TREATMENT OF VIRAL INFECTIONS

Technical Field

This invention relates to novel compositions and preparation of matter which possess activity for the potential treatment for viral infections, especially potent anti-AIDS activity.

Background Art

The human immunodeficiency virus ( HIV) is the retrovirus which caused the acquired immunodeficiency syndrome (AIDS) in human. HIV rapidly replicate in a human host cell and appears to preferentially attack helper

T-cells ( t-lymphocytes ) and possibly other human cells, e. g. , certain cells within the brain. The helper T-cells are invaded by the virus and the T- cells becomes an HIV virus producer. The helper T-cells are quickly destroyed and their number is depleted to such an extent that the body's B-cells as well as other T-cells normally stimulated by helper T-cells no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes, etc.

The HIV virus will gradually erode the ability of the human's immune system to resist various pathogens, that the human falls prey to various other diseases (secondary infections or unusual tumors) such as herpes, cytomegalovirus, Kaposi's sarcoma and Epstein-Barr virus related lymphomas among others . These secondary infections are conventionally treated separately using other medications. In some humans infected with HIV virus ( commonly referred to as AIDS virus and which is meant herein to include mutants thereof) the infected persons seem to live on with little or no symptoms, but appear to have persistent infections. Another group of humans suffers mild immune system depression showing various

symptoms of weight loss, malaise, fever, swollen lymph nodes etc. These syndromes have been called persistent generalized lymphadenopathy syndrome (PGL) and AIDS related complex (ARC) and they may or may not develop into AIDS . In all cases , those infected with the HIV virus are believed to be persistently infective to others.

Azidothymidine (AZT) was the first clinically useful drug against AIDS with significant decrease in mortality and frequency of opportunistic infections. However, severe toxicity, in particular, the bone marrow suppression (anemia, leukopenia) was associated with long term administration of AZT. After the initial immunologic improvement, i.e. , increase in CD4 + cells, there was further decline of immunologic conditions, despite the continued AZT treatment.

Other effective inhibitors of HIV replication include (a) a variety of 2', 3'- dideoxynucleosides , {such as 2', 3'-dideoxycytidine (ddC), 2', 3'- dideoxyasenosine (ddA), 2', 3'-dideoxyguanosine (ddG), 2', 3,- dideoxyinosine (ddl)}, (b) 2', 3'-didehydro-2', 3'-dideoxynucleosides {i.e., 2', 3'-didehydro 2', 3'-dideoxycytidine (d4C), 2', 3'-didehydro-2', 3'-dideoxythymidine (d4T)}, (c) 3'-fluoro-2', 3'-dideoxynucleosides {i.e., 3'-fluoro-2\ 3'-dideoxythymidine (FddT), 3'-fluoro- 2', 3'-dideoxy-5- chlorouridine (FddCIU)}, (d) various 3'-azido-2', 3'-dideoxynucleosides other than AZT {i.e.3'-azido-2', 3'-dideoxyuridine (AzddU), 3'-azido- 2',3'-dideoxy-5-chlorouridine (AzddCIU) and 3'-azido-2', 3'-dideoxy-2, 6- diaminopurineriboside (AZddDAPR)}, (e) various carbolic nucleoside analogues {i.e., carbocyclic 2', 3'-didehydro-2', 3'-dideoxyguanosine (carbovir), iso-ddA, and the carbocyclic oxetanocin analogues cyclobut-A and cyclobut-G}, (f) various acyclic nucleoside analogues {i.e., adenallene, cytallene, (g) the phosphonylmethoxyalkl derivatives {i.e., (PMEA) [9-(2-phosphonylmethoxyethyl) adenine} and (PMEDAP) [9- (2- phosphonylmethoxyethyl)-2, 6-diaminopurine]} (h) acyclic uridine analogues {i.e., 1- [ ( 2-hydroxyethoxy ) methyl] 6-phenylthiothymine

(HEPT)}, and (i) and benzodiazepine derivatives {i.e., ( + )-S- 4, 5, 6, 7-

Tetrahydro-9-chloro-5-methyl-6-(3-methyl-2 butenyl)-imidazao[4 , 5 , 1-jk] [1 , 4]-benzodiazepin-2 ( lH )-thione. See E . De Clercq, Design of Anti- AIDS Drugs Elsevier Science Publishers 1990.

