395 are enriched with other therapeutic nucleoside derivatives, such as those mentioned above, which include acyclic nucleosides of the type described, and in particular the general formula (A ) [Wherein Z 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) represents a methyleneoxy group (—OCH ₂ ) and Y
Represents a hydroxy group], and pharmaceutically acceptable derivatives thereof. Examples of such derivatives are salts or esters, and basic salts such as alkali metal (eg sodium) or alkaline earth metals, and pharmaceutically acceptable organic acids such as lactic acid, acetic acid, malic acid or p-toluenesulfonic acid. Pharmaceutically acceptable salts, and also pharmaceutically acceptable salts of mineral acids such as hydrochloric acid or sulfuric acid.

An ester of a compound of formula (A) which may conveniently be used in accordance with the present invention is a 1-terminal position of the 9-side chain of a compound of formula (A)
_Formyloxy or C _1-16 in one or both
(Eg C _1-6 ) alkanoyloxy (eg acetoxy or propionyloxy), optionally substituted aralkanoyloxy (eg phenyl-C _1-4 alkanoyloxy such as phenyl-acetoxy) or optionally substituted Including those containing optionally aroyloxy (eg benzoyloxy or naphthoyloxy) ester groups. The aralkanoyloxy and aroyloxy ester groups may be substituted, for example, by one or more halogen (eg chlorine or bromine) atoms, or an amino, nitrile or sulfamido group, the aryl part of the group being from 6 carbon atoms. Advantageously contains up to 10.

Particularly preferred examples of compounds of the above general formula (A) for use according to the invention are 9-[(2-hydroxy-1-hydroxymethylethoxy) methyl] guanine, 2-amino-9- (2-hydroxyethoxy). Methyl) purines, and especially 9- (2-hydroxyethoxymethyl) guanine (acyclovir). The latter compound has been found to have a particularly good reinforcing effect, especially when the compound of formula I (A) is 3'-azido-3'-deoxythymidine as described in the examples.

In the antibacterial area, the broad spectrum of antibiotics is
It has also been found to be effective in potentiating the activity of azidonucleosides. They are used for a wide variety of drugs, for example: benzyl pyridines, eg British Patent Specification No. 1,
405,246, such as 2,4-diamino-
5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine (trimethoprim) and their homologues; sulfonamides such as sulfazimidine; rifampicin; tobramycin; fusidic acid; chloramphenicol; clindamycin and erythromycin Includes.

Accordingly, in yet another aspect, there is provided a combination according to the invention, wherein the second drug is at least one of the above antiviral or antibacterial agents, or a class of drugs.

Other formulations suitable for use in accordance with the invention are those in which the second agent is, for example, interleukin II, suramin, phosphonoformate, HPA23, 2 ', 3'-dideoxynucleosides, such as 2', 3'-dideoxy. It includes cytidine and 2 ', 3'-dideoxyadenosine, or agents that are suitable for increasing the number and / or function of lymphocytes, such as levamisole or thymosin.

It will be appreciated that the compounds and formulations according to the present invention may also be used in combination with other immunomodulatory therapies including, for example, bone marrow and lymphocyte transplantation.

Those with retrovirus infections, such as AIDS
Has been associated with infections that have been seen since day one. Thus, for example, a combination of 3'-azido-3'-deoxythymidine (AZT) and acyclovir is an AI with apparently herpes infections.
A combination of AZT and 9-[(2-hydroxy-1-hydroxymethylethoxy) methyl] guanine proved to be particularly useful in the treatment of patients with DS, whereas the combination of AZT and 9-[(2-hydroxy-1-hydroxymethylethoxy) methyl] guanine was found in AIDS patients with cytomegalovirus infections by day. It is recognized to be useful in therapy.

Generally preferred pyrimidines of formula (I) and (I) A for use according to the invention are of formula (II) [In the formula, R ¹ is hydroxy, mercapto, amino, alkylthio, aralkoxy, alkoxy, cyano, alkylamino or dialkylamino, and the alkyl group may be optionally bonded to form a heterocycle; R ² is hydrogen. , acyl, alkyl, aroyl or sulfonate; R ³ is hydroxy, mercapto, amino, triazolyl, alkylamino, dialkylamino wherein the alkyl groups can form a heterocyclic ring optionally coupled, aralkoxy, alkoxy, or alkylthio R ⁴ is alkyl, substituted alkyl, halo, perhalomethyl, hydroxy, alkoxy, cyano, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or hydrogen], and pharmaceutically acceptable derivatives thereof. is there.

In general formula (I), the dotted lines from the 2- to 6-positions are intended to indicate the presence of single or double bonds at those positions, the relative positions of the single and double bonds being the substituents. For example, it is determined whether R ¹ and R ² are groups capable of keto-enol tautomerism.

A preferred class of pyrimidine nucleosides according to the invention are cytidine derivatives, for example compounds of formula (II) in which R ³ is amino or alkylamino and in particular the 3 ′ azido group is in the erythro configuration (“down azide”); Thymidine and uridine derivatives in either the erythro or threo (“upazide”) configuration (eg compounds of formula (I) wherein R ³ is other than amino or alkylamino); unsaturated between the 5C and 6C positions It is a nucleoside.

Generally preferred purines of formula (I) and (I) A for use according to the invention are of formula (II) A Wherein R ⁶ and R ⁷ can be equal or different and are selected from amino, hydrogen, hydroxy, mercapto, alkylthio, alkoxy, aralkoxy, cyano or alkylamino and their pharmaceuticals. It is a chemically acceptable derivative.

A preferred class of purine nucleosides according to the invention is
Adenine derivatives, for example compounds of formula (II) A R ⁶ is amino or substituted amino, and guanine derivatives, for example, those such as R ⁶ has limited other than amino or substituted amino, and R ⁷ is amino or substituted amino Is a compound of formula (III)

Advantageously, the acyl groups include alkyl or aryl groups such as: With regard to the compounds of formulas (II) and (II) A above, the alkyl group advantageously contains from 1 to 8 carbon atoms, in particular from 1 to 4 carbon atoms, eg a methyl or ethyl group, optionally May be substituted with one or more suitable substituents as described below. The above aryl groups, including the aryl portion of groups such as aralkoxy, are preferably phenyl groups optionally substituted with one or more substituents as described below. Said alkenyl and alkynyl groups advantageously contain from 2 to 8, in particular from 2 to 4, carbon atoms, for example ethenyl or ethynyl, optionally substituted by one or more suitable substituents as described below. Can be done.

Suitable substituents on said alkyl, alkenyl, alkynyl and aryl groups are halogen, hydroxy, C
_1-4 alkoxy, C _1-4 alkyl, C _6-12 aryl, C _6-12 aralkoxy, carboxy, amino, and amino are singly or doubly substituted by C _1-4 alkyl, and doubly substituted. When, the alkyl group is optionally selected from substituted amino that may optionally be attached to form a heterocycle.

Yet another class of preferred compounds of formula (II) is R ¹ ,
One or more of R ² , R ³ and R ⁴ is as defined below, ie R ¹ is hydrogen, mercapto, C _1-4 alkoxy or amino; R ² is hydrogen, methyl, C There _1-2 alkanoyl or benzoyl; R ³ is hydroxy, mercapto, an amino or substituted amino; R ⁴ is hydrogen when R ³ is amino or substituted amino, and other than amino or substituted amino R ³ halogen time is, _{perhalomethyl, C 2 to 3} alkyl, C
Those which are _2-3 alkenyl or substituted ethenyl, as well as carboxy groups (eg succinate),
C _1-6 thioesters, optionally substituted aryl esters, mesylates, glucuronides, or linear or branched alkyl esters optionally substituted with mono-, di- or tri-phosphates. Includes 5 derivatives of the compound.

Still another class of preferred compounds of formula (II) B is where R ⁶ is amino, C _1-4 alkylamino, mercapto, hydroxy or C _1-4 alkoxy; and / or R ⁷ is amino, C _{1 to 4} alkylamino or hydrogen, as well as carboxy groups (eg succinate), C _1-6 thioesters, optionally substituted aryl esters, mesylates, glucuronides,
Alternatively, it includes 5 derivatives of the compound, including straight chain or branched alkyl esters that are optionally substituted with mono-, di- or tri-phosphates.

Compounds of formula (I) suitable for use in the treatment or prophylaxis of viral infections are those wherein R ¹ is hydroxy, mercapto, C _1-5 alkoxy, amino, C _6-12 aralkoxy, or the 2 and 5 ′ positions. R ² is hydrogen, methyl or benzoyl; R ³ is hydroxy, mercapto, amino, substituted amino or C _6-12 aralkoxy; R ⁴ is as defined; However, A in formula (I)
Are compounds of formula (II) in which is not a thymine residue, and pharmaceutically acceptable derivatives thereof. The azido group is advantageously in the erythro configuration. Particularly preferred is that only ^one of the substituents R ^{1 to} R ⁴ on the pyrimidine ring is that of a thymine residue (of which
R ¹ and R ³ are hydroxy, R ² is hydrogen, and R ⁴ is methyl). Preferred compounds of formula (I) for use in the treatment or prevention of viral infections are those of formula (I) as defined above but further wherein B is a thymine residue.
Of a compound of formula (I), and especially when the compound is 3'-azido-3'-deoxythymidine.

Compounds of formula (I) suitable for use in the treatment or prevention of bacterial infections include R ¹ is oxygen, sulfur, benzyloxy or methoxy; R ² is hydrogen or benzoyl; R ³ is defined above. And R ⁴ is methyl or halogen, provided that A in formula (I) is not a thymine residue, and compounds of formula (II), and pharmaceutically acceptable derivatives thereof.

The 3'-azido group can be in either configuration, but the erythro configuration is particularly preferred and the preferred pharmaceutically acceptable derivative is a simple organic acid, preferably the _{5'ester of a C1-18} acid.

Particularly preferred is ^one of the substituents R ^{1 to} R ⁴ on the pyrimidine ring.
Only that of thymine residues, where R ¹ and R ³ are hydroxy, R ² is hydrogen, and R ⁴ is methyl
And a compound as described above which is different from the above.

Preferred compounds of formula (I) A for use in the treatment or prevention of bacterial infections include those compounds of formula (I) A as defined above for formula (I) but further wherein B is a thymine residue. , And especially the compound is 3'-azido-3'-
That is when it is deoxythymidine.

"Pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt, ester, or salt of the ester, or the parent 3'-azidonucleoside or therapeutically effective metabolite thereof when administered to a recipient. Or any other compound capable of providing (directly or indirectly) a residue. Examples of non-ester compounds are 5'-C- and 2-
It is a derivative in which a C-atom is bound by an oxygen atom to form an anhydro group.

Preferred esters of compounds of formula (I) are straight chain or branched chain alkyl, alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxymethyl), aryl where the non-carbonyl portion of the ester group is (Eg phenyl optionally substituted by halogen, C _1-4 alkyl or C _1-4 alkoxy); sulfonate esters, such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); and Includes mono-, di- or triphosphate esters. Any reference to any of the above compounds also includes a reference to their pharmaceutically acceptable salts.

With regard to the above esters, unless otherwise indicated, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, especially from 1 to 4 carbon atoms. Any aryl moiety present in the ester advantageously consists of a phenyl group.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) and their pharmaceutically acceptable derivative pairs are base salts derived from suitable bases, such as alkali metals (eg sodium), alkaline earth metals ( For example magnesium) salt,
Ammonium and NX ₄ ⁺ (where X is C _1-4 alkyl), and mineral salts such as the hydrochloride salt.

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

Some of the compounds according to the invention are new. Accordingly, the present invention further provides formula (I) B other than [Wherein C is a purine or pyrimidine base bound at the 9- or 1-position, respectively], and pharmaceutically acceptable derivatives thereof; (a) C is adenine, guanine, Compounds of formula (I) B, which are uridine, cytidine or thymine bases, and their 5'-mono- or 5'-triphosphate esters; (b) C is a uridine base and 3'-azido group is 5'-O of a compound of formula (I) B in the erythro configuration
-Acetate, 5'-O-trityl and 5'-O-
(4-methylbenzenesulfonate) derivative; (c) C is (i) 5-bromovinyluridine or 5-trifluoromethyluridine residue, and 3'-azido group is erythro configuration; (ii) Uridine A residue and the 3'-azido residue is in the threo configuration; and (iii) a 5-iodo or 5-fluorouridine residue, and the 3'-azido group is in the erythro or threo configuration. I) a compound of B; and a 5'-O-trityl derivative of the compound; (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 in the erythro configuration; or (iii) a 5-methylcytidine residue and a 3'-
Formula (I) B wherein the azido group is in the threo or erythro configuration
(E) C is 4-chloro-2 (1H) pyrimidinone or 4- (1H-1,2,4-triazol-1-yl) -2 (1
H) pyrimidinone (optionally substituted with fluorine or methyl at the 5-position), and the 5'-O-of the compound of formula (I) B wherein the 3'-azido group is in the erythro configuration. Acetate ester; (f) 5'-O of the compound of formula (I) B wherein C is a cytidine residue and the 3'-azido group is in the erythro configuration.
-[(4-methoxyphenyl) diphenylmethyl] derivative; and (g) 5'-O of the compound of formula (I) B, wherein C is an adenine residue and the 3'-azido group is in the threo configuration.
-Trityl derivatives.

Preferred compounds are those mentioned above in binding therapy, above those specifically excluded above.

The compounds of the formulas (I) and (I) A, which are also indicated here as active ingredients, and their pharmaceutically acceptable derivatives are for the treatment of oral, intestinal, intranasal, topical (buccal and buccal and Administration may be by any suitable route including sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection, and the active ingredient selected.

In general, a suitable dose is in the range of 3.0 to 120 mg / kg recipient body weight per day, preferably 6 to 90 mg per day.
/ kg body weight range, and most preferably 1 per day
Within the range of 5 to 60 mg / kg body weight. The desired dose is
Preferably administered at appropriate intervals throughout the day 2,
Present as 3, 4, 6 or more divided doses. The divided doses are, for example, from 10 per unit dosage form.
It may be administered in a unit dosage form containing up to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient. Experiments with 3'-azido-3'-deoxythymidine have demonstrated that doses achieve peak plasma concentrations of active compound of from about 1 to about 75 μM, preferably from about 2 to 50 μM, most preferably from about 3 to about 30 μM. Suggest that it should be administered as follows.
This is accomplished, for example, by intravenous injection of a solution of 0.1 to 5% of the active ingredient in saline, or orally as a pill containing from about 1 to about 100 mg / kg of the active ingredient. sell. The desired blood level is about 0.01
By continuous perfusion providing up to about 5.0 mg / kg / hour,
Alternatively it may be maintained by intermittent perfusion containing from about 0.4 to about 15 mg / kg of active ingredient.

The formulations according to the invention may be administered in the same manner as described above to provide the desired therapeutic amount of the active ingredient and other therapeutic agents associated therewith. The dose of the formulation depends on the condition being treated,
It may depend on the particular active ingredient and other related agents, as well as other clinical factors such as the weight and condition of the patient, and the route of administration of the formulation. As noted above, as indicated above, the active ingredient and the other therapeutic agent may be administered simultaneously (eg, in a single pharmaceutical formulation) or separately (eg, in a separate pharmaceutical formulation) and are generally combined. The article may be administered by topical, oral, enteral or parenteral (eg, intravenous, subcutaneous or intramuscular) routes.

In particular, the formulations according to the present 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 the oral route, 1
A dose of the active ingredient of from 1 to 200 mg / kg / day, preferably from 5 to 50 mg / kg / day is generally sufficient. For administration by the parenteral route, a dose of active ingredient of 1 to 100 mg / kg / day, preferably 2 to 30 mg / 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 sufficient to effectively inhibit nucleoside transport,
And preferably in the range of 0.1 to 100 mg / kg / day, and especially in the range of 1 to 20 mg / kg / day.

Formulations according to the invention in which the second agent is either a renal excretion inhibitor or a glucuronidation inhibitor, or both, may be administered to the relevant subject in a conventional manner. However, for administration by the oral route, 1 to 200 m
A dose of active ingredient of up to g / kg / day, preferably 5 to 50 mg / kg / day is generally sufficient. For administration by the parenteral route, a dose of active ingredient of 1 to 100 mg / kg / day, preferably 2 to 30 mg / kg day is generally sufficient. The amount of renal excretion / glucuronidation inhibitor in the formulation is independent of the amount of active ingredient, and 4-100 mg / kg /
Day, preferably 5-60 mg / kg / day, most preferably 10-40
A range of mg / kg / day is sufficient.

