WO1995027519A1

WO1995027519A1 - Antiviral compounds, compositions and uses thereof

Info

Publication number: WO1995027519A1
Application number: PCT/US1995/003964
Authority: WO
Inventors: Lincoln M. Polan
Original assignee: Polan Lincoln M
Priority date: 1994-04-07
Filing date: 1995-03-31
Publication date: 1995-10-19
Also published as: AU2234095A

Abstract

The present invention provides novel antiviral compounds, which may be used alone or in combination with other antiviral agents in compositions, such as pharmaceutical compositions, to inhibit the growth or replication of a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-1 or HIV-2, in the treatment or prevention of viral infection. The compounds of interest are iodized tannin and iodo-derivatives of benzoic acid.

Description

ANTIVIRAL COMPOUNDS, COMPOSITIONS AND USES THEREOF

Technical Field of the Invention This invention relates to anti-viral, in particular, anti-retroviral, compositions, and methods of using the same to treat afflicted hosts.

Background of the Invention Acquired immune deficiency syndrome (AIDS) is a fatal disease, reported cases of which have increased dramatically within the past several years. Estimates of reported cases in the very near future also continue to rise dramatically. Consequently, there is a great need to develop drugs and vaccines to combat AIDS.

The AIDS virus was first identified in 1983. It has been known by several names and acronyms. It is the third known T-lymphocyte virus (HTLV-III) , and it has the capacity to replicate within cells of the immune system, causing profound cell destruction. The HIV DNA polymerase leads to the integration of the pro viral double stranded DNA into the host cell genome.

The AIDS virus is a retrovirus, a virus that uses reverse transcriptase during replication. This particular retrovirus is also known as lymphadenopathy-associated virus (LAV) , AIDS-related virus (ARV) and, most recently, as human immunodeficiency virus (HIV) . Two distinct families of HIV have been described to date, namely HIV-1 and HIV-2. The acronym HIV will be used herein to refer to HIV viruses generically.

Specifically, HIV is known to exert a profound cytopathic effect on the CD4+ helper/inducer T-cells, thereby severely compromising the immune system. HIV infection also results in neurological deterioration and, ultimately, in the death of the infected individual. AIDS can be likened to the Trojan horse of diseases. HIV enters the victim unrecognized as an antigen and seeks sites in the anatomy that are out of the mainstream of antibiotic reaction. The HIV genome is incorporated into the genetic material of the then diseased host and upon replication, it replicates with it. The hybrid cells must contain HIV genomes to remain antigenetic.

After a latent period of established total immune depression, the virus then proliferates and destroys the victim's immune system in a secondary manner.

The field of viral che otherapeutics has developed in response to the need for agents effective against retroviruses, in particular HIV. There are many ways in which an agent can exhibit anti-retroviral activity. For example, HIV requires at least four viral proteins for replication: reverse transcriptase (RT) , protease (PR) , transactivator protein (TAT) , and regulator of virion- protein expression (REV) . Accordingly, viral replication could theoretically be inhibited through inhibition of any one or all of the proteins involved in viral replication.

Anti-retroviral agents, such as AZT and ddC, are known to inhibit RT. There also exist antiviral agents that inhibit TAT. Nucleoside derivatives, such as AZT, are the only clinically active agents that are currently available for antiviral therapy. Although very useful, the utility of AZT and related compounds is limited by toxicity and insufficient therapeutic indices for fully adequate therapy.

Synthetic peptides also are being developed for potential use as inhibitors of the retroviral PR in the treatment of AIDS. Although these inhibitors are effective in preventing the retroviral PR from functioning, the inhibitors suffer from some distinct disadvantages. First, since the active site of the PR is hindered, i.e., has reduced accessibility as compared to the remainder of the PR, the ability of the inhibitors to access and bind in the active site of the PR is impaired. Secondly, the peptide inhibitors that bind to the active site of the PR are generally poorly soluble in water, causing distinct problems in drug delivery.

The chemistry of iodine in the human is very complex. It follows its basic use as an essential chemical in mammals and their cellular makeup. At the other end of the iodine spectrum is its total antibiotic action to bacteria, viruses and spores. Iodine is recognized and widely used for its germicidal effect on microbial disease causing agents.

Iodine is trapped by the thyroid gland. Ninety percent is in organic combination with the follicular colloid as thyroglobulin containing thyroxine, diiodotyrisine, and triiodothyronine.