Some of these compounds, i.e. , ddC , ddl and d4T have already been the subject of clinical trials . However, ddC usefulness is hmited by painful peripheral neuropathy. Such neuropathy may also occur following administration of d4T; on the other hand , the use of ddl may in some instances be complicated by acute pancreatitis.

Objects and Advantages

Hence, design of additonal compounds that may eliminate or at least minimize the untoward effects and provide better incorporation is definitely needed . It is also hoped that each of these new compounds will possess a wide cytotherapeutic index , high bioavailability , a broad spectrum of antimicrobial activity, an ability to cross the blood-brain barrier and a more convenient dosing schedule. The methods and compositions of compounds herein described have these tenets in mind.

Disclosure Of Invention

It is the principal object of this invention to provide a more effective treatment of viral infections in humans while eliminating or at least reducing the unwanted side effects of conventional treatments .

It is a further object of the present invention to provide such a new and improved method of treatment of patients infected by the human immunodeficiency virus (HIV) .

Briefly, the above and further objects of the present invention are realized by providing a method of treatment of viral infections utilizing the compounds disclosed herein.

Brief Description of Drawings

The above mentioned and other objects and features of this invention and the manner of attaining them will become apparent, and the invention itself will be best understood by reference to the following description of the embodiment of the invention in conjunction with the accompanying drawings , wherein:

FIG . 1 is a compositiion wherein Y differs as follows :

Formula I H

0 II Formula II HO— p —

OH

0 0 r, " "

Formula IU HO— p — O — P —

I

OH OH

0 0 0

Formula IV HO— P P ¹¹ —— 0 r 0s ——P H —— 00 rs ——p 'I -

I 1 II I OH OH OH

G . 2 is a composition wherein B , n , X , Y and Z differ as follows :

FIG . 3 is a compound wherein B , n , X , Y and Z differ as follows :

1. -CH ₂ -CH=C=CH-B

Detailed Description

The rationale for the general design of the compounds of this invention is based on the "bivalent ligand" approach. ( See M. Erez, et. al. J. Med Chem. 1982 , 25,847; P.S. Portoghese et. al. Life Sci. 1982, 31 , 1283) . It involves molecules that contain two pharmacophores linked by a spacer which plays an important role in modulating selectivity and potency. This modulation may be accomplished through both pharmacophores binding simultaneously to vicinal recognition sites that are either identical or homologous. Bimorphanans are good examples that possess high selectivity and potent antagonist activity at k opioid receptors (See P .S . Portoghese et. al. J. Med . Chem. 1987, 30, 238. ) Another reason is that one portion of the molecule would be readily recognized by the virus cell and may initiate the incorporation process ., Once the whole compound is incorporated, the chain will be terminated by the appropriate functional groups of the nucleoside, such as azide, fluoride, didehyro, dideoxy, and carbocyclic etc. of the other portion. Such prodrug approach based on the development of new isomeric dimeric derivatives has recently shown some promise against DNA viruses (see F. Puech et. al. J. Med. Chem. 1988, 31 , 1897 ) . However, only the ara-A dinucleosides were evaluated as had been for the ara-C dinucleosides (See C . C . Smith, J. Med. Chem. 1967 , 10, 774 and H .E . Renis, J. Med. Chem. 1967, 10, 777) .