A formulation according to the invention in which the second agent is interferon conveniently comprises from 5 to 250 mg / kg of active ingredient per day; and a suitable effective dose range of interferon is 3 × body surface per day. From 10 ⁶ to 10 × 10 ⁶ IU / m ² body surface, preferably 4 × 10 ⁶ to 6 × 10 ⁶ IU / m ² per day
Up to. The active ingredient and interferon are about 5 mg / kg of active ingredient for interferon 3 × 10 ⁶ IU / m ² to about 250 mg / kg of active ingredient for interferon 10 × 10 ⁶ IU / m ² per day. Preferably, interferon is 4 × 10 ⁶ IU / m ² per day, and the active ingredient is about 5 mg / kg per day.
To 6 × 10 ⁶ IU / m ^{2 of} interferon per day should be administered at a rate of about 100 mg / kg of active ingredient per day.

Interferon is preferably administered by injection (eg subcutaneously, intramuscularly or intravenously), while the active ingredient is preferably administered orally or by injection,
Administration can be by any of the modes described herein. The interferon and active ingredient may be administered together or separately, and each daily dose may be administered, preferably as divided doses.

For formulations according to the invention in which the second agent is another therapeutic nucleoside, a suitable effective oral dose range of the active ingredient is from 2.5 to 50 mg / kg body weight per day, preferably from 5 to 10 mg / kg per day. And a suitable effective oral dose range for the second therapeutic nucleoside is 5 to 5 per day.
Up to 100 mg / kg body weight, preferably 15 to 75 mg / kg per day
Up to. The ratio of the active ingredient to the second therapeutic nucleoside for oral administration is preferably about 1: 1 to 1:10, more preferably about 1: 2 to 1: 8.

A suitable effective IV dose range for the active ingredient is generally about 1.5 to 15 mg / kg per day, and a suitable effective IV dose range for the therapeutic nucleoside is generally about 5 to 30 mg / kg per day. . The ratio of the active ingredient to the second therapeutic nucleoside for intravenous administration is preferably in the range of about 2: 1 to 1:20, more preferably in 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 a divided dose.

For formulations according to the invention where the second agent is an antibacterial agent, a suitable effective dose range of the active ingredient is from 2.5 to 50 mg /
up to kg / day, preferably from 5 to 10 mg / kg / day,
And a suitable effective dose range for antibacterial agents is 2 to 1000 mg / k
It is up to g / day, preferably in the range of 50 to 500 mg / kg / day. The preferred ratio of active ingredient to antibacterial agent is 2
It is in the range 0: 1 to 1: 500, especially 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, 3'- with acyclovir and probenecid
The formulation of azido-3'-deoxythymidine (AZT) is A
It has the dual advantage of enhancing the activity of ZT and increasing its availability. Similarly, a combination of a compound of formula (I) A with two or more of the same assortment of second therapeutic agents, such as AZT with sulfazimidine and trimethoprim, also forms part of the invention.

While it is possible for the active ingredient to be administered alone, it is preferable to present it 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 thereof 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 injurious to the patient. Formulations include those suitable for oral, enteral, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Generally, it is prepared by bringing the active ingredient into a uniform and intimate combination with a liquid carrier or a finely divided solid carrier, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration include discrete units, such as capsules, each containing a predetermined amount of the active ingredient.
They may be present as cachets or tablets; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water emulsions or water-in-oil liquid emulsions. The active ingredient may also be presented as a pill, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets
Binders (eg povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrating agents (eg sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethylcellulose), surfactants Alternatively, the active ingredient in free-flowing form, eg in powder or granules, mixed with a dispersant, may be prepared by compression in a suitable machine. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may provide a slow or controlled release of the active component, eg using hydroxypropylmethylcellulose in various proportions, to provide the desired release profile. Can be formulated to provide

Formulations suitable for topical administration in the mouth include lozenges consisting of a flavoring agent, usually an active ingredient in sucrose and acacia or tragacanth; an inert base, such as gelatin and glycerin, or saccharose and acacia. Pastel agents consisting of the active ingredient; as well as gargles consisting of the active ingredient in a suitable liquid carrier.

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

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Suitable formulations for parenteral administration include antioxidants, buffers,
Aqueous and non-aqueous isotonic sterile injection solutions which may contain bacteriostats and solutes which render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous solutions which may include suspending and thickening agents Includes non-aqueous sterile suspensions. The formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in lyophilized form requiring only the addition of a sterile fluid carrier, eg water for injection, immediately before use. 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 a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

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

Examples of such veterinary preparations are: (a) those adapted for oral administration, eg drench (eg aqueous or non-aqueous solutions or suspensions);
Tablets or pills; powder, granules or pellets for admixture with feed; paste for application to the tongue; (b) those suitable for parenteral administration, eg by subcutaneous, intramuscular or intravenous injection, eg sterile solutions Or a suspension; or (where appropriate) an intramammary injection in which the suspension or solution is introduced into the breast via the teat; (c) compatible with topical application, eg a cream, ointment or spray applied to the skin. Or (d) those which fit in the vagina, such as pestry, cream or form;

It will be appreciated that formulations such as those described above, whether single or separate, are suitable for presentation of the formulations according to the present invention and may be prepared in the same manner.

In addition to the ingredients specifically indicated above, the formulations of the present invention may include other agents conventional in the art with regard to the type of formulation in question, such as those suitable for oral administration are sweeteners, It should be understood that other agents such as thickening and flavoring agents may be included.

 Compounds of formula (I) A and their pharmaceutically acceptable
Derivatives, the disclosures of which are incorporated herein by reference,
For example, Synthetic Procedures Yours in Ni
Euclaic Acid Chemistry (Synthetic Pr
ocedures in Nucleic Acid Chemistry) 〔1, 321 (196
8), Krenitzky (T.A.Krenitsky), etc.], Jie Med
・ J.Med.Chem.26, 981, (1983)]; New
Kratsk Acid Chemistry, Improved
And New Synthetic Processes Mesooo
N's and Technics (Nucleic Acid Chemistry, Im
proved and New Synthetic Processes, Methods and Tec
hniques) [Parts 1 and 2, L.D. Townsen
d), edited by R.S.Tipson, [Jie Wheelie
(J.wiley)] 1978]; J.R.Horwitz, etc.
[J.Org.Chem.],29, (1964
(July) 2076-2078]; Imazawa, etc. [Jie
・ Org Chem (J.Org.Chem.),43(15) (1978) 304
4 ~ 3048]; Watanabe (K.A. Watanabe) etc. [Jie Ol
Gu Chem (J.Org.Chem.),45, 3274 (1980)]; and
R.P.Glinski etc. [Jie Chem Sos
・ Chem Komiyun (J.Chem.Soc.Chem.Commun.),915
(1970)] in this technical field.
Use well known techniques or are described in them
It can be prepared in a conventional manner using the same technique as described above.

The present invention further includes processes for the preparation of compounds of formula (I) and their pharmaceutically acceptable derivatives, which are of formula (III) [Wherein A is as defined above and M represents a precursor group for a 3'-azide group] or a derivative thereof (eg ester or salt) (B) Formula (IV a) or (IV b) reacted with an agent that aids in conversion to an azido group or under conditions; [Wherein, ▲ R ¹ _a ▼, ▲ R ² _a ▼, ▲ R ³ _a ▼, ▲ R ⁴ _a ▼, ▲
R ⁶ _a ▼ and ▲ R ⁷ _a ▼ are the groups R ¹ , R ² , R ³ , R ⁴ and R ⁴ , respectively.
R ⁶ and R ⁷ or a precursor group therefor,
Provided that at least ^one of ▲ R ¹ _a ▼, ▲ R ² _a ▼, ▲ R ³ _a ▼ and ▲ R ⁴ _a ▼ in formula (IV a) or the group ▲ R ⁶ _{a in} formula (IV b) At least one of ▼ and ▲ R ⁷ _a ▼ represents a precursor group] with an agent that serves to convert the precursor group to the corresponding desired group, or under conditions; ) Expression (V a) or (V b) [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined above] or their functional equivalents can be prepared by converting a compound of formula (V a) Reacted with a compound that serves to introduce the desired ribofuranosyl ring in the 1-position or in the 9-position of the compound of formula (Vb); or (D) for the preparation of a compound of formula (II) (V
b) Pudding of formula (VI) Reacting with a pyrimidine nucleus of the formula: wherein Py represents a 1-pyrimidinyl group; and thereafter or simultaneously with one or more of the following optional transformations: (i) Formula (I) A compound of formula (I) is formed into a pharmaceutically acceptable derivative thereof; and (ii) when a pharmaceutically acceptable derivative of a compound of formula (I) is formed, the derivative of formula (I) Conversion to the parent compound of I) or another pharmaceutically acceptable derivative of the compound of formula (I).

In the above method according to the present invention, the selection of precursor compounds in methods (A) to (D) is mainly dictated by the particular compound that it is desired to produce, and the agents and conditions are the technical field of nucleoside synthesis technology. It will be appreciated that there is a corresponding selection from what is known in. Examples of such conversion methods are given below for guidance and it will be understood that they depend on the desired compound and may be modified in a conventional manner. In particular, if, for example, the conversion which results in an undesired reaction of the labile group is described separately, such a group may be protected in the usual way, with subsequent removal of the protecting group after completion of the conversion.

Thus, for example, for method (A), the formula (III a)
Alternatively, the group M in the compound of (III b) may represent, for example, a halogen (eg chlorine), hydroxy or organic sulfonyloxy (eg trifluorosulfonyloxy, methanesulfonyloxy or p-toluenesulfonyloxy) group.

For the preparation of compounds of the formula (I) in which the 3'-azido group is in the threo configuration, the group M is a hydroxy group in the erythro configuration, the 5'-hydroxy group of which is advantageously protected, for example by the trityl group. With the formula (III a) or (III
The compounds of b) may be treated with, for example, triphenylphosphine, carbon tetrabromide and lithium azide. Separately,
M may represent an organic sulfonyloxy-removable group in the erythro configuration, which may be converted to an azido group in the threo configuration by treatment with, for example, lithium or sodium azide, the 5'-hydroxy group being similarly protected as described above. . Removal of the 5'-trityl protecting group was followed by removal of
It can be carried out, for example, under mildly acidic conditions or by treatment with zinc bromide.

For the preparation of compounds of formula (I) in which the 3'-azido group is in the erythro configuration, formula (IIIa) or (III in which the group M is a halogen (eg chlorine) group in the threo configuration is used.
The compounds of b), whose 5'-hydroxy is advantageously protected eg with a trityl group, may be treated with eg lithium or sodium azide. The 3'-threo-halogen (eg chlorine) starting material is, for example, the corresponding 3 '
The corresponding 3'-erythro-organosulfonyloxy by reacting the erythro-hydroxy compound with, for example, triphenylphosphine and carbon tetrachloride, or separately by treatment with an organic sulfonyl halide (e.g. trifluoromethanesulfonyl chloride). It is obtained by forming a compound and then halogenating it, for example as described above. Separately, the formula (III
The 3'-threo-hydroxy or organic sulfonyloxy compound of a) or (III b) is treated with, for example, triphenylphosphine, carbon tetrabromide and lithium azide to form the corresponding 3'-erythro-azide compound. You can.

With respect to method (B), the following are examples of various methods by which the precursor groups in formula (IV a) can be converted to the desired R ¹ , R ² , R ³ and R ⁴ groups: a) R ¹ is When showing an alkoxy (eg methoxy or ethoxy) group, such compounds are those wherein ▲ R ¹ _a ▼ is 2,
It may be prepared from the corresponding compound of formula (IV a) exhibiting a 5'-O-anhydro bond, conveniently in the presence of potassium carbonate, for example by treatment with a suitable nucleophile such as alkoxide; b) R ¹ is mercapto When representing a group, such a compound may be prepared from the corresponding compound of formula (IV a) in which ▲ R ¹ _a ▼ represents an alkoxy (eg ethoxy) group, eg by treatment with hydrogen sulfide; c) R ² When R represents an alkyl group, such compounds are treated from the corresponding compound of formula (IV a) in which R ² _a represents a hydrogen atom, for example by treatment with an alkylating agent such as N, N-dimethylformamide dimethyl acetal. D) when R ³ represents a mercapto group, such compounds may be of the formula (IV a) in which ▲ R ³ _a ▼ represents a suitable removable group, for example 1,2,4-triazolyl. Correspondence From a compound such as by treatment with an alkali metal (eg sodium) mercaptan; e) When R ³ represents an amino group, such a compound is
It may be prepared from the corresponding compound of formula (IV a) in which R ³ _a represents a hydroxy group by treatment in a cylinder with an aminating agent such as hexamethyldisilazane and ammonium sulfate; f) R ⁴ is halo (eg chloro). ) Group, such compounds have the formula (IV a) in which ▲ R ⁴ _a ▼ represents a hydrogen atom.
Can be prepared from the corresponding compound of 1 by treatment with a halogenating agent such as m-chloroperbenzoic acid.

Similar methods and also, for example, those described in the above references, describe the desired R ⁶ of the precursor group in formula (IV b) and
It can be used to carry out the conversion to the R ⁷ group.

With regard to method (C), this involves, for example, the appropriate pyrimidine or purine of formula (V a) or (V b) or their salts or protected derivatives Where Y is a group to be removed, such as acetoxy or benzoyloxy or halo, such as a chloro group, and the 5'hydroxy group may optionally be protected, for example by a p-toluenesulfonyloxy group. However, it can be carried out by subsequently removing the protective group, if any.

With regard to method (D), the reaction of the compounds of formulas (Vb) and (VI) is conveniently carried out in the presence of a phosphatase and, if desired, the 3'-azido anomer is separated in the usual manner.

When a compound of formula (I) is formed, such compound forms a compound of formula (I) with a phosphorylating agent such as PO.
It may be converted to a pharmaceutically acceptable phosphate or other ester by reaction with Cl ₃ , or a suitable esterifying agent such as an acid halide or anhydride. Compounds of formula (I), including their esters, may be converted into their pharmaceutically acceptable salts in the usual manner, eg by treatment with a suitable base.

When a derivative of a compound of formula (I) is formed, such compound may be converted into the parent compound, for example by hydrolysis.

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The term "active ingredient" as used in the examples means a compound of formula (I) or (I) A, or a pharmaceutically acceptable derivative thereof.

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

Formulation C mg / tablet Active substance 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4 359 The following Preparations D and E are prepared by direct compression of the mixed ingredients. The lactose used in production E is a direct compression type [Daily Crest- "Zeparox" (Dairy Cr
est- “Zeparox”)].

Formulation D mg / capsule active ingredient 250 Pregelatinized starch NF15 150 400 Formulation E mg / capsule active ingredient 250 Lactose 150 Avicel 100 500 Formulation F (controlled release formulation) This formulation is a wet solution of the ingredients (below) and povidone solution. Produced by granulation, subsequent addition of magnesium stearate and compression.

mg / tablet (a) Active ingredient 500 (b) Hydroxypropyl methylcellulose (Methocel K4M Premium) 112 (c) Lactose, BP 53 (d) Povidone, BPC 28 (e) Magnesium stearate 7 700 Example 2 Capsule formulation Formulation A capsule The formulation is mixed with the ingredients of Formulation D from Example 1 above,
And it manufactures by filling in a 2 part hard gelatin capsule. Formulation B (below) is similarly prepared.

Formulation B mg / capsule (a) Active ingredient 250 (b) Lactose, BP 143 (c) Sodium starch glycolate 25 (d) Magnesium stearate 2 420 Formulation C mg / capsule (a) Active ingredient 250 (b) Macrogol 4000, BP 350 600 capsules are prepared by melting Macrogol 4000 BP, dispersing the active ingredient in the melt, and filling the melt in two-part hard gelatin capsules.

Formulation D mg / capsule Active ingredient 250 Lecithin 100 Peanut oil 100 450 Capsules are prepared by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion in soft elastic gelatin capsules.

Formulation E (Controlled Release Capsule) The following controlled release capsule formulation is made by extruding components a, b and c using an extruder, followed by spheronizing and drying the extrudate. The dried pellets are then coated with a controlled release membrane (d) and filled into two-part hard gelatin capsules.

mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose, BP 125 (d) Ethylcellulose 13 513 Example 3 Injectable formulation Formulation A Active ingredient 0.200g Hydrochloric acid solution, 0.1M Appropriate amount, from pH 4.0 Up to 7.0 Sodium hydroxide solution 0.1M qs pH 4.0 to 7.0 Sterile water qs 10ml Dissolve active ingredient in most of water (35 ° -40 ° C) and adjust pH with hydrochloric acid or sodium hydroxide as needed. Adjust the pH to 4.
Adjust between 0 and 7.0. The batches were then made up to volume with water and filtered into sterile 10 ml brown glass vials (type 1) suitable for sterile micropore filtration and sealed with sterile stoppers and overseals.

Formulation B Active ingredient 0.125g Sterilized, Pyrodiene-free, pH 7 phosphate buffer
Appropriate amount Total amount 25 ml Example 4 Intramuscular injection weight (g) Active ingredient 0.20 Benzyl alcohol 0.10 Glycofurol 75 1.45 Water for injection Appropriate amount Total amount 3.00 ml Dissolve the active ingredient in glycofurol. Then benzyl alcohol is added and dissolved and water is added up to 3 ml. The mixture was then filtered through a sterile micropol filter and sterile 3 ml brown glass vial (1
Sealed).