Tannins in the diet have been shown to lower the occurrences of neoplasms. Tannic acid and elegiac acid are naturally occurring plant phenols with anti-mutagenic and anticarcinogenic activities. Jnt. J. Cancer, Vol. 51, 425- 432. Tannic acid may inhibit neoplasms by decreasing the metabolic activation of procarcinogens. Tannin in very low concentrations irreversibly inhibits the neoplastic activity of fibroblasts in vitro. Tannin acts as transport form having ready penetration of the blood brain barrier. It rapidly enters the central nervous system and is hydrolyzed there.

New classes of antiviral agents to be used alone or in combination with AZT and/or other agents are urgently needed for effective antiviral therapy against HIV. New agents which may be used to prevent HIV infection are also important.

It is an object of the present invention to provide novel compositions, in particular pharmaceutical compositions, which inhibit the growth or replication of a 5/27519 PCJ7US95/03964

virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-1 or HIV-2. Yet another object of the present invention is to provide a novel method of treating an animal, in particular a human, infected with a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-l or HIV-2.

It is an additional object of the present invention to provide novel compositions, in particular pharmaceutical compositions, which prevent infection of an animal, in particular a human, with a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-l or HIV-2. A related object of the present invention is to provide a novel method of treating an animal, in particular a human, to prevent infection with a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-l or HIV-2.

These and other objects of the present invention, as well as additional inventive features, will become apparent from the description herein.

SUMMARY OF THE INVENTION

The present invention provides novel antiviral compounds, in particular anti-retroviral compounds, in which iodine is present. The compounds of interest are iodized tannin and iodo-derivatives of certain benzoic acid compounds.

The present invention also relates to the use of iodized tannin, an iodized benzoic acid having the formula:

wherein R , R , R , and R are independently selected from the group consisting of hydrogen, acetyl, and iodo, provided that at least one of R , R₂, R_and R is iodo, or a mixture thereof to treat a host that is infected with HIV. The invention also relates to mixtures of such compounds.

The aforementioned compounds and mixtures thereof may be used in a composition, such as a pharmaceutical composition, which may additionally comprise one or more other antiviral agents. Such compounds are believed to be capable of inhibiting the growth or replication of a virus, in particular a retrovirus, specifically a human immunodeficiency virus, such as HIV-l or HIV-2. The compounds and related compositions, therefore, are expected to have utility in the therapeutic treatment of animals, such as a humans, infected with a virus, particularly a retrovirus, specifically a human immunodeficiency virus, such as HIV-l or HIV-2, or in the prophylactic treatment of an animal, such as a human, to prevent viral infection.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

There are differing theories as to how antibodies against viral disease are formed and for what reasons and when. It has been shown that individuals form antibodies against viral coat proteins that are antigenic, but also form antibodies against protein complexes of the host that are close structural analogues of the viral coat protein. It is believed that HIV induces the host immune cells to produce antibodies or factors which destroy the immune cells of the host by reacting with certain protein complexes of those immune cells. In this regard, HIV may be regarded as a "smart" virus, causing the host's immune system to be turned against itself.

Thus, it is believed that HIV causes the immune cells to be cytopathic to themselves. The resultant antibodies may be the source of the neuropathology. In such an instance, HIV may not directly do the damage to the host's immune system, but rather the antibodies that the host itself is induced to produce by its own immune cells, to attack themselves.

The iodine moieties and the tannic iodide are not problematic. Elemental iodine has a strong affinity for proteins on a nonselective basis, as do tannin and tannin iodide. The antiviral action comes, first, because the molecular proteins of the antigen react with the free iodine of these antiviral compounds in the body fluids and the life cycle of the antigen is ended. Iodine is an inherent part of the host cell or its environment which has a tolerance for higher micro-levels of iodine. In the case of neoplasms which are more active in replication, increased amounts of iodine and tannin are acquired by neoplastic cells than in normal host cells. This joint acquisition of iodine and tannin tends to end the replication of diseased cells. For treatment of neoplasm with these medications, the percentage of tannin iodide in the dosage would be increased.

The most useful antimicrobial agents that modify functional groups of proteins and nucleic acids are the halogens and hydrogen peroxide. These are super-oxidizers. Functional SH groups are oxidized to S-S forms, in bacteria, viruses and spores. Amino groups, indole groups and phenolic groups of tyrosine are degraded.