An example of a compound of this invention with this general design is the Thymidylyl (3' — >5' )-azido-3'-deoxythymidine having the Formula I. When we submitted this compound to the AIDS antiviral screening program of the National Cancer Institute, it was assigned the No. of (NSC-D-631744) . It is found to be active. Testing performed under the National Cancer Institute's protocol for AIDS antiviral screening (See O .W . Weislow, et. al. , J. National Cancer Inst. 81 ,577-586 (1989) showed Formula I with a therapeutic index of 19.8 X 10 ³ compared to 1.2 X 10 ^J that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggest an

additional advantage. Other compounds of similar design are also disclosed in this invention.

The compound of Formula I may be administered per se or in the form of a pharmaceutically acceptable salt , e. g . an alkali metal salt such as sodium or potassium, or an alkaline earth salt or an ammonium salt (all of which are hereinafter referred to as a pharmaceutically acceptable base salt) .

As another feature of this invention, there is also disclosed the methods of administering thereof the mono- , di- or triphosphate of the Formula I or their pharmaceutically acceptable base salts (i.e. , alkali metal, alkaline earth or ammonium salt) to treat AIDS, to inhibit the replication of the

AIDS virus in infected human cells and to prevent AIDS from developing in humans infected with the AIDS virus or carrying antibodies to the AIDS virus. The mono- , di- and triphosphates of the Thymidylyl (3' — >5 ) - azido-3'-deoxythymidine are of the Formulas II, III and IV respectively.

The present invention also discloses compounds of Formula I, II, III, IV and their appropriate salts for use in the treatment of the conditions refered to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment of such conditions. The above mentioned pharmaceutically acceptable salts may be prepared in a conventional manner, e. g. , treatment of the compound with an appropriate base.

The use of antisense oligodeoxynucleotides in the development of anti-HIV agents has expanded the knowledge of oligonucleotide analog chemistry . Anti-HIV and other biological activities found for oligonucleotides suggest that sequence-specific and sequence-nonspecific mechanisms of action can be found. Areas in which these compounds are considered to be very limited included all the biological areas, such as cellular uptake, toxicology and pharmacokinetics . Also, improved and cheaper methods of large scale

synthesis are vital to the question of cost relative to effective dose . See J.S. Cohen, Antisense oligonucleotides as an approach towards Anti- AIDS therapy; Design of Anti-AIDS Drugs . ED . by E . De Clerq Elsevier Science Publishers 1990, page 195-224.

Prior art described above and references therein, recognized some oligonucleotides and their analogs exhibited potent antiviral activity. The effect of oligomer length was explored by Matsukura et. al. who found the longer sequences were more effective than the shorter sequences at the same molar concentration of nucleotide unit. For instance, the 28-mer gave complete protection against the virus, while the corresponding 14-mer had only moderate effect, whereas the 5-mer failed to significantly inhibit the cytopathic effect of the virus. See M. Matsukura et. at. 1987. Proc . Natl. Acad . Sci. USA 84 , 7706-7710. They and others are directing their attention to the higher sequence oligomers after concluding that shorter oligonucleotide have no significant activity.

However, it has now been discovered by us that there are indeed unforeseen advantages in the use of shorter isomeric and nonisomeric oligonucleotides type compounds such as the dinucleotides as exemplified by Formula I . Formula I is found to have potent antiviral activity and better therapeutic index than the corresponding nucleoside when tested at the National Cancer Insitiute performed under their protocol for AIDS antiviral screening . Formula I (Thymidylyl 3' — >5' )-azido-3'- deoxythymidine) has a therapeutic index of 19.8 X 10 compared to 1.2 X 10 "" that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggest an additional advantage. Moreover, they are simpler and much less expensive for large scale synthesis than the longer chain oligonucleotides .