Example 5 Syrup Preparation A Weight (g) Active ingredient 0.2500 Sorbitol solution 1.5000 Glycerol 2.0000 Sodium benzoate 0.0050 Fragrance, peach 17.42.3169 0.0125ml Purified water Suitable amount 5.0000ml Dissolve active ingredient in a mixture of glycerol and most purified water . An aqueous solution of sodium benzoate is then added to the solution, followed by the sorbitol solution and finally the perfume. Make up volume with purified water and mix well.

When the active ingredient is poorly soluble, the following formulation (B) is used.

Formulation B Weight (g) Active ingredient 0.250 Sorbitol solution 1.500 Glycerol 0.005 Dispersible cellulose 0.005 Sodium benzoate 0.010 ml Flavor Purified water Suitable amount Total 5.000 ml Sorbitol solution, glycerol and 1 part of purified water are mixed. Dissolve sodium benzoate in purified water,
Then add the solution to the bulk. Add dispersible cellulose and flavor and disperse. The active ingredient is added and dispersed. Adjust the volume with purified water.

Example 6 Suppository mg / suppository active ingredient (63 μM) ^* 250 hard fat, BP (Witepsol H15-Dynamitsu Nobel) 1770 2020 ^* Active ingredient is used as a powder in which at least 90% of particles are 63 μm or less in diameter To do.

Melt 1/5 volume of Witepsol H15 in a steam-jacketed pan at a maximum of 45 ° C. The active ingredient is passed through a 200 μm sieve and added to the melt base using a Silverson equipped with a cutting bed with stirring until a smooth dispersion is achieved. Keeping the mix at 45 ° C, add the remaining Witepsol H15 to the suspension and stir to ensure uniform mixing. The entire suspension is passed, with continuous stirring, through a 250 μm stainless steel sieve and cooled to 40 ° C. 2.02 g of mixture at a temperature between 38 ° C and 40 ° C
In a suitable 2 ml plastic mold. Cool the suppository to room temperature.

Example 7 Petsalry mg / petsalley active ingredient (63 μm) 250 anhydrous dextrose 380 valerian starch 363 magnesium stearate 7 1000 The above ingredients are directly mixed and a pestry is prepared by direct compression of the resulting mixture.

The following Examples 8-10 describe the preparation of formulations containing a compound of formula (I) A (active ingredient) and other therapeutic nucleosides specified.

Example 8 Injection Formulation A Weight (mg) Acyclovir 400 Active ingredient 200 1M NaOH As needed Sterilized water Appropriate amount 10 ml Formulation B weight (mg) 2-Amino-9- (2-hydroxyethoxymethyl) purine 400 Active ingredient 200 1M NaOH sterile water as needed qs total 10 ml For the above formulation, add therapeutic nucleoside to 1M NaOH solution and stir until dissolved. Add active ingredient and dissolve. Add sterile water to 10 ml. Filter through sterile strainer and fill into sterile vials. Lyophilize.

Example 9 Tablet Formulation A Weight (mg) Acyclovir 500 Active ingredient 125 Povidone 14 Sodium starch glycolate 25 Magnesium stearate 6 670 Formulation B Weight (mg) Active ingredient 125 2-Amino-9- (2-hydroxyethoxymethyl) purine 125 Povidone 8 Sodium Starch Glycolate 12 Magnesium Stearate 3 273 In Formulations A and B above, the therapeutic nucleoside and the active ingredient are mixed with sodium starch glycolate and granulated with a solution of povidone. After drying, the granules are mixed with magnesium stearate and compressed.

Example 10 Capsules Formulation A Weight (mg) Acyclovir 250 Active ingredient 62.5 Lactose 170.5 Sodium starch glycolate 15 Magnesium stearate 2 500 The ingredients are mixed and filled into hard gelatin capsules.

Formulation B Weight (mg) Active ingredient 125 2-Amino-9- (2-hydroxyethoxymethyl) purine 125 Lactose 133 Sodium starch glycolate 15 Magnesium stearate 2 400 The ingredients are mixed and filled into hard gelatin capsules.

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

Example 11 Injection Interferon 3 megaU Active ingredient 200 mg Sterile buffer pH 7 Appropriate amount 50 ml Interferon and active ingredient are dissolved in sterile water. Filter through a sterile strainer and fill sterile vials.

Examples 12-15 below describe the preparation of formulations containing a compound of formula (I) A (active ingredient) such as 3'-azido-3'-deoxythymidine in combination with a nucleoside transport inhibitor such as dipyridamole. To do.

Example 12 Tablet weight (mg) 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. Turn into. The granules are dried, sieved and mixed with magnesium stearate and then compressed into tablet form.

Example 13 Capsule Weight (mg) Nucleoside Transport Inhibitor 300 Active Ingredient 100 Lactose 100 Sodium Starch Glycolate 10 Polyvinylpyrrolidinone 10 Magnesium Stearate 3 Total Weight 523 The active compound is mixed with lactose and sodium starch glycolate and Wet granulate with a solution of vinylpyrrolidinone. The granules are dried, sieved and mixed with magnesium stearate and filled into hard gelatin capsules.

Example 14 Cream weight (g) Nucleoside transport inhibitor 7.5 Active ingredient 5.00 Glycerol 2.00 Cetostearyl alcohol 6.75 Sodium lauryl sulphate 0.75 White soft paraffin 12.50 Liquid paraffin 5.00 Chlorocresol 0.10 Purified water qs 100.00 Active compound in a mixture of purified water and glycerol. Melt and heat to 70 ° C. The remaining ingredients together, 70
Heat at ℃. Both are added together and emulsified. Cool the mixture and fill the container.

Example 15 Intravenous injection amount (mg) (1) Active ingredient 200 Nucleoside transport inhibitor 300 Glycerol 200 Sodium hydroxide solution Suitable amount pH 7.0-7.5 Water for injection Suitable amount Total 10 ml Glycerol is added to a small amount of water for injection. The two active compounds are added and the pH is adjusted to 7. with sodium hydroxide solution.
Adjust from 0 to 7.5. Bring the solution to volume with additional water for injection. Under aseptic conditions, the solution is sterilized by filtration, filled into sterile ampoules and the ampoules are sealed.

Amount (mg) (2) Active ingredient 100 Nucleoside transport inhibitor 150 Mannitol 125 Sodium hydroxide solution Appropriate amount pH 8.0 to 9.0 Water for injection Appropriate amount 2.5 ml Dissolve the active compound and mannitol in 1 part of water for injection. The pH is adjusted to 8.0-9.0 with sodium hydroxide solution and made up to volume with additional water for injection. Under sterile conditions, the solution is sterilized by filtration, filled into sterile vials, and the water removed by lyophilization. The vial is sealed under a nitrogen atmosphere and closed with a sterile stopper and metal collar.

The following Examples 16-18, in combination with a glucuronidation / renal excretion inhibitor such as probenecid,
The preparation of formulations containing a compound of formula (I) A (active ingredient) such as 3'-azido-3'-deoxythymidine is described.

Example 16 Tablet weight (mg) Active ingredient 100 Glucuronidation / renal excretion inhibitor 200 Lactose 105 Starch 50 Polyvinyl prolidinone 20 Magnesium stearate 10 Total weight 485 The active compound is mixed with lactose and starch, and polyvinyl. Wet granulate with a solution of pyrrolidinone. The granules are dried, sieved and mixed with magnesium stearate and then compressed into tablet form.

Example 17 Capsule weight (mg) Active ingredient 100 Glucuronidation / renal excretion inhibitor 100 Lactose 100 Sodium starch glycolate 10 Polyvinylpyrrolidinone 10 Magnesium stearate 3 Total weight 323 Active compound as lactose and sodium starch glycolate Mix and wet granulate with a solution of polyvinylpyrrolidinone. The granules are dried, sieved and mixed with magnesium stearate and filled into hard gelatin capsules.

Example 18 Intravenous injection amount (mg) (1) Active ingredient 200 Glucuronidation / renal excretion inhibitor 300 Glycerol 200 Sodium hydroxide solution Appropriate amount pH 7.2-7.5 Water for injection Appropriate amount 10 ml Water for injection a little Add to. The two active compounds are added and the pH is adjusted to 7. with sodium hydroxide solution.
Adjust from 0 to 7.5. The solution is made up to volume with additional water for injection. Under aseptic conditions, the solution is sterilized by filtration, filled into sterile ampoules and the ampoules are sealed.

Amount (mg) (2) Active ingredient 100 Glucuronidation / renal excretion inhibitor 150 Mannitol 125 Sodium hydroxide solution Appropriate pH 8.0 to 9.0 Water for injection Appropriate amount 2.5 ml Active compound and mannitol in 1 part water for injection Melt. The pH is adjusted to 8.0-9.0 with sodium hydroxide solution and made up to volume with additional water for injection. Under sterile conditions, sterilize the solution by filtration and fill sterile vials,
Then the water is removed by freeze-drying. The vial is sealed under a nitrogen atmosphere and closed with a sterile stopper and metal collar.

Animal Formulations (Examples 19-22) Example 19 Active ingredient per tablet for small animals 120.0 mg Corn starch 20.0 mg Microcrystalline cellulose 100.0 mg Magnesium stearate 1.5 mg Active ingredient, microcrystalline cellulose and corn starch are mixed together . Sufficient starch solution is added with continuous stirring to obtain a moistened mass, which is passed through a sieve,
Obtain granules. Sieve magnesium stearate. Tablets are obtained by direct compression of the granules.

Example 20 Medicated granules in feed Weight (g) Active ingredient 6.0 Povidone 1.0 Lactose 93.0 Hydroalcoholic mixture Appropriate The active ingredient is mixed with lactose. To this is added hydroalcohol containing dissolved povidone. Sufficient aqueous alcohol is added to obtain a moistened mass, which is passed through a sieve to obtain granules, which are subsequently dried.

Example 21 Oral paste Weight (g) Active ingredient 24 Xanthan gum 0.5 Methyl hydroxybenzoate 0.1 Polysorbate 80 0.1 Purified water qs 100.0 ml Polysorbate 80 and methyl hydroxybenzoate are dissolved in a large amount of water. Xanthan gum is added and dispersed and swelled. The active ingredient is added and dispersed and diluted to volume.

Example 22 Ointment weight (g) Active ingredient 12 White soft paraffin 88.0 White soft paraffin is melted at 60 ° C. The active ingredient is added and dispersed, cooled and loaded into a collapsible metal tube.

Example 23 3'-azido-3 ', 5'-dideoxy-5'-[(N, N
-Dimethylthiocarbamoyl) thiol] thymidine (a) 3'-azido-3 'in dry pyridine (20 ml).
-To the solution of deoxythymidine was added 3'-azido- by adding methanesulfonyl chloride (2.7 ml).
5'of 3'-deoxythymidine (3.0 g, 11.2 mmol)
-The hydroxyl groups were mesylated. The reaction was allowed to proceed at 5 ° C for 1 hour and then poured into ice water. The precipitate was collected by filtration. Reaction of 3'-azido-3'-deoxy-5'-mesylthymidine obtained from the first step with potassium carbonate (0.78 g, 5.6 mmol) in DMF (75 ml) gave the desired product. Was given. The reaction mixture was placed on an oil bath,
It was heated at 80 ° C. for 6 hours and then poured into ice water. The product was extracted from water with ethyl acetate. Remove the solvent in vacuo,
Then, the resulting oil was added to silica gel with CHCl ₃ : MeOH (9: 1 v /
Flash chromatography was performed by elution in v).
The product was obtained in low yield. Melting point = 184-186 ° C.

(B) Sodium salt of dimethyldithiocarbamic acid dihydrate (0.642 g, 3.58 mmol) and 1N in MeOH.
Tetrabutylammonium hydroxide solution 3.58 ml
Was added to 25 ml of DMF. Boil the solution, add water and MeOH.
Was removed. After cooling, 2,5'-O dissolved in 15 ml DMF
Anhydro-3'-azido-3'-deoxythymidine (0.85 g, 3.4 mmol) was added. Reaction mixture at 55 ° C
Heated overnight in an oil bath. The reaction mixture was poured into ice water and the precipitate was removed by filtration. The product was extracted from the filtrate with ethyl acetate. The ethyl acetate was removed in vacuo and the resulting oil was washed with silica gel on CHCl ₃ : MeOH (95: 5 v /
Purified by flash chromatography by elution in v). Chromatography required a second time on silica gel. The second elution was CHCl ₃ : MeOH (98: 2 v /
v) Final purification was carried out on C ₁₈ with water: methanol (3:
This was performed by reverse layer chromatography eluting in 7). The yield was 2.5%.

Example 24 3'-Azido-3'-deoxy-5'-O-acetyl-
4-thiothymidine 3'-azido-3'-deoxy-5'-O-acetyl-4- (1,2,4-triazole) thymidine [phosphorus (Lin)
J.Med.Chem., 26, 1691 (198).
3)] (1.41 g, 3.9 mmol) was dissolved in 100 ml of acetone and 30 ml of water, and then 0.39 g of NaSH.xH ₂ O [Sun (Sun
g), J. Chem. Sos. Chem.
m.Comm.), 522 , (1982)]. The mixture was stirred for 30 minutes, the volume reduced to 1/2 and extracted with 200 ml CHCl ₃ . CHCl ₃ was washed with 100 ml water and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the resulting oil was placed on a silica gel pad (6.5 x 3 cm), followed by CHCl.
_It was eluted with ₃ 750 ml. The solvent was removed in vacuo to produce a yellow oil which was recrystallized from i-PrOH to yield 0.64g (1.9 mmol; 48.7%); mp = 75-78 ° C.

Example 25 3'-Azido-3'-deoxy-4-thiothymidine 3'-Azido-3'-deoxy-5'-O-acetyl-4-thiothymidine (0.25 g; 0.76 mmol, Example 21)
It was dissolved in a mixture of 5 ml dioxane and 5 ml concentrated NH ₄ OH and stirred for 18 hours. The solvent was removed in vacuo and the residue applied to a silica gel column, subsequently had to CHCl ₃ / EtOAc
Elution with (3: 1 v / v). Appropriate fractions were combined and the solvent was removed in vacuo to give a yellow oil which was dissolved in Et ₂ O and concentrated to form crystals; 0.16 g (0.56 mmol; 7).
4%); melting point = 116-118 ° C.

Example 26 3-N-Methyl-3'-azido-3'-deoxythymidine 3'Azido-3'-deoxythymidine (0.5 g; 1.9 mmol) and N, N-dimethylformamide dimethyl acetal [Zemlicka, Col・ Chetuk Chem.Comm., 35 , 3572 (197)
2)] (0.9 ml; 7.5 mmol) was refluxed in 20 ml CHCl ₃ for 48 hours. The solvent was removed in vacuo and the material placed on a silica column. Elution with EtOAc / CHCl ₃ (1: 1 v / v) produced pure material as a viscous oil; 0.26 g (0.9 mmol, 47%).

Example 27 3'-Azido-3'-deoxy-2-thiothymidine The synthesis of 3'-azido-2-thiothymidine is 2,3'-
O-anhydro-5'-tritylthymidine [JJFox, J.Org.Chem.], 2
8 , 936 (1963)].

2,3'-O-anhydro-5'-tritylthymidine (1
0.5 g, 22.4 mmol) was added to a solution of sodium (0.52 g, 22.4 mmol) in dry ethanol (1.2),
The reaction mixture was then refluxed for 6 hours. The reaction mixture was cooled and neutralized with 1N HCl. Remove the solvent in vacuo,
Then, the produced oil was loaded on silica gel with CHCl ₃ : MeOH (94: 6 v /
Purified by flash chromatography by elution in v). 1- (2'-deoxy-5'-trityl-D
A 30% yield of -lyxofuranosyl) -2-ethoxythymine was obtained. 2-Ethoxythymidine derivative (3.5 g, 16.8
DMF35 containing 2.2 ml triethylamine
dissolved in ml. The cold solution was saturated with H ₂ S. The reaction mixture was placed in a steel bomb and heated to 95 ° C. 27 hours later,
TLC showed no starting material remained. The reaction mixture was evacuated with N ₂ for several hours and poured into ice water. The product was collected by filtration and on silica gel CHCl ₃ / MeOH
Purified by flash chromatography by elution at (97: 3 v / v). Of 1- (2'-deoxy-5'-trityl-β-D-lyxofuranosyl) -2-thiothymine
A 37% yield was obtained. UV _max 277 nm at pH 1 and pH 1
The 241 nm in 1 indicated the formation of 2-thiothymidine.

The 3'-hydroxyl group of the thiothymidine derivative was mesylated as follows: methanesulfonyl chloride (665 m
l, 3.5 eq) at 5 ° C with dry pyridine (15 ml)
1- (2'-deoxy-5'-trityl-β- D-
To a solution of lyxofuranosyl) -2-thiothymidine (1.25 g) was added once every four hours 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 on silica gel,
Performed by flash chromatography with elution with ethyl acetate: hexane (1: 1 v / v). The yield was 50%.