Tannin and the salicylates act as iodophores and increase the effectiveness of iodine as an antiviral agent; iodine hydrolyzes in aqueous solution according to the following formula:

I² + H-_jO = HOI + I^~ + H⁺ Hypoiodous acid

HOI = H —r* + 01- Hypoi.odi.te i.on

I + I~ = I ~ Triiodides 3H0I = HI0₃ + 2H⁺ + 2I~ The iodized salicylates of the present invention promote the formation of iodic acid HIO_.

Maximal antibiotic action occurs with iodine in the form of I at pH values below 6. Virus, spores and bacteria are killed rapidly at low concentrations of molecular iodine (I_) by its conjunction with proteins.

Tannin and iodine change the macromolecular constituents of organisms. These involve damages to cell walls, to irreversibly inactivate cell proteins and to cause disruption to DNA and RNA and their replicative process. Iodine additions may be tolerated on a differential basis by cells that are subject to thyroid hormones, tyrosine and triiodothyronine.

Tannins are generally divided into two groups, hydrolyzable and nonhydrolyzable. All references herein to tannin is meant to refer to hydrolyzable tannin. Such tannins are esters of sugars, such as glucose, and include tannins such as corilagin. Reference is made to the description of tannic acid that appears in The Merck Index, 10th Edition, entry no. 8928, and the references cited therein which are incorporated herein by reference.

No organic iodine is in erythrocytes. Iodine ions enter nearly all tissues including erythrocytes. The thyroid cells have a remarkable capacity for trapping and concentrating iodine in the formation of the thyroid hormone. These iodine ions are an essence of the medication delivered to the viral antigens. A maximum amount of the iodine in the components of the medication is required to be delivered to the virus and to bypass the thyroid. The greatest amount of the iodine in the blood is in the plasma. When the thyroid has furnished more than a normal amount of thyroxine and triiodothyronine, the thyroid stimulating hormone will be depleted and will allow the medication to circulate freely and deliver iodine as an antiviral agent to the antigen. Tannin incorporates itself into cellular proteins. Iodine combines chemically with proteins. The antiviral compositions of the present invention penetrate tissue constituents preventing cell DNA synthesis by HIV. Such action, along with tannin and iodine reacting with the part of free cellular subunits, prevents proliferation of HIV individually and in the infected cells.

In the case of iodine, the viral cell attains passivity, a state of equilibrium to a substance foreign to its metabolism, which combines with the protein and other molecules, ending or impairing the metabolic functions of the antigen cellular structures and preventing replication.

In this process, it is imperative that the concentration of ionic iodine in the plasma is at the maximum tolerable to the human cell and destructive to the viral program for replication as part of an active transport mechanism. This antireplicative process is heightened by the action of iodides of the medication which inhibit the virus's acquisition of substances necessary for the virus and the proviral particles of infection and replication.

In specific relation to HIV, tannins initially were shown to be have activity against HIV and to inhibit reverse transcriptase in vitro . Further studies have demonstrated that tannins by their chebulinic acid and punicalin are able to block the binding of HIV rgp 120 to cellular coat CD of the host. Biochem . Pharm . , Vol. 43, No. 11, 2479-80. These tannins may cause rgp 120 to be stripped away from the virion, a mechanism of action discussed in Antijnicroj . Agents and Chemother. , Vol. 36, No. 3, 509-520. These tannin compounds are not toxic to stimulated human blood lymphocytes at concentrations above their maximal effective concentration and therefore represent a possible potent agent against HIV. In accordance with the present invention, it is believed that the iodine moieties assist in the damage and penetration of the antigenic cell wall and amplify the interference caused by tannin with viral rgp 120 and cellular CD4.

The disease action of HIV will be cut short by the iodized moiety directly as an active part of the therapeutic agent to which it is compounded and which will continue to perform its molecular biological antibiotic action and, secondly, by the residual action of the iodine support of the thymic function in immunology.

All references referred to herein are hereby incorporated by reference.

As indicated, the present invention employs tannin that has been reacted with iodine to form iodo-derivatives. The reaction to introduce the iodine into the tannin is straightforward. For example, iodine can be directly reacted with the tannin in a suitable organic solvent, such as ethyl alcohol.

The present invention also employs iodo-derivatives of certain benzoic acids having the formula:

wherein R , R , R , and R are independently selected from the group consisting of hydrogen, acetyl, and iodo, provided that at least one of R , R_, R_and R is iodo.