As an additional feature, this invention discloses methods and compositions of other compounds useful in treating viral infections, including AIDS

virus or human and/or animals carrying or infected with the AIDS virus or having antibodies to the AIDS virus. These compounds include the shorter isomeric and nonisomeric nucleotide type compounds, such as dinucleotides , trinucleotides , etc . i.e. , one , two , or more nucleosides linked by the (3' — >5' ) linkages to the chain terminating nucleosides or other chain terminating chemical moieties, such as AZT , ddl, ddC , ddG , ddA, d4T , d4C ,FddT , FddCIU , AzddU , AzddCIU, AzddDAPR , Carbovir, iso-ddA, cyclobut-A, cyclobut-G and others. Several examples of these include, but not limited to, are Inosylyl (3' — >5' )- 2' , 3'-dideoxyinosine, Cytidylyl ( 3'— >5' )-2' , 3'-dideoxycytidine, Guanosylyl (3'— >5" )-2' , 3'- dideoxyguanosine and adenylyl (3' — >5' )-2' , 3'-dideoxyadenine; Thymidylyl (3'— >5' )-2' , 3'-dideoxyinosine, Thymidylyl (3'— >5' ) 2 , 3'- dideoxycytidine , Thymidylyl (3' — >5' )-2' , 3'-dideoxyguanosine and Thymidylyl ( 3' — >5' )-2' , 3'-dideoxyadenine. More examples are to be found in Figures 1-3.

The mono- , di and triphosphate of these shorter sequence nucleotides are also included as part of this invention. A similar line of reasoning is applied here to as was described for the Formula I mentioned above. The prepartation of these compounds is accomplished using similar procedures and other usual methods known in the art for preparing such short chain oligonucleotides .

The present invention also discloses above mentioned compounds and their appropriate salts for use in the treatment of the conditions refered to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment of such conditions. The above mentioned pharmaceutically acceptable salts may be prepared in a conventional manner , e. g . , by the treatment of the compound with an appropriate base.

In general, for the above AIDS virus infections, a suitable effective dose of the Formula I, Thymidylyl (3* — >5' )-azido-3'-deoxythymidine) and other

shorter sequence nucleotides mentioned above and their mono- , di and triphosphates or their pharmaceutically acceptable basic salts (all of which are herein after referred to as the administered ingredient) will be administered as prescribed. The desired dose is preferably as two, three, four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered as unit dosage forms . The dosages will be changed according to new clinical data and procedures for administering the compounds as appropriate.

Administration may be by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual, vaginal, and parenteral

(including subcutaneous , intramuscular, intravenous, and intradermal , with oral or parenteral being preferred. It will be appreciated that the preferred route may vary with, for example, the condition and age of the recipient .

The administered ingredients may be used in conjunction with other medicaments such as 9-[ [2-hydroxy-l-(hydroxymethyl) ethoxy] methyl] guanine, 9-(2-hydroxylethoxymethyl) guanine (acyclovir) , 2-amino-9- (2 hydroxyethoxymethyl) purine, suramin , ribavarin, antimoniotungstate (HPA-23) , interferon, e. g. , •= . interferon, interleukin II, and phosphonoformate ( Forscarnet) or in conjunction with other immune modulation including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin, which would increase lymphocyte numbers and/or function as is appropriate.

While it is possible for the ingredients to be administered alone, it is preferable to present them as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one administered ingredient, as above defined, together with one or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier( s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof .

The formulations of this invention include those suitable for oral, rectal, 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, e. g . , tablets and sustained release capsules, and/or may be prepared by any methods well known in the art of pharmacy.

Such preparation methods include the step of bringing into association the to be administered ingredients, with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in a aqueous liquid or a non- aqueous liquid; or as an oil- in water liquid emulsion or a water-in-oil liquid emulsion and as a bolu, etc.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by loading 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 be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations suitable for topical administration include lozenges, comprising the ingredients in a flavored basis, usually sucrose and acacia

or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin , or sucrose and acacia; and mouth washes comprising the ingredient to be administered in a suitable liquid carrier. Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered and a pharmaceutically acceptable carrier. A preferred topical delivery system is a transdermal patch containing the ingredient to be administered.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising , for example, cocoa butter or a salicylate . Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken , i.e. , by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient .

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

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants , buffers, bacteriostats and solutes which render the formulations isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents . The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the

sterile liquid carrier, for example, water for injections , immediately prior to 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 administered ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may included other agents conventional in the art, giving due regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents .

A synthesis of the compound of Formula I, (Thymidylyl 3' — >5' (-azido-3'- deoxythymidine ) , Chemical Abstracts Registry number (87774-91-2 ) is described by A. Rosenthal ( See A. Rosenthal, Z . Chem. 23 (5 ) , 178-179) as an intermediate for the preparation of oligodeoxyribonucleotides with modified deoxyribose at the 3 '-end by the triester method.

The following examples illustrate the invention:

EXAMPLE 1

Preparation of 5'-0-(4-monomethoxytrityl)-thymidine

Thymidine (7.26g, 30m mole) was stirred with p-anisyl chloro diphenyl methane (9.26g, 30m mole) in a mixture of dimethyl formamide (60 ml) and pyridine ( 60 ml) for 20 hours at room temperature to give a clear greenish solution. This method is disclosed by F . Puegh et. al. J. Med. Chem. 1988, 31 , 1897. The clear greenish solution was poured into ice water (500

ml) . The gummy precipitate was collected . The greenish gum was purified by chromatography on a silica gel column ( 65 g) by eluting with a gradient of chloroform and methanol mixtures. A pure product ( 1.1 g) of 5-0-(4- monomethoyx trityl ) -thymidine was obtained from the chloroform: methanol (9.1 ) fraction. It has Rf value of 0.66 on a thin layer chromatography ( TLC ) system of silica gel and chloroform-methanol (9.1 ) in contrast to thymidine Rf value of 0.29.

EXAMPLE 2

Preparation of Triethylammonium salt of 5'-0-(4-monomethoxy trityl)- thymidine 3'-( 2-chlorophenyl) phosphate

A solution of 1 , 2 , 4-triazole ( 0.84 g , 12.37 m mole) , 2 chlorophenyl phosphoro dichloridate ( 1.16 g , 4.76 m mole) and triethylamine ( 1.0 g, 9.99 m mole) in acetonitrile ( 10 ml) was stirred for 0.5 hour at room temperature. The above mixture was added to a solution of 5'-0-(4- monomethoxy trityl) -thymidine ( 1.0 g, 1.9 mole) in pyridine ( 11 ml) . The solution became clear and was stirred for 0.5 hour. A solution of triethyliamine ( 1.2 g) , water ( 1 ml) and pyridine (4 ml) was then added . After 15 minutes, the solution was diluted with saturated sodium bicarbonate ( 180 ml) and extracted with methylene dichloride (70 ml) three times. The combined methylene dichloride was washed with saturated sodium bicarbonate, water and dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (20 g) using a chloroform/methanol gradient. Fraction 6 and 7 eluted with chloroform/methanol (9:2 ) were combined to give 0.5 g of pure product. Thin layer chromatography analysis of product on a silica gel plate in solvent system of n-butanol: acetic acid: water ( 18:1 :1 ) showed a single spot with a Rf value of 0.66 and in solvent system of chloroform: methanol (9 : 1 ) indicated a single spot with a Rf value of 0.18.

EXAMPLE 3

Preparation of Blocked Thymidylyl (3' — >5' )-3'-azido-3'-deoxythymidine

The product from Example 2 , (450 mg = 0.55 m mole) and 3'-azido-3'- deoxythymidine, (AZT , 200 mg = 0.74 m mole) were dissolved in 4 ml of anhydrous pyridine and evaporated to dryness under high vacuum. This process was repeated twice to give a white foam.

The white foam was dissolved in 4 ml of dry pyridine . To this solution was added ( l-mesitylene-2 sulfonyl-3-nitro-l , 2 , 4-triazole) (MSNT , 370 mg , 1.25 m mole) and the mixture stirred at room temperature for 1 hour.