Lithium azide (0.3 g, 6 mmol) in dry DMF 20 ml
And 1- (2'-deoxy-3'-mesyl-5'-trityl-β- D -lyxofuranosyl) -2-
Thiothymine (0.72 g, 1.2 mmol) was added. The DMF solution 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 by flash chromatography on silica gel, eluting with CHCl ₃ : MeOH (98: 2 v / v). The yield was 78%. The 2100 cm ^-1 band in the IR indicated the presence of alkyl azide. UV confirmed the presence of 2-thiothymidine.

The final product was 3'-azido- in 80% acetic acid (5 ml).
The 5'-hydroxyl group of 3'-deoxy-2-thio-5'-tritylthymidine (0.1g) was prepared by deprotecting on a steam bath for 45 minutes. 3'-azido-3'-
Deoxy-2-thiothymidine (0.021 g) was obtained in 37% yield by chromatography on silica gel by elution with CHCl ₃ : MeOH (96: 4 v / v).

Example 28 3'-Azido-3'-deoxy-2-ethoxythymidine 3'-Azido-3'-deoxy-5'-mesylthymidine (2.6 g, 7.5 mmol) in dry ethanol (25 ml).
With 2 equivalents of potassium carbonate (1.08 g, 7.5 mmol) and 5
By refluxing for 3 hours, 3'-azido-3'-deoxy-2-ethoxythymidine was produced. Neutralize the solution,
Then it was taken as oil in a vacuum. Oil on silica gel,
Purified by flash chromatography by elution with ethyl acetate: methanol. The desired product was isolated in 39% yield; mp = 98-100 ° C.

Example 29 3'-Azido-3'-deoxy-2-methoxythymidine 3'-Azido-3'-deoxy-2-methoxythymidine was added to 3'-azido-3'-deoxy-5'-mesylthymidine (1.6 g). , 4.6 mmol) by the method of Example 25. The yield was 42%; melting point = 47-51 ° C.

Example 30 3'-Azido-2 ', 3'-dideoxy-5-methylisocytidine 2,5'-O-anhydro-3'-azido-3'-deoxythymidine (0.35 g; 1.4 mmol) was added with ammonia. It was dissolved in 15 ml of presaturated MeOH and placed in a cylinder at 77 ° C. (oil bath) for 48 hours [Skaric and Matulic-Adamic, Helv.Chim.Acta, 63. , 2179 (1980)].
The reaction was incomplete by TLC (6: 1 v / v CHCl ₃ / MeOH). The solvent was removed in vacuo and the resulting oil was placed on a silica gel column and subsequently eluted with CHCl ₃ / MeOH (6: 1 v / v). Appropriate fractions were combined and combined to give 0.14 g (0.53 g) of the title compound.
Mmol; 38%) formed; melting point = 107-108 ° C.

Example 31 3'-azido-5-chloro-2 ', 3'-dideoxyuridine 3'-azido-2', 3'-dideoxyuridine (0.25
g; 1 mmol) 2 ml of dry dimethylacetamide (DMAC)
2 ml of 0.5M HCl in DMAC.
Was added. m-Chloroperbenzoic acid (0.227 g; 1.6 mmol) was added in 10 portions or in 2 portions and the mixture was allowed to come to room temperature. After 2 hours, 4 ml of water was added and the solution was filtered. The aqueous DMAC solution was extracted with Et ₂ O (3 x 3 ml) and Et ₂ O was evaporated in vacuo to an oil which was placed on a silica gel column. Elution with CHCl ₃ : MeOH (15: 1 v / v), combination of appropriate fractions and evaporation in vacuo produced an oil which crystallized from Et ₂ O to give 58.5 mg (0.2 mmol, 20 %) Was obtained; melting point = 169-170 ° C.

UV (nm): at pH 1 λ _max = 276 (ε = 7400) λ _min = 2
39 (ε = 500); at pH 13 λ _max = 274 (ε = 6400),
λ _min = 249 (ε = 3800) H ¹ NMR (DMSD-d ₆ ) δ8.29 (S, 1H, H6), 6.04 (t, 1
H, H1 ', J = 5.5Hz), 5.49-5.29 (m, 1H, 5'-O
H), 4.44 to 4.20 (m, 1H, H3 '), 3.88 to 3.71 (m, 1
H, H4 '), 3.71 to 3.53 (m, 2H, H5'), 2.61 to 2.31
(M, 2H, H2 ') ; Elemental _{analysis: C 9 H 10 N 5 O} 4 Calculated Cl: C37.58 H3.50 N24.35 Cl12.32 measurements: C37.67 H3.54 N24.39 Cl12.40 Example 32 3'-Azido-5-bromo-2 ', 3'-dideoxyuridine 3'-Azido-5-bromo-2', 3'-dideoxyuridine was prepared from known 3'-azido-2 ', 3'-dideoxyuridine [TAKrenilsky et al., J. Med. Chem., 26 , 891 (1983)] (0.827)
g, 3.3 mmol), the 5'-hydroxyl group was first acylated with acetic anhydride (15 ml), and then the 5-position was acetic acid (0.5 m).
l) and bromine (0.566g) by bromination. 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 methanol ammonia to remove the acetyl group. The desired product was isolated by chromatography on silica gel, eluting with CHCl ₃ : MeOH (95: 5 v / v). The yield was 32%; melting point = 148-149 ° C.

Example 33 3'-Azido-2 ', 3'-dideoxy-5-iodouridine 3'-Azido-2', 3'-dideoxy-5-iodouridine was added to 2 ', 3'-dideoxy-5-iodouridine (10 g, 28 mmol) from the literature [Krenitzky (TAK
renitsky) et al., J.Med.Chem., 2
6 , 891 (1983)], melting point = 126-130 ° C.

Example 34 3'-Azido-2 ', 3'-dideoxy-5-trifluoromethyluridine 3'-Azido-2', 3'-dideoxy-5-trifluoromethyluridine was prepared by the following four step reaction. .

The 5'-hydroxyl group of 2 ', 3'-dideoxy-5-trifluoromethyluridine (5.0 g, 16.9 mmol) was added to a suspension of dichloromethane (1.4 ml), pyridine (70 ml) and 3A molecular sieve (55 g). Tritylated by addition of triphenylmethyl chloride (5.65 g, 20.3 mmol) to the starting material in. The reaction mixture was stirred at room temperature for 4 days. After filtration and evaporation in vacuo, the oily product was chromatographed on silica gel, eluting with CH ₂ Cl ₂ : MeOH (95: 5 v / v). The product fractions were combined and the solvent removed in vacuo. The oil formed was triturated with water and the solid formed was collected by filtration. The 3'-hydroxyl group was chlorinated by dissolving 5'-protected uridine (3.0 g) in dimethylacetamide (30 ml) containing triphenylphosphine (3.27 g) and adding carbon tetrachloride (51 ml). did. The reaction mixture was stirred at room temperature overnight. 1 ml of methanol was added. The reaction mixture was taken as an oil and on silica gel CH ₂ Cl ₂ : EtOAc (9: 1 v /
Chromatography by elution in v). The desired product was collected as an oil. Oil, 1- (3'-chloro-2'-
Deoxy-5'-trityl-threo-β- D -ribofuranosyl) -5-trifluoromethyluracil was prepared by the method of V. Kohli et al. [Tetrahedron Letters (T
etrahedron Letters), 21 , 2683, 1980], and dissolved in nitromethane (80 ml), and nitromethane (80 ml).
The reaction mixture was deprotected by adding zinc bromide (4.45 g) dissolved in (ml) and stirred at room temperature overnight. Further zinc bromide (3.0 g) was added the next day and the reaction mixture was left at room temperature overnight. While gently heating, add zinc bromide (3.7
The final addition of g) 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 on silica gel CH ₂ Cl ₂ : MeOH.
Chromatography by elution at (95: 5 v / v). The final product is 1- (3'-chloro-2'-deoxy-β.
-D -ribofuranosyl) -5-trifluoromethyluracil (0.48 g, 1.53 mmol) was obtained by treatment with lithium azide (0.19 g, 3.8 mmol) in dimethylacetamide (4.8 ml). The reaction mixture, 90
Heated at 0 ° C for 4 hours. The reaction mixture was taken as an oil and chromatographed on silica gel by elution with CHCl ₃ : MeOH (95: 5 v / v). Chromatography required a second time. CH ₂ Cl ₂ : MeOH (97: 3 v / v) on silica gel
Elution with produced a substantially pure product. Crystallization from toluene led to pure product in 10% yield.

Example 35 3'-azido-2 ', 3'-dideoxycytidine 3'-azido-2', 3'-dideoxycytidine was prepared by
3'-azido-2 ', 3'-dideoxyuridine (2.2 g,
7.9 mmol), the method of Krenitsky (TAKrenitsky) [J. Med. Chem., 26 , 891.
(1983)] as an HCl salt. 40% yield
Melting point = 174.5-176.5 ° C.

Example 36 3'-Azido-2 ', 3'-dideoxy-5-methylcytidine 3'-Azido-2', 3'-dideoxy-5-methylcytidine was converted into 3'-azido-3'-deoxythymidine (0 .
8 g, 3.0 mmol) was prepared by the method of Example 35.
The yield was 19%.

Example 37 Threo 3'-azido-2 ', 3'-dideoxycytidine The synthesis of threo 3'-azido-2', 3'-dideoxycytidine was carried out in 4 steps from 2'-deoxyuridine.

The 5'-hydroxyl group of 2'-deoxyuridine is synthesized by Synthetic Procedures in Numeric Acid Chemistry.
cleic Acid Chemistry), 1 , 321, (1968).

Threo 3'-azido-2 ', 3'-dideoxy-5'-
Trityl uridine was prepared by adding 2'-deoxy-5'-trityl uridine (5.0 g, 10.6 mmol) to triphenylphosphine (3.07 g, 11.7 mmol, 1.1 equivalent) and carbon tetrabromide (3.88 g, 11.7 mmol, 1.1). Equivalent) and DMF (80m
It was prepared by treatment with lithium azide in l) (5.21 g, 106 mmol, 10 eq). Carbon tetrabromide was added last. The reaction proceeded overnight at room temperature. Methanol (5 ml) was added. The solution was taken in vacuo as an oil and flash chromatographed on silica gel by elution with ethyl acetate. Deprotection of the 5'-hydroxyl group was accomplished by heating in 80% acetic acid for 20 minutes on a steam bath. Upon cooling, trityl carbinol precipitated and was filtered off. The filtrate was dried and triturated in ethyl ether. The product, threo 3'-azido-
2 ', 3'-dideoxyuridine was used without further purification. The final product, threo 3'- as the HCl salt
Azido-2 ', 3'-dideoxycytidine is exactly the same method used to prepare the erythro isomer from the uridine homolog [TAKrenitsky et al., J. Med. Chem. 26 , 891, (1983)]. The yield was 0.021 g, 7%.

Example 38 9- (3'-azido-2 ', 3'-dideoxy-α-D-
Ribofuranosyl) adenine 9- (3'-azido-2 ', 3'-dideoxy-α- D
- ribofuranosyl) adenine, N ₆ - octanoyl adenine (2.0 g, 7.7 mmol) and 3'-azido-3 '
From deoxythymidine (1.13 g, 4.2 mmol), M. Imazawa and Ecstein (F. Eckstein)
The method described by J.Org.Ch
em.), 43 , 3044, (1978)] in two steps; melting point = 120-122 ° C.

_{UV pH1λ max 258nmλ min 230nm pH13λ max} 260nmλ min 229nm Elemental _{analysis: C 10 H 12 N 8 O} 2 Calculated: C43.48 H4.38 N40.56 measurements: C43.28 H4.45 N40.38 Example 39 9- (3'-azido-2 ', 3'-dideoxy-β-D-
Ribofuranosyl) adenine 9- (3'-azido-2 ', 3'-dideoxy-β- D
- ribofuranosyl) adenine, N ₆ - octanoyl adenine (2.0 g, 7.7 mmol) and 3'-azido-3 '
From deoxythymidine (1.13 g, 4.2 mmol), M. Imazawa and Ecstein (F. Eckstein)
The method described by J.Org.Ch
em.), 43 , 3044 (1978)].
Melting point = 184-185 ° C.

_{UV pH1λ max 257nmλ min 230nm pH13λ max} 260nmλ min 228nm Elemental _{analysis: C 10 H 12 N 8 O} 2 Calculated: C43.48 H4.38 N40.56 measurements: C43.33 H4.45 N40.41 Example 40 5'-acetyl-3'-azido-3-benzoyl-3 '
-Deoxythymidine 5'-acetyl-3'-azido-3'-deoxythymidine (0.75 g, 2.4 mmol) was dissolved in pyridine (5 ml) and benzoyl chloride (1.4 ml, 12 mmol, 5 eq) was added at room temperature. It was The reaction mixture was stirred overnight and then poured into ice water (250 ml). PH of aqueous solution is 1
Adjusted to. The product was extracted with chloroform, the organic layer was washed with water, dried over MgSO _4, and filtered. Chloroform was removed and the oily product was flash chromatographed on silica gel, eluting with chloroform. The product was collected as an oil.

H ¹ NMR (DMSO-d ₆ ): δ8.04 to 7.50 (m, 6H; 3N-benzoyl and 6H), δ6.12 (dd, 1H, J _{1 ′, 2a ′} = 5.6H.
z, J _{1 ', 2b'} = 6.7Hz, 1'H), δ4.55 to 3.96
(M, 4H; 3'H, 4'H, 5'H), δ2.62 to 2.38
(M, 2H, 2'H), δ2.07 (s, 3H, 5'acetyl CH
₃ ), δ1.90 (d, 3H, J _5,6 = 1.0Hz, 5CH ₃ ) Elemental analysis value: C ₁₉ H ₁₉ N ₅ O ₆ Calculated value: C55.20 H4.63 N16.94 Measured value: C55.29 H4.64 N16.93 Example 41 Threo-3'-azido-5-bromo-2 ', 3'-dideoxyuridine Threo 3'-azido-5-bromo-2', 3'-dideoxyuridine Prepared from 2'-deoxyuridine in a 5 step reaction.

The protection of the 5'-hydroxyl group of 2'-deoxyuridine with a triphenylmethyl group was carried out in the usual way. 3'-
The hydroxyl was mesylated. 2'-deoxy-3'-
Mesyl-5'-trityluridine (22 g, 50 mmol)
Was added to a solution of sodium azide (7.84 g, 120 mmol, 3 eq) in dimethylformamide (380 ml) at 80 ° C to introduce the 3'-azide group in the correct stereochemistry. The reaction lasted 35 hours. Ice water (2)
And the precipitate was collected by filtration. The product was chromatographed on silica gel with chloroform: methanol (1: 1 v /
Chromatography eluting in v) isolated in 51% yield. The 5'-hydroxyl position was deprotected with 80% acetic acid on a steam bath for 25 minutes. After cooling, trityl carbinol was filtered off. The filtrate was concentrated in vacuo to a thick oil. The product was chromatographed on silica gel with chloroform: methanol (8
5:15 v / v) to isolate by flash chromatography eluting. Threo-3'-azido-2 ', 3'-dideoxyuridine at the 5-position was replaced with erythro-3'-azido-
Bromination was done in exactly the same manner as outlined for the bromination of 2 ', 3'-dideoxyuridine.

UV pH1 λ _max 280, ε = 9400, λ _min 244 ε = 2600 pH13 λ _max 276, ε = 6700, λ _min 251 ε = 3700 H ¹ NMR (DMSO-d ₆ ): δ 11.86 (s, 1H, 3-NH), δ8.
02 (s, 1H, 6H), δ5.99 (dd, 1H, J _{1 ', 2a'} = 3.0
Hz; J _{1 ', 2b'} = 7.5Hz, 1'H), δ5.1 (t, 1H, J ₅ ,
CH ₂ = 5'OH = 5.4Hz, 5'OH), δ4.49 (m, 1H, 3 '
H), δ4.05 (m, 1H, 4'H), δ3.71 (m, 2H,
5'H), δ2.72 (m, 1H, 2b '), δ2.18 (m, 1H,
2a ') Elemental _{analysis: C 9 H 10 BrN 5 O} 4 -0.25H 2 O-0.1C 2 H 4 O 2 Calculated: C32.25 H3.21 N20.44 Br23.32 measurements: C32.17 H3.21 N20.33 Br23.19 Example 42 1- (3′-azido-2 ′, 3′-dideoxy-β-D-
Erythro-pentofuranosyl) -2- (benzyloxo) -5-methyl-4- (1H) -pyrimidinone sodium (0.4 g, 17.4 mmol, 2.6 eq) reacted with dry benzyl alcohol (10 ml) at room temperature for 1 hour Let 2,5'-O-anhydro-3'-azido-3'-deoxythymidine (1.65 g, 6.6 mmol) was added. The reaction was continued for 1 hour. After pouring into ice water (250 ml), the pH 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 MgSO _4, and remove the ethyl acetate in vacuo. The resulting oil was chromatographed on silica gel, eluting first with ethyl acetate and then with ethyl acetate: methanol (9: 1 v / v). Product containing fractions were collected and the solvent removed in vacuo to produce an oil. The oil crystallized after being covered with ethyl ether;
Melting point = 125-126.5 ° C.