Of particular interest are 2,4-acetyl-5-iodo-benzoic acid and 2-acetyl-5-iodo benzoic acid. It is believed that superior performance will be obtained with a composition that comprises a mixture of iodized tannin, 2,4-acetyl-5-iodo-benzoic acid and 2- acetyl-5-iodo benzoic acid. Preferably, the formulation will contain 8 parts of iodized hydrolyzable tannin, 2.4 parts of acetyl salicylic acetate iodide, and 2 parts of acetyl salicylic iodide. The formulation will, preferably, provide about 33% I, about 40% hydrolyzable tannin and about 27% salicylics. As an alternate preferred composition, it is believed that a formulation comprising about 8% tannic iodide, about 62% iodized acetyl salicylic acetate, and about 30% iodized acetyl salicylic acid will prove to be useful for the purposes specified herein. The aforementioned iodine containing compounds, obtained in accordance with the present inventive method, may be used alone or in combination with other antiviral agents in compositions, such as pharmaceutical compositions, to inhibit the growth or replication of a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-l or HIV-2. It is expected that such compositions will have utility in the therapeutic treatment of an animal, in particular a human, infected with one or more of the above-cited viruses and in the prophylactic treatment of an animal, in particular a human, who is at risk for infection with one or more of the same viruses.

The compounds of the present invention can be shown to inhibit a retrovirus, such as the human immunodeficiency virus, specifically HIV-l or HIV-2. As one skilled in the art will appreciate, the compounds of the present invention probably will inhibit other retroviruses and may inhibit viruses, other than retroviruses. Examples of viruses that may be treated in accordance with the present invention include, but are not limited to, Type C and Type D retroviruses, HTLV-1, HTLV-2, HIV, FLV, SIV, MLV, BLV, BIV, equine infections, anemia virus, avian sarcoma viruses, such as Rous sarcoma virus (RSV) , hepatitis type A, B, non- A and non-B viruses, arboviruses, varicella viruses, measles, mumps and rubella viruses. The iodine containing compounds of the present inven¬ tion, derivatives thereof, and/or prodrugs thereof, may be formulated into various compositions for use in therapeutic and prophylactic treatment methods. The present inventive composition may be used to treat a virally infected animal, such as a human. The composi¬ tions of the present invention are particularly useful in inhibiting the growth or replication of a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-l and HIV-2. The compositions also are expected to be useful in the treatment of animals, such as humans, infected with other viruses, such as those listed above. Furthermore, such compositions should find utility in the prophylactic treatment of animals, such as humans, who are at risk for viral infection.

Compositions for use in the prophylactic or therapeu¬ tic treatment methods of the present invention comprise one or more of the aforementioned iodine containing compounds, derivatives thereof, and/or prodrugs thereof, and a pharma- ceutically acceptable carrier. Pharmaceutically acceptable carriers are well-known to those who are skilled in the art, as are suitable methods of administration. The choice of carrier will be determined in part by the particular, compound, as well as by the particular method used to administer the composition.

One skilled in the art will appreciate that various routes of administering a drug are available, and, although more than one route may be used to administer a particular drug, a particular route may provide a more immediate and more effective reaction than another route. Furthermore, one skilled in the art will appreciate that the particular pharmaceutical carrier employed will depend, in part, upon the particular compound employed and the chosen route of administration. Accordingly, there is a wide variety of suitable formulations of the composition of the present invention. Formulations suitable for oral administration may consist of liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or fruit juice; capsules, sachets or tablets, each contain- ing a predetermined amount of the active ingredient, as solid or granules; solutions or suspensions in an aqueous liquid; and oil-in-water emulsions or water-in-oil emul¬ sions. Tablet forms may include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. The antiviral iodine containing compounds of the present invention, derivatives thereof, and/or prodrugs thereof, alone or in combination with other antiviral compounds, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwash- es comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

Formulations for rectal administration may be present¬ ed as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate. Similarly, the active ingredient may be combined with a lubricant as a coating on a condom. Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations may be presented in unit-dose or multi-dose sealed containers, such as 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.

The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a prophylactic or therapeutic response in the infected individual over a reasonable time frame. The dose will be determined by the potency of the particular naphthoquinone compound employed, the severity of the disease state, as well as the body weight and age of the infected individual. The size of the dose also will be determined by the existence of any adverse side effects that may accompany the particular compound employed. It is always desirable, whenever possible, to keep adverse side effects to a minimum.