Saturated sodium bicarbonate ( 1.5 ml) was then added and stirred for an additional 15 minutes . A yellow solution resulted which was poured into 30 ml of saturated sodium bicarbonate solution and extracted with methyhlene dichloride ( 3 X 25 ml) . The combined methylene dichloride extracts were dried over dried sodium sulfate and evaporated. The residue was dissolved in methylene dichloride and purified on a column of silica gel (20 g) using a gradient of methylene dichloride and methanol. Fractions 3 and 4, eluates of methylene dichloride: methanol (9: 1 ) were combined based upon TLC on silica gel adsorbent and solvent system of n-butanol: acetic acid : water ( 18: 1 : 1 ) with a Rf value of 0.85 and evaporated to dryness to give 0.4 g of white solid.

EXAMPLE 4

Thymidylyl (3' — >5' )-3'-azido-3'-deoxythymidine ( Formula I)

The product from Example 3, (400 mg) , syn-4-nitrobenzaldoxime , m. w. 166 (1.2 g = 7.2 m mole) and 1 , 1 , 3, 3-tetramethyl guanidine, F . W. = 115, (0.828 g =7.2 m mole) was dissolved in 24 ml of dioxane/water ( 1:1 ) to give a yellow solution . The yellow solution was stirred at 40 degrees Centigrade overnight for 20 hours. The solution was then cooled and evaporated to

dryness. The yellow solid was purified by column chromatography of 30 g of silica gel using a gradient consisting of methylene dichloride and methanol. Fraction 4 was eluted with methylene dichloride: methanol (8 :2 ) was found to be the major fraction with an Rf value of 0.53 in the TLC system of Silica gel G and butanol: glacial acetic acid: water ( 18: 1 : 1 ) . Fraction 4 was evaporated to dryness and was taken in 14 ml of 80% acetic acid . The clear solution was allowed to stand at room temperature overnight. The solution was diluted with water (30 ml) and extracted with methylene dichloride ( 3 X 10 ml ) . The aqueous solution was evaporated to a gummy residue which was triturated with acetone, followed by either to give a white powder (0.2 g) of Formula I . The product has an Rf value of 0.35 in the TLC system of Silica Gel G and n-butanol: acetic acid: water (18:1 : 1 ) . Mass spectra (El) gave a (m-1 ) + 570 ( C20 H26 Oil N7P) .

SUMMARY

Novel compositions and methods of preparing compounds comprising the shorter sequence isomeric and non-isomeric nucleotide-type compounds , such as dinucleotides , trinucleotides , etc . , i.e. , one , two , or more nucleosides linked by the (3' — >5' ) linages to the chain terminating nucleosides, some examples of which are shown in Figures 1 - 3.

The unforseen advantages of these types of compounds, as exemphfied by Formula I, are potent antiviral activity and possessing better therapeutic index than the corresponding nucleoside when tested at National Cancer Institute performed under their protocol for AIDS antiviral screening. Formula I (Thymidylyl (3' — >5' )-3'-deoxythymidine) has a therapeutic index of 19.8 X 10" compared to 1.2 X 10 ³ that was indicated for AZT under the same AIDS antiviral screening protocol. Higher levels of protection than AZT provided at different concentrations also suggests an additional advantage . Moreover, they are simpler and much less expensive for the large scale synthesis than the longer chain oligonucleotides.

Although the description above contains many specificities, these should not be construed as limiting the scope of the invention, but as merely providing illustrations of some of the presently preferred embodiments of this invention. For example, the chain termination nucleosides can be replaced by other chain terminating chemical moieties, such as phosphonylmethoxyalkyl derivatives (i.e. , PMEA and PMEDAP type compounds) , acyclic uridine analogs (i.e . , HEPT like compounds) , benzodiazepine derivatives, etc . Thus, the scope of the invention should be determined by the appended claims and their legal equivalents, rather than by the examples or illustrations given.