UV pH1 unstable pH13 λ _max 256, ε = 10700, λ _min 240, ε = 8900 H ¹ NMR (DMSO-d ₆ ): δ7.8 (d, 1H, J ₆₅ = 1.2Hz, 6
H), δ7.49 to 7.38 (m, 5H, 2-phenyl), δ6.08
(Dd, 1H, J _{1 ', 2a'} = 5.0Hz; J _{1 ', 2b'} = 7.0Hz,
1'H), δ5.37 (s, 2H, 2CH ₂ ), δ5.25 (t, 1H,
_{J 5 'CH 2 5'OH = 5.4Hz} , 5'OH), δ4.36~4.32
(M, 1H, 3'H), δ3.85-3.81 (m, 1H, 4 '
H), δ3.7 to 3.58 (m, 2H, 5'H), δ2.53 to 2.34
(M, 2H, 2'H), δ1.82 (d, 3H, J _5.6 = 1.0Hz,
5CH ₃₎ Elemental _{analysis: C 17 H 19 N 5 O} 4 Calculated: C57.14 H5.36 N19.60 measurements: C57.02 H5.43 N19.53 Example 43 1- (3'-azido - 2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -2-ethoxy-5-methyl-4- (1H) -pyrimidinone Threo 3'-azido-5'-O-mesylthymidine (1.
08G, 3.13 mmol) was dissolved [a threo-3'-azidothymidine preparation] to EtOH100ml, and NaHCO ₃ (0.26
g, 3.13 mmol) at reflux for 18 hours. The reaction mixture was cooled and filtered. The solvent was removed in vacuo and the residue placed on a silica gel column, followed by
9: 1 (v / v) and eluted with CHCl ₃ / MeOH. Combine the appropriate fractions,
The solvent was removed in vacuo to give 0.7 g (2.4 mmol, 75.7
%) Produced; melting point = 120-122 ° C.

At UV (nm) pH 1, λ _max = 260 (ε = 9300), λ _min ＝
237 (ε = 5500), λ _shoulder = 221 (ε = 7500); pH13
At λ _max = 256 (ε = 10000), λ _min = 240 (ε = 7
700).

H ¹ NMR (DMSO-d ₆ ): δ7.58 (s, 1H, H6), δ6.0 (d
d, 1H, H1 ', J = 2.9, 4.56Hz), δ5.06 (t, 1H,
5'OH, J = 4.91Hz), δ4.51 to 4.47 (m, 1H, H
3 '), δ 4.34 (q, 2H, -OCH _2- , J = 7.14Hz), δ
4.10 ~ 4.05 (m, 1H, H4 '), δ3.73 (t, 2H, H5',
J = 5.62Hz), δ2.82-2.73 (m, 1H, H2b '), δ2.2
1-2.14 (m, 1H, H2'a), δ1.82 (s, 3H, 5C
_{H 3), δ1.31 (t,} 3H, -CH 2 -CH 3, J = 6.65Hz).

Elemental _{analysis: C 12 H 17 N 5 O} 4 Calculated: C48.81 H5.80 N23.72 measurements: C48.59 H5.86 N23.64 Example 44 threo 3'-azido-2 ', 3' -Dideoxy-4-thiothymidine Threo 3'-azido-5'-O-trityl-3'-deoxy-4- (1,2,4-triazolo) thymidine (1.25 g,
2.2 mmol) [W.Sung, New Kratsk.
Nucleic Acids Research, (198
1), 9 , 6139] was dissolved in 100 ml of acetone and 30 ml of water and then treated with 0.22 g of NaSH. × H ₂ O. The mixture was stirred for 3 hours. Reduce the capacity by half,
Then, it was extracted with 300 ml of CHCl ₃ . CHCl ₃ was washed with 50 ml water, dried over Na ₂ SO ₄ and removed in vacuo to produce an oil. By dissolving this oil in 100 ml of 80% HOAc,
The 5'-O-trityl group was removed. The solution was heated on a steam bath for 2 hours, then cooled, diluted with 100 ml of water and filtered. The solvent was removed in vacuo and the oil placed on a silica gel column. Elution with 20: 1 (v / v) CHCl ₃ / MeOH, taking the appropriate fractions, followed by removal of the solvent in vacuo to 0.
18 g (0.62 mmol, 28%) formed; melting point = 65-67
° C.

UV (nm): at pH 1 λ _max = 337 (ε = 20700) λ _min ＝
280 (ε = 1200), λ _shoulder = 238 (ε = 3400); at pH13 λ _max = 320 (ε = 18400), λ _min = 257
(Ε = 1700); H ¹ NMR (DMSO-d ₆ ) δ7.63 (s, 1H, H1 ′, J = 2.93,
4.89Hz), δ5.06 (s, 1H, 5'OH), δ4.50-4.46
(M, 1H, H3 '), δ 4.10 to 4.04 (m, 1H, H4'), δ
3.73 (d, 2H, H5 ', J = 5.61Hz), δ 2.78 to 2.68
(M, 1H, H2b ′), δ2.20 to 2.14 (m, 1H, H2 ′
a), δ2.00 (s, 3H , 5CH 3) Elemental _{analysis: C 10 H 13 N 5 O} 3 S0.1C 2 H 6 O-0.25H 2 O Calculated: C41.90 H4.86 N23. 95 S10.97 Measured value: C41.99 H4.73 N23.88 S10.91 Example 45 4-amino-3′-azido-5-bromo-2 ′, 3′-dideoxyuridine 3′-azide-2 ′, The 3'-dideoxyuridine was prepared according to the method of Visser [Synthetic Procedures in Nucleic Acid Chemistry (Sy
nthetic Procedures in Nucleic Acid Chemistry), 1
Vol., Page 410], acylation and bromination,
5'-acetyl-3'-azido-5-bromo-2 ', 3'
-Dideoxyuridine was obtained. This material was treated with 5 equivalents of 1,2,4-triazole and 2 equivalents of 4 in dry pyridine.
5'-acetyl-3'-azido-5-bromo-4- (1,2,4-triazolyl) -2 ', 3'-dideoxyuridine by reaction with -chlorophenyldichlorophosphate for 7 days at room temperature. Was obtained as a yellow oil in moderate yield. Treatment with ammonia-saturated methanol at room temperature was at 0 ° C. for 18 hours, after recrystallizing ethyl acetate and filtering the resulting crystals, 4-amino-3′-azido-5-bromo-2 ′, 3′-dideoxyuridine. 173 mg (0.5 mmol,
6.3%); melting point = 162-165 ° C. (decomposition).

UV (nm): At pH 1, λ _max = 300, 215 (ε = 10700, 12
100), λ _min = 253 (ε = 1500); at pH13 λ _max = 288 (ε = 7300), λ _min = 260 (ε
= 3900) H ¹ NMR (DMSO-d ₆ ) δ8.3 (s, 1H, H6), δ7.85 (broad s, 1H, 4-NH ₂ ), δ7.05 (broad s, 1H, 4)
_{-NH 2), δ6.0 (t,} 1H, H1 ', J = 5.94Hz), δ5.33
(T, 1H, 5'-OH, J = 5.01Hz), δ 4.4 to 4.3 (m,
1H, H3 '), δ3.9-3.5 (m, 3H, H4', H5 '), δ2.
31 (t, 2H, H2 ', J = 6.27Hz).

Elemental analysis value: Calculated as C ₉ H ₁₁ N ₆ O ₃ Br: C32.64 H3.35 N25.38 Br24.13 Measurement value: C32.52 H3.41 N25.32 Br24.04 Example 46 3′-azide -5-Bromovinyl-2 ', 3'-dideoxyuridine 5-Bromovinyl-2'-deoxyuridine (BVD
U) by the method of Jones et al. [Tetrahedron Letters, 45 , 4415 (197
9)] was used to synthesize in similar yield. BVDU was tritylated and mesylated by the method of Horwitz et al. [J.Org.Chem., 31 , 205 (1966)]. The product was treated with an equimolar amount of sodium bicarbonate in refluxing methanol to give 3 ', 2-O.
-Anhydro-5-bromovinyl-2'-deoxyuridine was produced. The product was treated with 3 equivalents of lithium azide in 1% water / dimethylformamide at 130 ° C. Silica gel chromatograph the crude material,
Subsequent suitable fractions were combined and evaporated to yield 3'-azido-5-bromovinyl-2 ', 3'-dideoxyuridine as a golden oil; UV (nm); λ _{max at} pH 1 = 292, 247, λ _min = 270, 2
38; at pH 13, λ _max = 253, λ _min = 238, λ _sh = 284; H ¹ NMR (DMSO-d ₆ ) δ8.06 (s, 1H, H ₆ ), δ7.25
(D, 1H, -CH = CHBr, J = 13.4Hz), δ6.85 (d, 1
H, = CHBr, J = 13.7Hz), δ6.07 (t, 1H, H _{1 '} ,
J = 6.3Hz), δ5.30 (broad s, 1H, 5'-OH),
δ4.42 (q, 1H, H _{3 ′} , J = 6.3, 6.1Hz), δ3.86〜
3.82 (m, 1H, H _{4 '} ), δ 3.68, 3.59 (m, 2H, H
_{5 '} ), δ 2.47 to 2.32 (m, 2H, H _2' ).

Elemental analysis value: Calculated as C ₁₁ H ₁₂ N ₅ O ₄ Br: C36.89 H3.38 N19.55 Measured value: C36,86 H3.41 N19.51 Example 47 Threo 3′-azido-5-chloro- 2 ', 3'-dideoxyuridine The title compound is 3'-azido-5-chloro-2', 3 '.
Prepared in a similar manner to dideoxyuridine (Example 31) to yield 0.15 g (0.5 mmol, 25%); melting point = 65.
° C.

UV (nm); at pH 1, λ _max = 278, 212 (ε = 8900),
λ _min = 240 (ε = 1600); at pH13 λ _max = 275 (ε = 6600), λ _min = 248 (ε
^{= 3300); H 1 NMR (} DMSO-d 6) δ11.89 (s, 1H, NH), δ7.94
(S, 1H, H ₆ ), δ6.00 (dd, 1H, H _{1 ′} , J = 2.93,
4.64Hz), δ5.1 (t, 1H, 5'OH, J = 5.1Hz), δ4.
50 ~ 4.46 (m, 1H, H _{3 '} ), δ 4.08 ~ 4.03 (m, 1H,
H _{4 '} ), δ 3.71 (t, 2H, H _5' , J = 5.32Hz), δ
_{2.77~2.67 (m, 1H, H 2} 'b), δ2.23~2.16 (m,
_{1H, H} 2 'a).

Elemental _{analysis: C 9 H 10 N 5 O} 4 Cl0.1H 2 O-0.1C 4 H 8 O 2 Calculated: C37.85 H3.72 N23.48 Cl11.89 measurements: C37.94 H3.91 N23.23 Cl11.86 Example 48 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Erythro-pentofuranosyl) -5-methyl-2- (pentyloxo) -4- (1H) -pyrimidinone 1- (3'-azido-2 ', 3'-dideoxy-β- D
-Erythro-pentofuranosyl) -5-methyl-2-
(Pentyloxo) -4- (1H) -pyrimidinone is replaced with 1
-(3'-Azido-2 ', 3'-dideoxy-β- D -erythro-pentofuranosyl) -2- (benzyloxo)
Prepared by the method used to prepare -5-methyl-4- (1H) pyrimidinone (Example 42). The final purification is
By _C18 , eluting with water: methanol (3: 7) by HPLC. The solvent was evaporated and the product collected as an oil.

UV pH1 λ _max 258 nm ε = 9400, λ _min 232 nm ε = 5900 pH13 λ _max 256 nm ε = 10600, λ _min 239 nm ε8200 NMR was taken in DMSO-d ₆ .

NMR: δ7.81 (s, 1H, 6H), δ6.04 (t, 1H, J
_{1 ', 2' = 6.7Hz,} 1'H), δ5.28 (t, 1H, J 5 'C
_{H 2, 5'OH = 5.1Hz, 5'OH} ), δ4.43~4.37 (m, 1H, 3
H), δ 4.27 (t, 2H, J ₂ -O (1CH ₂ , 2CH ₂ ) = 6.6Hz,
2-O (CH ₂ ) ₁ ), δ3.88 to 3.84 (m, 1H, 4 ′
H), δ 3.70 to 3.50 (m, 2H, 5′CH ₂ ), δ 2.50 to 2.3
4 (m, 2H, 2'H) , δ1.80 (s, 3H, 5CH 3), δ1.7
2~1.68 (m, 2H, 2- O (CH 2) 2), δ1.38~1.30
(M, 4H, 2-O (CH ₂ ) ₃ and ₄ ), δ 0.92 to 0.87
(M, 3H, 2-O (CH 3) 5).

Elemental analysis: Calculated as C ₁₅ H ₂₃ N ₅ O ₄ 1 / 4H ₂ O: C52.70 H6.93 N20.48 Measured value: C52.63 H6.92 N20.48 Example 49 3'-azide-3 -Benzoyl-3'-deoxy-5 '
-Mesylthymidine Similar to that used in Example 40 for preparing 5'-acetyl-3'-azido-3-benzoyl-3'-deoxythymidine from 5'-acetyl-3'-azido-3'-deoxythymidine. Depending on the method, 3'-azido-3-
Benzoyl-3'-deoxy-5'-mesylthymidine was prepared from 3'-azido-3'-deoxy-5'-mesylthymidine; melting point = 86-88 ° C.

UV pH1 λ _max 259 nm ε = 21200, λ _min 230 nm ε = 6400 pH13 λ _max 265 nm ε = 9600, λ _min 248 nm ε = 8000 H ¹ NMR (DMSO-d ₆ ) δ8.00 to 7.58 (m, 6H, 6H and phenyl), δ6.15 (T, 1H, J _{1 ', 2'} = 6.1Hz, 1 '
H), δ 4.55 to 4.47 (m, 3H; 3'H and 5'CH ₂ ),
δ4.12 to 4.10 (m, 1H, 4'H), δ3.28 (s, 3H,
5'-SO ₂ CH ₃ ), δ 2.65 to 2.4 (m, 2H, 2'H), δ
1.89 (d, 3H, J _5,6 = 1.3Hz, 5CH ₃ ) Elemental analysis value: Calculated as C ₁₈ H ₁₉ N ₅ O ₇ S: C48.10 H4.26 N15.58 S7.13 Measurement value: C48 .00 H4.23 N15.39 S7.10 Example 50 Threo 3'-azido-2 ', 3'-dideoxy-5-iodouridine 5-iodo-2'-deoxyuridine was prepared by the method of Horwitz et al.・ Chem (J.Org.Chem.),
31, (1966), 205], followed by tritylation and mesylation. The product was heated with 3 equivalents of lithium azide in anhydrous dimethylformamide at 74 ° C for 48 hours. 2
Silica gel chromatography of the reaction mixture with 0: 1 CHCl ₃ : MeOH (v / v), subsequent combination of suitable fractions and evaporation was performed with threo 3′-azido-2 ′, 3′-dideoxy-5-.
This gave iodo-5'-trityluridine. The 5'-hydroxyl was added to 0 with saturated zinc bromide / nitrile methane solution.
Deprotected at ° C. Silica gel chromatography of the crude product using 9: 1 CHCl ₃ / MeOH (v / v), followed by combination of suitable fractions and evaporation was performed using threo 3′-azide-
2 ', 3'-dideoxy-5-iodouridine was produced as a solid; mp = 80 ° C.

UV (nm); at pH 1 λ _min = 247; at pH 13 λ _max = 277; λ _min = 252; H ¹ NMR (DMSO-d ₆ ) δ8.37 (s, 1H, H6), δ6.00
(T, 1H, H1 ', J = 6.17Hz), δ5.4-5.3 (m, 1H,
5'OH), δ 4.4 to 4.3 (m, 1H, H3 '), δ 3.9 to 3.8
(M, 1H, H4 '), delta 3.7-3.6 (m, 2H, H5').

Elemental _{analysis: C 9 H 10 N 5 O} 4 I0.4C 4 H 8 O 2 Calculated: C30.73 H3.21 N16.90 I30.63 measurements: C30.93 H3.09 N16.61 I30. 94 Example 51 1- (5'-O-acetyl-3'-azido-2 ', 3'-
Dideoxy-β-D-erythro-pentofuranosyl)-
5-methyl-4- (1,2,4-triazol-1-yl)
2- (1H) -pyrimidinone 5′-acetyl-3′-azido-3′-deoxythymidine was added to 5 equivalents of 1,2,4-triazole and 2 equivalents of 4-chlorophenyldichlorophosphine in dry pyridine. The reaction was performed at room temperature for 10 days. Silica gel column chromatography of the crude product using 1: 1 EtOAc / hexane (v / v), followed by combination and evaporation of the appropriate fractions,
An oil was produced. Crystallization from EtOAc yielded the title compound as a solid, 2.7 g (7.5 mmol; 60%); mp = 14
3-145 ° C.