The dosage may be in unit dosage form, such as a tablet or capsule. The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of iodine-containing compound(s) , alone or in combination with other antiviral agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.

The specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host. The dose administered should be an "antiviral effective amount" or an amount necessary to achieve an "effective level" in the individual patient.

Since the "effective level" is used as the preferred endpoint for dosing, the actual dose and schedule may vary, depending upon interindividual differences in pharmacokinetics, drug distribution, and metabolism. The "effective level" may be defined, for example, as the blood or tissue level desired in the patient that corresponds to a concentration of one or more iodine containing compound(s) , which inhibits a virus, such as HIV, in an assay known to predict for clinical antiviral activity of chemical compounds. The "effective level" for compounds of the present invention also may vary when the compositions of the present invention are used in combination with AZT or other known antiviral compounds or combinations thereof.

One skilled in the art can easily determine the appropriate dose, schedule, and method of administration for the exact formulation of the composition being used, in order to achieve the desired "effective concentration" in the individual patient. One skilled in the art also can readily determine and use an appropriate indicator of the "effective concentration" of the compounds of the present invention by a direct (e.g., analytical chemical analysis) or indirect (e.g., with surrogate indicators such as p24 or RT) analysis of appropriate patient samples (e.g., blood and/or tissues) . As general guidelines only, it is believed that an initial dose of 675 mg for the preferred formulation discussed above, for each day for two days (equivalent 225 mg I/dose) will be preferred, followed by a dose of 1350 mg each day for the following 3 days. The final optimum dose is contemplated to be 2700 mg 3 times/day after meals. For prophylaxis, it is contemplated that a dose of about 675 mg per day will be preferred.

Alternatively, if the clinical environment permits, the minimum treatment dose of 675 mg should be administered for a period of five to ten days at which time the serum TSH should be measured to determine the adequacy of iodine content of plasma. This should be compared with the iodine content of the plasma determined prior to start of treatment and the serum TSH at that time If TSH has not been depleted, the dose should be increased at intervals of five to ten days until TSH production and release is to a low normal or non-detectable amount. At this time the patient's clinical picture should be used as a back-up control with close observation of cardiac, nervous system and adrenal functions. The iodine and tannic contents of the plasma should be at a maximum that does not damage the clinical picture. The protocol for dosage should be 1/2 minimum dose of 350 mg per day for five days. If readily accepted by the patient the dose should then be increased by 90 mg (1/4 of minimum dose) each 10 days until optimum dose of 2700 mg is reached. At any time during the use of this protocol that the patient's clinical picture declines the dose should be reduced. The TSH test is an important parameter.

In the treatment of some virally infected individuals, it may be desirable to utilize a "mega-dosing" regimen, wherein a large dose of the naphthoquinone, derivative thereof, and/or prodrug thereof is administered, time is allowed for the compound to act, and then a suitable reagent is administered to the individual to inactivate the active compound(s) .

The pharmaceutical composition may contain other pharmaceuticals, in conjunction with the iodine containing compound, derivative, and/or prodrug, when used to therapeutically treat acquired immunodeficiency syndrome (AIDS) . Representative examples of these additional pharmaceuticals include antiviral compounds, immunomodulators, immunostimulants, and antibiotics. Exempletive antiviral compounds include AZT, ddl, ddC, gancylclovir, fluorinated dideoxy-nucleotides, nonnucleoside analog compounds such as nevirapine (Shih et al., PNAS, 8_8: 9878-9882, 1991), TIBO derivatives such as R82913 (White et al. , Antiviral Research, 16.: 257-266, 1991), and BI-RJ-70 (Shih et al. , Am . J. Med . , 90 (Suppl. 4A) : 8S-17S, 1991) . Exempletive immunomodulators and immunostimulants include various interleukins, CD4, cytokines, antibody preparations, blood transfusions, and cell transfusions. Exempletive antibiotics include antifungal agents, antibacterial agents, and anti- Pneumocystitis carnii agents.