UV (nm) at pH 1 λ _max = 324, 245, 215 (ε = 930
0, 10000, 20500), λ _min = 282, 233 (ε = 2100, 820)
0); at pH 13, λ _max = 276 (ε = 6000), λ _min = 242
(Ε = 2000) H ¹ NMR (DMSO-d ₆ ) δ9.34, 8.40 (2s, 2H, triazolyl), δ8.23 (s, 1H, H6), δ6.12 (t, 1H, H1 ′,
J = 6.16Hz), δ4.48-4.17 (m, 4H, H3 ', H4', H
5 '), δ2.35 (s, 3H, 5'-acetyl), δ2.07
(S, 3H, 5CH ₃₎ Elemental _{analysis: C 14 H 16 N 8 O} 4 Calculated: C46.67 H4.48 N31.10 measurements: C46.58 H4.51 N31.02 Example 52 1- ( 3'-azido-2 ', 3'-dideoxy-β-D-
Erythro-pentofuranosyl) -4-dimethylamino-
5-Methyl-2- (1H) -pyrimidinone 5'-acetyl-3'-azido-3'-deoxy-4
-(1,2,4-Triazolyl) thymidine was dissolved in dry acetonitrile at room temperature under nitrogen atmosphere. 20 equivalents of dimethylamine were added in one portion and the reaction mixture was stirred for 30 minutes. The solvent was removed, the residue was dissolved in ammonia saturated methanol and the solution was stirred for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc. The title compound gradually precipitated from solution and was filtered to give a white solid; mp = 157-159 ° C.

UV (nm): at pH 1, λ _max = 299, 224 (ε = 14900, 79
00), λ _min = 254 (ε = 2500); at pH 13 λ _max = 287 (ε = 14000), λ _min = 243
(Ε = 6800).

H ¹ NMR (DMSO-d ₆ ) δ7.63 (s, 1H, H6), δ6.06
(T, 1H, H1 ', J = 6.53Hz), δ5.22 (t, 1H, 5'
OH, J = 5.2Hz), δ 4.37 to 4.34 (m, 1H, H3 ′), δ
3.83 ~ 3.80 (m, 1H, H4 '), δ 3.65 ~ 3.60 (m, 2H,
H5 '), δ3.06 (s, 6H, N (CH 3) 2), δ2.29~2.2
3 (m, 2H, H2 ' ), δ2.11 (s, 3H, 5-CH 3).

Elemental _{analysis: C 12 H 18 N 6 O} 3 Calculated: C48.97 H6.16 N28.56 measurements: C49.06 H6.20 N28.50 Example 53 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Erythro-pentofuranosyl) -5-methyl-2- (isopentyloxo) -4- (1H) -pyrimidinone The title compound was converted into 1- (3'-azido-2 ', 3'-dideoxy-β- D- Erythro-pentofuranosyl) -2-
Prepared by a method similar to that used to prepare (benzyloxo) -5-methyl-4 (1H) -pyrimidinone (Example 42).

UV pH1 (nm) λ _max 258 ε = 9000, λ _min 237 ε = 600
0, pH13 (nm) λ _max 255 ε = 10000, λ _min 239 ε = 8000 H ¹ NMR (DMSO-d ₆ ): δ7.79 (s, 1H, 6H), δ6.02
(T, 1H, J _{1 ', 1'} = 6.3Hz, 1'H), δ5.23
_{(T, 1H, J 5 '} OH, 5' H = 5.2Hz, 5'OH), δ4.4
~4.3 (m, 3'H and _{2-O-CH 2 -CH 2} CH (C
H ₃ ) ₂ ), δ3.9 to 3.8 (m, 1H, 4'H), δ3.7 to 3.5
(M, 2H, 5'H), δ2.5 to 2.3 (m, 2'H), δ1.
_{78 (s, 3H, 5CH 3} ), δ1.7~1.5 (m, 3H, 2-OCH 2 -
_{CH 2 -CH (CH 3) 2} ), δ0.92 and 0.89 (d, 6H, J =
_{6.3Hz, 2-O (CH 2} ) 2 CH (CH 3) 2).

Elemental _{analysis: C 15 H 23 N 5 O} 4 Calculated: C53.40 H6.87 N20.76 measurements: C53.14 H6.92 N20.62 Example 54 3-Acetyl-3'-azido-5 ' -O- (3-chlorobenzoyl) -3'-deoxythymidine 3'-azido-5'-O- (4-chlorobenzoyl) -3'-deoxythymidine (0.3 g, 0.
74 mmol) and silver cyanide (0.4 g, 3.0 mmol)
To this mixture was added excess acetyl chloride (2.6 g, 33 mmol) in several portions. TLC CHCl ₃ / MeOH 20: 1 (v /
The mixture was stirred at room temperature until the starting material disappeared (4 h) as confirmed by v). The reaction mixture is filtered,
The filtrate was then evaporated to dryness under reduced pressure. The oily residue formed is chromatographed on silica gel in chloroform /
Elution with hexan 1: 1 (v / v) followed by chloroform gave 0.21 g (64%) of the desired product as an oil.

UV (nm): at pH 1 λ _max 273 (ε = 9000), λ _min 251
(Ε = 6200); at pH 13 λ _max 266 (ε = 8800), λ
_min 247 (ε = 7000) H ¹ NMR (DMSO-d ₆ ) δ1.68 (s, 3H, 5-CH ₃ ), δ2.47
(S, 3-COCH ₃ ), δ2.3 to 2.5 (m, 2′H), δ4.1
-4.2 and 4.4-4.7 (m, 4H, 3'H, 4'H and 5'H), δ 6.1 (t, 1H, J _{1 ', 2'} = 6.3Hz, 1 '
H), δ7.5~8.0 (m, 5H , 6H and phenyl) Elemental _{analysis: C 19 H 18 N 5 O} 6 Cl-0.2CHCl 3 Calculated: C48.89 H3.89 N14.85 Cl12.03 Measurements: C49.05 H3.94 N14.79 Cl12.56 Example 55 3'-azido-5-cyano-2 ', 3'-dideoxyuridine 5-iodo-2', 3'-dideoxyuridine in pyridine 2 ', 3'-dideoxy-3', 5 'was reacted with acetic anhydride (2.1 eq.) In room temperature for 2 hours at room temperature.
-Diacetyl-5-iodouridine was obtained. Nucleoside (1 eq), potassium cyanide (1.3 eq) and potassium acetate (1.3 eq) were combined in dry DMSO and heated under nitrogen at 97 ° C for 2 hours. Remove the solvent in vacuo,
The residual oil was then applied to a silica gel column, followed by 1:
Elute with 1 CHCl ₃ / EtOAc (v / v). Appropriate fractions were collected, combined and evaporated to give 5-cyano-2 ', 3'-dideoxy-3', 5'-diacetyluridine. The compound was dissolved in ammonia-saturated methanol and at 0 ° C.
Stir for 18 hours. The solvent was removed in vacuo at room temperature to give crystals of the title compound; mp = 160-162 ° C.

UV (nm): at pH 1, λ _max = 276, 215 (ε = 13500, 11
200), λ _min = 238 (ε = 1700); at pH 13 λ _max = 276 (ε = 10100), λ _min = 240
(Ε = 3400) H ¹ NMR (DMSO-d ₆ ): δ8.81 (s, 1H, H6), δ6.00
(T, 1H, H1 ', J = 5.94Hz), δ5.3-5.21 (m, 2
H, 5'OH, 3'OH), δ 4.28-4.15 (m, 1H, H
3 '), δ3.82 to 3.77 (m, 1H, H4'), δ3.7 to 3.5
(M, 2H, H5 '), δ2.18 (t, 2H, H2', J = 5.75H
z).

Elemental _{analysis: C 10 H 11 N 3 O} 5 0.25H 2 O Calculated: C46.61 H4.50 N16.31 measurements: C46.67 H4.71 N16.54 Example 56 1- (3'-azido -2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -5-methyl-2-pentyloxy-4- (1H) -pyrimidinone 2,5'-O-anhydro-1- (3'-azido-2 ',
3'-dideoxy-β-D-threo-pentofuranosyl) thymine was added to potassium t- in pentan-1-ol.
Butoxide (0.5 eq) was added to the solution. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. The solvent was removed in vacuo and the residue applied to a silica gel column. 20: 1
Elution with CHCl ₃ / MeOH (v / v), followed by combination and evaporation of the appropriate fractions produced a clear oil which gradually formed crystals of the title compound on standing; mp = 110-111
° C.

UV (nm): at pH 1, λ _max = 255 (ε = 10200), λ _min
= 237 (ε = 6200), λ _sh = 222 (ε = 9000); at pH 13 λ _max = 251, 226 (ε = 11600 9600), λ _min = 238
(Ε = 8600) H ¹ NMR (DMSO-d ₆ ) δ7.58 (s, 1H, H6), δ5.98 (d
d, 1H, H1 ', J = 2.98, 4.88Hz), δ5.07 (t, 1H,
5'OH, J = 5.42Hz), δ4.5-4.47 (m, 1H, H
3 '), δ 4.31 to 4.25 (m, 2H, -OCH _2- ), δ 4.1 to 4.
06 (m, 1H, H4 '), δ3.73 (t, 2H, H5', J = 5.62
Hz), δ2.82 to 2.72 (m, 1H, H2 '), δ2.2 to 2.14
(M, 1H, H2 ') , δ1.82 (s, 3H, 5-CH 3), δ1.7
5 to 1.65 (m, 2H, pentyl), δ1.4 to 1.3 (m, 4H,
Pentyl), δ0.92~0.87 (m, 3H, pentyl) Elemental _{analysis: C 15 H 23 N 4 O} 4 Calculated: C53.40 H6.87 N20.76 measurements: C53.31 H6.90 N20 .74 Example 57 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -2-benzyloxy-5
-Methyl-4 (1H) -pyrimidinone The title compound was converted into 1- (3'-azido-2 ', 3'-dideoxy-β- D -threo-pentofuranosyl) -5-methyl-2-pentyloxy-4. Prepared in a similar manner as described for-( 1H ) -pyrimidinone (Example 56), substituting benzyl alcohol for pentan-1-ol; mp = 137-139 ° C.

UV (nm): at pH 1, λ _max = 266 (ε = 9100), λ _min
= 235 (ε = 3000); at pH 13 λ _max = 256 (ε = 1150
0), λ _min = 240 (ε = 9600).

_{^{H 1 NMR (DMSO-d 6}} ) δ7.6 (s, 1H, H6), δ7.49~7.37
(M, 5H, phenyl), δ6.01 (dd, 1H, H1 ′, J = 2.
52, 5.0Hz), δ5.35 (s, 2H, benzyl), δ5.1 to 5.
0 (m, 1H, 5'OH), δ4.5-4.4 (m, 1H, H3 '),
δ 4.1 ~ 4.0 (m, 1H, H4 '), δ 3.77 ~ 3.67 (m, 2H,
H5 '), δ2.85 to 2.70 (m, 1H, H2'), δ2.25 to 2.15
(M, 1H, H2 ') , δ1.83 (s, 3H, 5-CH 3).

Elemental _{analysis: C 17 H 19 N 5 O} 4 0.25H 2 O Calculated: C56.43 H5.43 N19.35 measurements: C56.51 H5.37 N19.36 Example 58 1- (3'-azido -2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -4-methoxy-5-methyl-2 (1H) -pyrimidinone 5'-acetyl-3'-azido-3'-deoxy-4
-(1,2,4-Triazolyl) thymidine was treated with 0.5N sodium methoxide in methanol for 24 hours at room temperature. PH of the solution with sulfonic acid resin (DOW50W, H ⁺ )
Neutralized to 7, the resin filtered off and the filtrate evaporated in vacuo to a solid. The solid was dissolved in a small amount of CHCl _3, and applied to a silica gel column and eluted with 2% MeOH in CHCl _3. Appropriate fractions were collected, combined and evaporated to dryness producing a white solid; mp 119-123 ° C.

UV (nm): at pH 1, λ _max = 276 (ε = 7500), λ _min
= 239 (ε = 1700); at pH13 λ _max = 276 (ε = 6400), λ _min = 243 (ε
= 1300).

H ¹ NMR (DMSO-d ₆ ) δ8.02 (s, 1H, H6), δ6.08
(T, 1H, H1 ', J = 5.86Hz), δ5.29 (t, 1H, 5'
OH, J = 5.48Hz), δ 4.41 to 4.33 (m, 1H, H3 '), δ
3.9 to 3.86 (m, 1H, H4 '), δ 3.86 (s, 3H, 4-OCH
₃ ), δ3.75-3.58 (m, 2H, H5 ′), δ2.4-2.3
(M, 2H, H2 ') , δ1.89 (s, 3H, 5-CH 3).

Elemental analysis: C ₁₁ H ₁₅ N ₅ O ₄ Calculated: C46.97 H5.38 N24.90 Measured: C47.06 H5.40 N24.86 Example 59 1- (3′-azide-2 ′, 3'-dideoxy-β-D-
Erythro-pentofuranosyl) -5-methyl-4- (1
-Pyrrolidinyl) -2- (1H) -pyrimidinone 5'-acetyl-3'-azido-3'-deoxy-4
-(1,2,4-Triazolyl) thymidine was dissolved in dry acetonitrile at room temperature under nitrogen atmosphere. Five equivalents of pyrrolidine were added dropwise once in 5 minutes and the reaction mixture was stirred for 2 hours. The solvent was removed in vacuo to produce an oil. The oil was dissolved in ammonia saturated methanol at room temperature and stirred for 4 hours. The solvent was removed in vacuo and the residue applied to a silica gel column. 20: 1 CHCl / MeO
Elution with H (v / v), followed by combination of appropriate fractions and evaporation gave the title compound as a white solid; mp = 168.
~ 171 ° C.

UV (nm): λ _{max at} pH 1 = 295, 233 (ε = 15700, 95
00), λ _min = 253 (ε = 2600); at pH 13 λ _max = 28
5 (ε = 15300), λ _min = 241 (ε = 7900).

H ¹ NMR (DMSO-d ₆ ) δ7.57 (s, 1H, H6), δ6.02
(T, 1H, H1 ', J = 6.5Hz), δ5.22 (t, 1H, 5'O
H, J = 5.15Hz), δ4.4 to 4.3 (m, 1H, H3 '), δ3.8
4 to 3.77 (m, 1H, H4 '), δ 3.67 to 3.51 (m, 6H, H
5 ', 4 pyrrolidine H's), δ 2.24 (t, 2H, H2',
J = 6.08Hz), δ2.14 (s , 3H, 5-CH 3), δ1.87~
1.78 (m, 4H, pyrrolidine).

Elemental _{analysis: C 14 N 20 N 6 O} 3 Calculated: C52.49 H6.29 N26.23 measurements: C52.37 H6.33 N26.17 Example 60 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Erythro-pentofuranosyl) -4-benzyloxy-
5-Methyl-2 (1H) -pyrimidinone 5'-acetyl-3 'dissolved in dry acetonitrile
-Azido-3'-deoxy-4- (1,2,4-triazolyl) thymidine was treated with benzyl alcohol (5 equivalents) and potassium t-butoxide (2 equivalents) in dry acetonitrile.
(Equivalent weight) suspension was added dropwise under nitrogen at room temperature for 5 minutes. The reaction mixture was stirred for 1 hour and the solvent removed in vacuo. Put the residue on a silica gel column, and 3:
Elute with 1 CHCl ₃ / EtOAc (v / v). Take an appropriate fraction,
Combined and evaporated to give a solid. Solid 1: 1 CHCl ₃ / EtO
Recrystallized from Ac (v / v) and the solid formed was filtered to yield the title compound; mp = 133-134 ° C.

UV (nm): at pH 1, λ _max = 276 (ε = 8000), λ _min
= 237 (ε = 2000); at pH 13 λ _max = 281 (ε = 810
0), λ _min = 237 (ε = 1600).

H ¹ NMR (DMSO-d ₆ ) δ8.05 (s, 1H, H6), δ7.45-7.3
5 (m, 5H, phenyl), δ6.07 (t, 1H, H1 ', J =
5.94Hz), δ5.35 (s, 2H, benzyl), δ5.27 (t,
1H, 5'OH, J = 5.20Hz), δ4.41 to 4.31 (m, 1H, H
3 '), δ3.91 to 3.83 (m, 1H, H4'), δ3.7 to 3.6
(M, 2H, H5 ′), δ2.4 to 2.3 (m, 2H, H2 ′), δ1.
9 (s, 3H, 5- CH 3).

Elemental analysis value: Calculated as C ₁₉ H ₂₁ N ₅ O ₅ : C57.14 H5.36 N19.60 Measurement value: C57.06 H5.37 N19.58 Example 61 3′-azide-2 ′, 3′− The dideoxyuridine was prepared according to the method of Visser [Synthetic Procedures, In-Neucratic Acid Chemistry (Sy
nthetic Procedures in Nucleic Acid Chemistry),
1, 410] to acylation and bromination according, to give the title compound; mp = 112 to 114 ° C..

UV (nm): at pH 1 λ _max = 279,210 (ε = 9500,1060
0), λ _min = 243 (ε = 2000); at pH 13 λ _max = 276
(Ε = 700), λ _min = 250 (ε = 4000).

H ¹ NMR (DMSO-d ₆ ) δ 11.88 (s, 1H, NH), δ 8.02
(S, 1H, H6), δ6.08 to 6.01 (m, 1H, H1 ′), δ4.
47 ~ 4.40 (m, 1H, H3 '), δ 4.27 ~ 4.24 (m, 2H, H
5 '), δ4.03 to 4.00 (m, 1H, H4'), δ2.41 to 2.34
(M, 2H, H2 '), δ2.09 (s, 3H, acetyl).

Elemental analysis value: Calculated as C ₁₁ H ₁₂ N ₅ O ₅ Br: C35.31 H3.23 N18.72 Br21.36 Measurement value: C35.29 H3.25 N18.66 Br21.45 Example 62 1- (3 ′ -Azido-2 ′, 3′-dideoxy-β-D-
Threo-pentofuranosyl) -5- (trifluoromethyl) uracil Protect the 5'-hydroxyl group of 5-trifluoromethyl-2'-deoxyuridine with a triphenylmethyl group and the 3'-hydroxyl group is mesylated. did. The product (3.0 g, 4.9 mmol) was reacted at 70 ° C. with 0.7 g LiN ₃ in 50 ml DMF for about 26 hours. The cooled reaction mixture was poured onto ice with stirring. The solid was isolated, washed with water and purified by flash chromatography using hexane / ethyl acetate (2: 1 v / v). Appropriate combination of fractions and removal of solvent gave tritiated product 0.83
G was given. This was dissolved in a saturated solution of zinc bromide in acetonitrile and stirred at 0 ° C overnight. After adding 100 ml of ammonium acetate (1M), the organic layer was separated and dried in vacuo. The residue is converted into CHCl / CH ₃ OH (20: 1v / v)
Was purified by flash chromatography. Fractions were combined and dried in vacuum. Yield of the title compound was 0.25 g (0.8 mmol, 5.3%); mp 1
18-120 ℃.

Elemental _{analysis: C 10 H 10 F 3 N} 5 O 4 Calculated: C37.39 H3.14 N21.80 F17.74 measurements: C37.31 H3.23 N21.75 F17.60 example 63 1- ( 3'-azido-2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) uracil protected the 5'-hydroxyl group of 2'-deoxyuridine and the 3'-hydroxyl group was mesylated.
The 3'-mesyl group was displaced with reversal of the configuration by heating with lithium azide (3 equivalents) in dimethylformamide at 80 ° C for 24 hours. The reaction mixture was poured into ice water and the product precipitated. After filtration, the moist product was deprotected. Final purification was by chromatography on silica gel eluting with chloroform / methanol (95: 5). Appropriate fractions were combined and the solvent was removed to give the title compound as a solid; mp = 142-1
45 ° C.

Example 64 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Erythro-pentofuranosyl) uracil 2'-deoxyuridine (30 g, 0.13 mol) 5'-
The hydroxyl group is determined by the method of Horwitz [J.Org.Chem., 31 , 205 (1966)].
To tritylate. 3'-hydroxyl group (12.6
g, 0.027 mol) was chlorinated by the method of Example 62. Dimethylacetamide was removed in vacuo and the thick oil was poured into water (500ml). The product is ether (3X)
It was extracted with. The solvent was removed and the resulting oil was chromatographed on silica gel, first with dichloromethane.
It was then eluted with 1% methanol in dichloromethane.
The product fractions were combined and the solvent removed in vacuo, deprotected at the 5'-hydroxyl group by heating in 80% acetic acid on a steam bath for 20 minutes without further purification. Trityl carbinol precipitated upon cooling and was filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel, eluting with ethyl acetate. HMPA
The 3'-chloro was displaced by heating in lithium azide (3 equiv.) At 90 ° C overnight. The reaction mixture was poured into water and extracted with chloroform. Chloroform contained the product and was dried over MgSO ₄ . Removal of chloroform produced a solid which was recrystallized first from ethyl acetate / methanol and then water. The recrystallized solid was dissolved in water and applied to a column of XAO. After washing with water, the title compound was eluted with ethanol. The ethanol was removed in vacuo to produce a solid; mp = 166.5
~ 168.5 ° C.

Example 65 1- (3'-Azido-2 ', 3'-dideoxy-erythro-β-D-pentofuranosyl-5-ethyl) uracil 5-chloromercuryuri-2'-deoxyuridine
From 2'-deoxyuridine (10 g, 0.044 mol), the method of Bergstron and Ruth [J. Carb Nyukuru and Nyukuru (J. Car
K. Nucl. and Nucl.), 4 , 257 (1977)]. 2'-deoxy-5-ethyluridine was prepared by a method such as Bergstrom [Jie am Chem.
Sos (J. Am. Chem. Soc.), 100 , 8106, (1978)]. The 5'-hydroxy group was protected by the method of Example 62. By the method of Example 64, the 3'-hydroxyl group was chlorinated and the 5'-hydroxyl group was deprotected. By heating with lithium azide (5 equivalents) in HMPA at 55 ° C for 1 hour, threo 3'-chloro-
The 2 ', 3'-dideoxyuridine was replaced with a configuration inversion. The title compound was purified by chromatography on silica gel, eluting with ethyl acetate. Removal of solvent from the appropriate fractions gave the desired compound; mp = 112.
5 to 115 ° C.

Example 66 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -5- (2-bromovinyl) uracil 5-bromovinyl-2'-deoxyuridine (BVD
U) by the method of Jones et al. [Tetrahedron Letters, 45 , 4415 (197
9)] was synthesized in the same yield. The BVDU can be obtained by a method such as Horwitz [[Jie Orug Chem (JO
rg.Chem), 31 , 205 (1966)]. This product (4.25 g, 6.5 mmol)
Was dissolved in 100 ml of DMF containing 0.995 g (19.5 mmol) of LiN ₃ and heated at 74 ° C. for 24 hours. Ice the reaction mixture
Pour into 600 ml with stirring. The solid formed is isolated,
Then, it was purified by chromatography as a rubber-like substance (2.48 g). Dissolution in 100 ml of 80% acetic acid and treatment by heating on a steam bath for 3 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, which was purified by flash chromatography in CHCl ₃ / CH ₃ OH (9: 1 v / v). Combination of appropriate fractions and removal of solvent gave a solid that was crystallized twice from aqueous methanol. Yield 0.66 g, 1.8 mmol, 27.7%; mp 165-166 ° C.

Elemental analysis value: Calculated as C ₁₁ H ₁₂ BrN ₅ O ₄ −0.5H ₂ O: C35.98 H3.57 N19.07 Br21.85 Measured value: C35.98 H3.57 N19.07 Br21.76 Example 67 1- (3'-azido-2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -5-methylisocytosine 1- (3'-azido-2 ', 3'-dideoxy-β-D
-Threo-pentofuranosyl) -2-methoxy-5-methyl-4 (H) -pyrimidinone (0.5 g, 2 mmol,
Combined in a bomb with methanol saturated with ammonia. After 6 days at room temperature, the bomb was heated in an oil bath at 65 ° C for 4 days. The reaction mixture was evaporated to dryness and CHCl ₃ / CH ₃ OH (9: 1
Purified by crystallization from v / v). The solid was washed with CHCl _3, and then air dried product 0.16 g, was obtained 0.6 mmol (30%); mp 158-160 ° C..

Elemental _{analysis: C 10 H 14 N 6 O} 3 1 / 4H 2 O as the measurement value: C44.36 H5.40 N31.04 measurements: C44.42 H5.36 N31.04 Example 68 1- (3' Azido-2 ', 3'-dideoxy-β-D-
Threo-pentofuranosyl) -3-methylthymine 5'-trityl-3'-threo-3'-azido-3 '
-Deoxythymidine (1.0 g, 1.95 mmol) and N, N
-Dimethylformamide dimethyl acetal [Zemlicka, Coll.Czec
h.Chem.Comm.), 35 , 3572, (1972)] (0.93 g, 7.8 mmol) was refluxed in 50 ml CHCl ₃ for 96 hours. Removal of solvent gave an oil which was further purified by flash chromatography using CHCl ₃ . Removal of solvent gave 0.54 g of foam. Deprotection was carried out by heating a foam in 50 ml 80% acetic acid on a steam bath for 2 hours. After removing the trityl carbinol by filtration, the reaction mixture was diluted with water. The filtrate was taken in vacuo as an oil and the oil was purified by flash chromatography using CHCl ₃ / EtOAc (2: 1 v / v). The solvent was removed to give the compound as an oil 0.20 g.

UV _max (nm) at pH 1 λ _max = 267 (ε = 8100), λ _sh
= 209 (ε = 8500); at pH13 λ _max = 267 (ε = 800)
0).

H ¹ NMR (DMSO-d ₆ ): δ7.56 (s, 1H, H6), δ6.07 (d
d, 1H, H _{1 '} ), δ 3.17 (s, 3H, N-CH ₃ ), δ 1.86
(S, 3H, 5-CH 3).

Elemental analysis: C ₁₁ H ₁₅ N ₅ O ₄ −0.4 HOAc −0.3H ₂ O Calculated: C45.62 H5.58 N22.54 Measured: C45.67 H5.60 N22.57 Example 69 (E) -3- [1- (3'-azido-2 ', 3'-dideoxy-β-D-erythro-pentofuranosyl) -1,2,3,
4-Tetrahydro-2,4-dioxo-5-pyrimidinyl]
2-Propenoic acid 2'-deoxyuridine was converted to the 5-chloromercury lily derivative in 96% yield according to literature methods [Bergstrom and Ruth, Dier.
Cal. Nucl., 4 , 267 (197)
7)]. 800 m of this product (50 g; 1.04 mol) in dry methanol containing ethyl acrylate (104 g; 1.04 mol)
and a 0.1 N solution of Li ₂ PdCl ₄ in MeOH (1040 ml). The solution was stirred for 4 hours and then treated with H ₂ S for 2 minutes. The suspension was filtered through a Celite pad and the filtrate was evaporated to dryness in vacuo. The residue was triturated with methanol to produce a solid which was filtered and dried to give a white solid 22g. This product is called Horowit
z) etc. [J.Org.Chem., 3
1 , 205 (1966)]. A portion of this material (7.06 g, 10.9 mmol) was added to NaH
It was dissolved in 100 ml of dry MeOH containing CO ₃ (0.92 g; 10.9 mmol) and refluxed for 6 hours. The solvent was removed in vacuo, the residue was stirred with water then filtered and air dried to give 6.1 g as a white solid. This product was converted to LiN ₃
It was dissolved in 50 ml DMF containing 1.63 g (33.2 mmol) / 1 ml water and heated at 125 ° C. for 4 hours. Reaction mixture on ice 2
Poured into 00 ml, the precipitate was removed and washed with water. This material is then dissolved in 100 ml of 80% HOAc and 4 ° C at 100 ° C.
Heated for hours. The reaction mixture was diluted with water and the precipitate was filtered off. The filtrate was evaporated to dryness to give 800 mg of oil. This oil was dissolved in 20 ml 0.5N NaOH and stirred at room temperature for 2 hours. The solution was adjusted to pH 3, the precipitate was filtered and air dried to give 550 mg (1.7 mmol) of the title compound: melting point> 250 ° C.

UV (nm): at pH 1, λ _max = 300 (ε = 20400), λ _min
= 230 (ε = 3900), λ = 262 (ε = 13100) at pH13 λ _max = 297,266 (ε = 15600,14800),
λ _min = 281,288 (ε = 13600,8600); H ¹ NMR (DMSO-d ₆ ): δ8.37 (s, 1H, H6), δ7.30
(S, 1H, -CH =, J = 15.5Hz), δ6.78 (d, 1H, =
CH-COOH, J = 15.93Hz), δ6.1 to 6.06 (m, 1H, H
1 '), δ 5.41 to 5.37 (m, 1H, 5'OH), δ 4.47 to 4.3
9 (m, 1H, H3 '), δ 3.87 to 3.83 (m, 1H, H4), δ
3.74 3.58 (m, 2H, H5 '), δ2.54 ~ 2.81 (m, 2H,
H2 ').

Elemental _{analysis: C 12 H 13 N 5 O} 6 Calculated: C44.59 H4.05 N21.67 measurements: C44.45 H4.06 N21.60 Example 70 (E)-3-[1- (3 '-Azido-2', 3'-dideoxy-β-D-threo-pentofuranosyl) -1,2,3,4
-Tetrahydro-2,4-dioxo-5-pyrimidinyl]
2-Propenoic acid 2'-deoxyuridine was converted to the 5-chloromercury lily derivative in 96% yield according to literature methods [Bergstrom and Ruth, Dier.
Calv Nyukuru Nyukuru (J.Carb.Nucl.Nucl.),
4 , 257, (1977)]. This product (50g, 1.04mol)
Was added to 800 ml of dry MeOH containing ethyl acrylate (10.4 g, 1.04 mol), and Li ₂ PdCl ₄ in MeOH (10.40 ml).
Dissolved in 0.1N solution. The solution is stirred for 4 hours, then
Treated with H ₂ S for 2 minutes. The suspension was filtered through a Celite pad and the filtrate was evaporated to dryness in vacuo. The residue
Trituration with MeOH produced a solid which was filtered and air dried to give 22 g of a white solid. This product was prepared by the method of Horowitz et al. [J.Or Chem.
g.Chem.), 31 , 205 (1966)]. A portion of this material (2.7 g; 4.2 mmol) was added to dry DM containing LiN ₃ (0.62 g; 12.7 mmol).
Dissolved in F (55 ml) and heated at 70 ° C. for 24 hours under N ₂ . The reaction mixture was poured onto 400 ml of ice, the precipitate was removed and purified by flash chromatography. 50: 1CH
Elution with Cl ₃ / MeOH (v / v) gave 1.48 g of the azide intermediate. This material was treated with 50% acetic acid (100 ml) at 100 ° C. for 3 hours. Dilution with water, filtration of the resulting suspension and evaporation of the filtrate in vacuum gave 710 mg of oil. This oil was dissolved in 50 ml NaOH and stirred at room temperature for 2 hours. The pH of the solution was brought to 3, the precipitate was filtered off and air dried,
240 mg (0.7 mmol, 50%) of the title compound were obtained; melting point =
250 ° C.

UV (nm): at pH 1, λ _max = 301 (ε = 19500), λ _min
= 230 (ε = 3600), λ _sh = 249 (ε = 12700) at pH13 λ _max = 299, 267 (ε = 1400, 13200), λ
_min = 232, 239 (ε = 1200, 7560).

H ¹ NMR (DMSO-d ₆ ): δ3.13 (s, 7H, H6), δ7.32
(D, 1H, -CH =, J = 15.87Hz), δ6.78 (d, 1H,
= C H -COOH, J = 15.62Hz ), δ6.01~5.98 (m, 1
H, H1 '), δ5.11 ~ 5.98 (m, 1H, 5'OH), δ4.50
~ 4.43 (m, 1H, H3 '), δ4.13 ~ 4.08 (m, 1H, H
4 '), δ3.80-3.75 (m, 2H, H5'), δ2.77-3.67
(M, 1H, H3 ′), δ2.30 to 2.20 (m, 1H, H2 ′) Elemental analysis: C ₁₂ H ₁₃ N ₅ O ₆ −1.5H ₂ O Calculated: C 41.15 H4.60 N19 .99 Measurement: C41.38 H4.50 N20.01 Example 71 (E) -3- [1- (3'-azido-2 ', 3'-dideoxy-β-D-erythro-pentofuranosyl)- (2,3,
4-Tetrahydro-2,4-dioxo-5-pyrimidinyl]
2-Propanoic acid 5'-Trityl-3'-mesyl-5-propanoate-2'-deoxyuridine was prepared according to the method of Example 69. This material was hydrogenated with 10% Pd / C in EtOH to give the propanoate derivative. This product was then treated as described in the above method to give the title compound; mp = 118-120 ° C.