Administration of the virus-inhibitory compound with other anti-retroviral agents and particularly with known RT inhibitors, such as ddC, AZT, ddl, ddA, or other inhibitors that act against other HIV proteins, such as anti-TAT agents, will generally inhibit most or all replicative stages of the viral life cycle. The dosages of ddC and AZT used in AIDS or ARC patients have been published. A virustatic range of ddC is generally between 0.05 μM to 1.0 μM. A range of about 0.005-0.25 g/kg body weight is virustatic in most patients. The preliminary dose ranges for oral administration are somewhat broader, for example 0.001 to 0.25 mg/kg given in one or more doses at intervals of 2, 4, 6, 8, 12, etc. hours. Currently, 0.01 mg/kg body weight ddC given every 8 hrs is preferred. When given in combined therapy, the other antiviral compound, for example, may be given at the same time as the naphthoquinone compound or the dosing may be staggered as desired. The drugs also may be combined in a composition. Doses of each may be less when used in combination than when either is used alone.

The present inventive compounds and methods are further described in the context of the following examples. These examples serve to illustrate further the present invention and are not intended to limit the scope of the invention. Unless otherwise specified, all references to "parts" in the Examples is meant to refer to parts by weight.

EXAMPLE I - PREPARATION OF IODIZED HYDROLYZABLE TANNIN

A solution of 5 parts of iodine in 50 parts of ethyl alcohol is added, with stirring, to a second solution comprised of 5 parts of tannic acid in 50 parts of ethyl alcohol. The resulting mixture is stirred for two hours, after which the solution is evaporated and the resulting iodized tannin is recovered. The principal product is identified as being the triester of glucose with 2,6-diiodogallic acid having the following formula:

EXAMPLE II - PREPARATION OF IODIZED ACETYL SALICYLIC ACETATE

2,4-dihydroxy benzoic acid from Aldrich (D10, 940-1) is added, with stirring, to a solution of iodine in acetic anhydride, with the iodine being present in excess. The mixture is heated at 65° C, resulting in the formation of iodized acetyl salicylic acid, the principal product being 2,4-acetyl-5-iodo-benzoic acid. The reaction scheme for this reaction is as follows:

2,4-dihydrobenzoic acid (CH₃ CO)₂ O (excess) (Aldriclι D10,940-l)

EXAMPLE III - PREPARATION OF IODIZED ACETYL SALICYLIC ACID

5-iodo-salicylic acid from Lancaster ( 1394 ) is mixed with an excess of acetic anhydride. The principal product recovered is 2-acetyl-5-iodo benzoic acid, which precipitates as needles from a chloroform extraction.

5-iodosalicylic acid Benzoic acid 2-acetyloxy,5-iodo

Claims

WHAT IS CLAIMED IS:

1. An antiviral composition which comprises an antiviral effective amount of at least one antiviral compound selected from the group consisting of iodized tannin and iodo-derivatives of benzoic acid compounds having the following formula,

wherein R , R , R , and R are independently selected from the group consisting of hydrogen, acetyl, and iodo, provided that at least one of R , R_, R.and R. is iodo; and a pharmaceutically acceptable carrier.

2. The composition of claim 1 wherein the iodo- derivatives of benzoic acid are selected from the group consisting of 2,4-acetyl-5-iodo-benzoic acid and 2-acetyl- 5-iodo benzoic acid.

3. The composition of claim 2 comprising iodized tannin, 2,4-acetyl-5-iodo-benzoic acid and 2-acetyl-5-iodo benzoic acid.

4. The composition of claim 3, which further comprises an antiviral effective amount of at least one additional antiviral compound.

5. The composition of claim 4, wherein said additional antiviral compound is selected from the group consisting of AZT, ddl, ddC, gancyclovir, fluorinated dideoxynucleotides, nevirapine, R82913, Ro 31-8959, BI-RJ- 70, acyclovir, α-interferon, and recombinant CD4.

6. A method of preventing or treating a viral infection, which method comprises administering to a host an antiviral effective amount of at least one compound selected from the group consisting of iodized tannin and iodo-derivatives of benzoic acid compounds having the following formula,

wherein R , R , R_, and R are independently selected from the group consisting of hydrogen, acetyl, and iodo, provided that at least one of R , R , R and R. is iodo.

The method of claim 6, wherein said host is a human.

8. The method of claim 7, wherein said viral infection is by a retrovirus.

9. The method of claim 8, wherein said retrovirus is a human immunodeficiency virus.

10. The method of claim 9 wherein the iodo- derivatives of benzoic acid are selected from the group consisting of 2,4-acetyl-5-iodo-benzoic acid and 2-acetyl- 5-iodo benzoic acid.

11. The method of claim 10 wherein an antivirally effective amount of a composition comprising iodized tannin, 2,4-acetyl-5-iodo-benzoic acid and 2-acetyl-5-iodo benzoic acid is administered.