UV (nm): At pH 1, λmax = 265 (ε = 9900), λmin
= 235 (ε = 3100); at pH13 λmax = 265 (ε = 740
0), λmin = 247 (ε = 5400); H ¹ NMR (DMSO-d ₆ ) δ7.68 (s, 1H, H6), δ6.11 to 6.0.
6 (m, 1H, H1 '), δ4.45-4.35 (m, 1H, H3'),
δ 3.85 to 3.80 (m, 1H, H4 ′), δ 3.68 to 3.53 (m, 1
H, H5 ') Elemental _{analysis: C 12 H 15 N 5 O} 6 Calculated: C44.31 H4.65 N21.53 measurements: C44.26 H4.68 N21.49 Example 72 Clinical trials 3'-azido -3'-deoxythymidine (AZT)
Two IDS patients received 2 every 8 hours on days 1 and 2 of treatment
It was orally administered at a dose of mg / kg. On days 2 and 3, patients were also given probenecid 500 mg every 6 hours and AZT
Was given on the third day. The maximum (Cmax) and course (Cmin) levels of AZT on day 3 (after administration of probenecid) were reduced 3-fold in total body clearance (cl / F), and the mean half-life of AZT during PB treatment (tl / 2) (from 0.88
(Up to 1.73 hours) was significantly higher than the level of response on day 1 which caused an extension in (up to 1.73 hours). AZT glucuronide / AZ in urine
The mean ratio of T was significantly reduced from 7.3 to 2.4 after PB treatment. The major pharmacokinetic parameters of AZT before and after concurrent administration of PB are summarized in Table 1.

Example 73 Antivirus activity Nucleoside transport inhibitors dipyridamole, dilazep and 6-[(4-nitrobenzyl) thio] -9-β- D
-Ribofuranosyl) purine 3'-azido-3'-
Table 2 shows the enhancement of the anti-friend leukemia virus (FLV) activity of deoxythymidine (AZT). FG-10 cells on a plate,
Inoculated one day before being infected with FLV. One day after infection,
A known concentration of test compound or formulation was added. Incubate the plate for 3 days and add fresh Matsukoi (Mc
Coy) 5A medium was replaced and incubated for another 3 days. The concentration of test compound / formulation that gave 50% inhibition of plaques was determined as shown in Table 2. Neither dipyridamole (10 μM) nor dilazep (5 μM) alone had any observed antivirus effects.

Example 74 Anti-I of 3'-azido-3'-deoxythymidine (AZT)
Patients with TP activity platelets 38,000 mm ^-3 were diagnosed with thrombocytopenic purpura (platelet count <100,000 mm ^-3 ) and treated every 6 hours with AZT 5 mg / kg IV for 6 weeks, during which His platelet count rose to 140,000 mm ^-3 . Treatment was then changed to 5 mg / kg / 4 hours orally for 4 weeks, discontinued for 4 weeks,
Then 2 weeks later to 93,000mm ^-3 and 4 weeks later to 7
Platelet was reduced to 0,000 mm ^-3 . 5 mg / kg / for 5 weeks
Oral treatment for 4 hours was recommended, and the platelet count rose to 194,000 mm ^-3 . A dose reduction of 2.5 mg / kg / 4 h orally caused a slight reduction in platelet count, but not within the diagnostic range of ITP.

Example 75 Treatment of Kaposi's Sarcoma with 3'-Azido-3'-deoxychemidine (AZT) In this study, 9 patients diagnosed with Kaposi's sarcoma (KS) were treated with AZT and the following effects: Was observed.

 One patient had a complete cure.

 Three patients showed lesion regression.

 KS remained stable in 2 patients.

 Lesions progressed in 3 patients.

= 50% response is the preferred current treatment for KS, recombinant α-
Comparable to that obtained with interferon treatment.

Example 76 AZT / acyclovir formulation against HIV in vitro In vitro efficacy of a formulation of AZT and acyclovir (ACV) against HIV was tested using the same method as in Example 79.

ACV alone showed little activity, a concentration of 16 μg / ml (max tested) showed less than 30% protection, whereas AZT showed 8
At μM, this method showed 100% protection.

Table 3 shows the formulation of those two drugs required to achieve 100% protection. Table 3 ACV ([mu] g / ml) AZT ([mu] M ) -0 8 0.5 2 1 1 1 4 0 8 8 8 The results show that ACV enhances the anti-virus activity of AZT about 3-fold.

Example 77 AZT / Interferon Combinations Against HIV In Vitro Peripheral blood mononuclear cells (PBMC) of healthy HIV seronegative volunteers were obtained by Ficoll-Hypaqve sedimentation of heparinized blood. Cells were treated with phytoagglutinin (PHA) 10 μg / ml and 20% fetal calf serum (FCS), antibiotics, l-glutamine and 10
% Interleukin-2 (IL-2) [Electronucleonics, Bethesda, Md.] RPMI1640 medium supplemented. PHA
After 4 to 6 days of exposure, the cells were dispersed at a concentration of 4 × 10 ⁵ cells / ml in a 25 cm ³ flask containing 5 ml of medium and then exposed to the drug and virus as detailed below. The day of virus inoculation is indicated as day 0. Fresh medium was added on day 4. Every 3-4 days thereafter, a portion of the cell suspension was taken for analysis and replaced with cell-free medium. Experiments 2 and 4 were completed after 14 days and Experiments 1 and 3 were completed after 16 days.

Beer stocks were stored in HIV partially frozen at -70 ° C.
-Cell-free supernatant of infected H9 cells. The 50% tissue culture infectious dose (TCID ₅₀ ) of the virus stock was 10 ⁵ / ml.

Four separate experiments were performed using PBMC from different donors. 40 × 10 ⁶ cells are added to the virus 10 ⁵ TCID ₅₀
Was suspended in 20 ml of a medium containing C. for 1 hour, then washed three times and resuspended in a virus-free medium. In Experiments 2 to 4, cells were treated with α interferon (rIFNα
A) Incubated in presence or absence medium for 24 hours and then exposed to AZT and virus. Virus was added directly to the culture in a small volume of medium and was not washed. The virus inoculation was 4 × 10 ³ , 10 ³ and 2 × 10 ³ TCID ₅₀ in experiments 2, 3 and 4, respectively. The drug concentration was adjusted so that the original concentration was maintained in each medium change.

In all experiments, serial 2-fold dilutions of fixed formulations of rIFNαA and AZT were tested. Each concentration of rIFNαA and AZT used in the formulation was also tested only to provide a reference point.

Replicate cultures in all experiments were maintained for each concentration and for infected and uninfected controls.
In Experiment 1, AZT 3.2 μM and rIFNαA128 unit / m
l (U / ml), and also five 2-fold dilutions of this formulation were tested.

In experiments 2 and 3, AZT 0.16 μM and rIFN
αA128U / ml was used, as well as 3-4 fold 2-fold dilutions of this formulation. In Experiment 4, AZT 0.08 μM and rIF
NαA128U / ml was used, as well as two 2-fold dilutions of this formulation.

After about 1 week, the cultures were evaluated every 3 to 4 days for the presence of viruses. Cells were evaluated for HIV antigen by indirect immunofluorescence; supernatants were evaluated for reverse transcriptase (RT), virus yield, and for HIV p24 antigen by radioimmunoassay.

In order to calculate the combined drug effect, a compound drug effect analysis of Chou and Talalay [Advences in Enzyme Legacy (Advences
in Enzyme Regulation), (1984), 24 , 27-55].

The data were also evaluated by the isobologram technique, a geometric method, to assess drug interactions. The concentration of AZT leading to the desired (eg 50% inhibition) effect is plotted on the horizontal axis and the concentration of rIFNαA leading to the same degree of effect is plotted on the vertical axis. A line is drawn in relation to those points and the concentration of drug effect in the formulation that leads to the same effect is plotted. If this point drops below the line, the formulation is considered synergistic.

In experiment 1, the concentration of AZT was completely inhibitory, which made it impossible to determine the combination effect. Experiments 2-4
In, a synergistic interaction of the two drugs was consistently observed (Tables 4-9). Synergy was evidenced in all measurements of virus replication used and rIFNα
It survived even when the effect of A alone was negligible. Synergy calculation is based on RT data from experiments 2-4, experiments 2 and 3
Data from virus and RI from Experiment 4
This was accomplished by applying a dual drug efficacy analysis to the A data. The isobologram method also indicated synergy, (A) Method A: 40 × 10 ⁶ cells were suspended in 20 ml of medium containing TCID ₅₀ HIV10 ⁵ at 37 ° C. for 1 hour, then washed and resuspended.

Method B: The indicated amount of virus is 2 × 10 ⁶ cells;
The cells were subsequently unwashed.

The formulation factor is determined by solving the equation for varying degrees of RT inhibition. A compounding factor value <1 indicates a synergistic effect. The compounding factor values shown are for the non-exclusive form of the equation (mutu
obtained using the ally non-exclusive form); the values obtained using the mutually exclusive form were always slightly lower.

Example 79 In vitro antimicrobial synergistic test 3'-Azido-3'-deoxythymidine and 8 known antimicrobial agents (listed in Table 11) were each treated with N, N-dimethylformamide for 30 minutes. Welcotest Bros (we
llcotest broth) was used to make microtiter dilutions.

Prior to the synergistic test, MIC determinations for the test organism (E.Coli CN314) were made individually for each compound. Table 11
Shows the MIC endpoint of each drug against E. Coli CN314.

Two-fold serial dilutions of test drug or 3'-azido-3'-deoxythymidine were placed in "flat-bottom" or "transfer" microtiter plates,
Each was manufactured. Plates containing the appropriate dilutions were combined to produce a series of 192 dilutions / formulation. A control consisting of compound alone was also included. The highest concentration of drug used was twice its MIC value (Table 11).

The test plates were inoculated with a bacterial seed culture containing approximately 5 × 10 ⁵ CFU / ml and then incubated at 27 ° C. for 18 hours. The holes were scored for bacterial growth or non-growth and the MIC was determined. “Fractional inhibition
tory concentration) ”(FIC) from the MIC value
Calculated by dividing the MIC by the MIC of each single agent.
The total fractionation (total fractional inhibitory concentration) was then calculated. Results of about 0.5 or less are synergistic indicators.

Table 11 Minimum inhibitory concentration (MIC) of test drug alone Compound MIC (μg / ml) tobramycin 0.4 fusidic acid 1000 chloramphenicol 3.1 clindamycin 100 erythromycin 25 rifampicin 6.2 3'-azido-3'-deoxythymidine 1.0 trimethoprim 0.125 The results of the sulfazimidine 32 synergistic experiment are shown in Table 12.

Example 80 Anti-HIV of 3'-azidonucleosides in vitro
Activity The in vitro activity of 3'-azidonucleosides (pharmaceuticals) was assayed in two cell lines; H9 (permissive for HIV replication but partially resistant to the cytopathic effect of HIV, OKT4 ⁺ T). Cell lines) and TM3 (T-cell clones specific for tetanus toxoid, immortalized by lethal irradiated HTLV-1 and selected for rapid growth and sensitivity to the cytopathic effect of HIV).

The inhibition assay was performed as follows: TM3 cells were treated with antigen + irradiation (40
00rad; 40Gy) stimulated with fresh autologous peripheral blood mononuclear cells (PBM), and 6 days before assay, interleukin-2
[IL-2, lecithin removal; Cellular Products (Cell
ular Products), Buffalo, New York] 15%
Cultured in complete medium containing (V / V). ATH8 cells were used without antigen stimulation. After 30 minutes pre-exposure to 2 μg / ml polybrene, target T-cells (2 × 10 ⁵ ) were pelleted, exposed to HIV for 45 minutes, resuspended in 2 ml fresh medium, and 5% CO 2 in culture tubes. ₂ Incubated at 37 ℃ in moist air containing ₂ Control cells were treated similarly, but were not exposed to virus. Cells were continuously exposed to IL-2 and drug. When using ATH8 cells in this assay system, 5 virus particles per cell were the minimum cytopathic dose of virus. HIV RF-II-induced H9 under lethal irradiation (10,000 rad) in cell culture experiments
Cells or uninfected H9 cells 5 × 10 ⁴ were added to target T cells 2 × 10 ⁵ . At various time points, total viable cells were counted under a microscope with a hemocytometer by the trypan blue dye exclusion method.

 The results are shown in Table 13.

Table 13 Compound ED ₅₀ (μM) 3′-azido-2 ′, 3′-dideoxycytidine 10 3′-azido-5-bromo-2 ′, 3′-dideoxyuridine 5 3′-azido-5-bromo-2 ′, 3′-Dideoxycytidine 5 (E) -3- [1- (3′-azito-2 ′, 3′-dideoxy-β- D -erythro-pentofuranosyl-1,2,3,4
-Tetrahydro-2,4-dioxo-5-pyrimidinyl]
2-Propenoic acid 100 Example 81 In vitro antibacterial activity of 3'-azidonucleosides Table 14 demonstrates the in vitro antibacterial activity of 3'-azidonucleosides against various bacteria at the minimum inhibitory concentration (MIC).

The standard used was Trimethoprim (TMP), and the medium used was the Wellcotest sensitivity Test agar with 7% thawed horse blood.
Agar).

The compounds used are: 1) 3'-azido-3'-deoxy-4-thiothymidine 2) 3'-azido-3'-deoxy-5'-O-acetyl-4-thiothymidine 3) 3'-azido-3'-deoxy-2-deoxy-
2-thiothymidine 4) 5'-acetyl-3'-azido-3-benzoyl-3'-deoxythymidine 5) 1- (5'-O-acetyl-3'-azide-
2 ', 3'-deoxy-β- D -erythro-pentofuranosyl) -5-methyl-4- (1,2,4-triazole-1)
-Yl) -2 (1H) -pyrimidinone 6) 1- (3'-azido-2 ', 3'-dideoxy-β
-D -erythro-pentofuranosyl) -2- (benzyloxo) -5-methyl-4- (1H) -pyrimidinone 7) 3'-azido-3'-deoxy-2-methoxythymidine 8) 3'-azide -5-bromo-2 ', 3'-dideoxyuridine

 ─────────────────────────────────────────────────── ─── Continuation of front page (31) Priority claim number 8608272 (32) Priority date April 4, 1986 (33) Priority claim country United Kingdom (GB) (31) Priority claim number 8615322 (32) Priority date June 23, 1986 (33) Priority claiming United Kingdom (GB) (31) Priority claiming number 877796 (32) Priority date June 23, 1986 (33) Priority claiming United States (US) (31) Priority Claim Number 877284 (32) Priority Date June 23, 1986 (33) Priority Claim Country United States (US) (72) Inventor Sandra Nusinof Lerman Old Scheuger Road, Durham, North Carolina United States 2720 (72) Inventor Martha Hader St Clair, Seven Oaks, Durham, North Carolina, United States 312 (72) Inventor Firi Tup Allen Huaman, Bruceton Road, Durham, North Carolina, USA 910 (72) Inventor, Georges Andrie Freeman, Karew Drain 107 (72) Inventor, Thomas Paul Jimmerman, Kiya, North Carolina, USA Brunson Court, Lilly 1415 (72) The inventor, Gerard Wolberg, Troon Court, Cary, North Carolina, USA 1109 (72) Paulo Em. Demiranda United States Raleigh, North Carolina Latdcliff Road 4828 (72) Inventor Sammy Ray Sheaver United States North Carolina North Carolina 103 Chapell Hill, Autumn Drive 103 (72) Inventor Leone Edward Kirk The Sade United States Raleigh, North Carolina 1630 (72) Inventor Danny Hillary King, Hillside Drive, Raleigh, North Carolina, USA 8237 (72) Inventor Richard Harlon Clemmons, Kary, E., North Carolina, USA. Maynard Road 221 (72) Inventor Jio Frey White United Kingdom Heartfordshire, Berkhamstead, Burhamstead Hill (no street number) Coopers Animal Health Limited

Claims (6)

(57) [Claims] 1. A glucuronidation inhibitor and / or renal excretion inhibitor, nucleoside transport inhibitor, other therapeutic nucleosides and antibacterial agents containing 3'-azido-3'-deoxythymidine as an active ingredient. An effect enhancer for at least one therapeutic agent selected from: 2. A glucuronidation inhibitor and / or renal excretion inhibitor selected from probenecid, acetaminophen, lorazepam, cimetidine, ranitidine, zomepirac, clofibrate, indomethacin, ketoprofen or naproxen. Reinforcing agent of paragraph 1. 3. A nucleoside transport inhibitor is dilazep or 6-[(4-nitrobenzoyl) thio] -9- (β-D.
-The enhancer of claim 1 selected from ribofuranosyl) purines. 4. Another therapeutic nucleoside is of the formula (In the formula, Z is a hydrogen atom, a hydroxy or amino group, 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 methylene group. Oxy group (-OC
H ₂ ), and Y is a hydroxy group) or is a pharmaceutically acceptable derivative thereof. 5. The enhancement according to claim 4, wherein the therapeutic nucleoside is selected from 9-[(2-hydroxy-1-hydroxymethylethoxy) methyl] guanine or 9- (2-hydroxyethoxymethyl) guanine. Agent. 6. An antibacterial agent is 2,4-diamino-5- (3 ',
The enhancer of claim 1 selected from 4 ', 5'-trimethoxybenzyl) purine or analogs thereof, sulfadimidine, rifampicin, tobramycin, fusidic acid, chloramphenicol, clindamycin or erythromycin.