COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS

Abstract: Disclosed herein are antiviral agents, pharmaceutical formulations comprising effective amounts of these agents and methods for treating mammals suffering from infections caused by viruses. The agents are analogs, isomers, homologs, derivatives and salts of aromatic polycyclic diones.

Description: COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS BACKGROUND OF THE INVENTION This application is a continuation-in-part of copending U.S. patent application Serial No. 417,163 filed October 4, 1989 which is a continuation-in-part of U.S. Patent Application Serial No. 324,177, filed March 16, 1989. This invention relates to antiviral compounds, composi¬ tions and pharmaceutical formulations comprising effective amounts of these compounds and methods for treating or prevent¬ ing infections caused by viruses in mammals. The ability of viruses to invade cells and parasitize cellular biochemical mechanisms for viral replication restricts the potential means and methods that can be used to selectively inhibit such replication. Very few antiviral agents which are non-toxic for non-infected cells are known. Furthermore, most antiviral agents are of limited effectiveness. Retroviruses are particularly elusive targets for antiviral agents precisely because these viruses differ radically in their mode of replication from the DNA-containing and other RNA-containing viruses. Retroviruses become in¬ tegrated into the cellular genome and their replication is probably mediated by cellular enzymes. This severely restricts the possibilities of eliminating the virus from the host cell. Only a few compounds are known to possess relatively selective (i.e. relatively noncytotoxic) anti-retroviral activity. The nucleoside analog 3'-azido-3'-dideoxythymidine also commonly known as azidothymidine (hereinafter referred to as AZT) and other nucleoside analogs (such as the dideoxycytidine analog of cytosine) owe their relative selectivity for virally-infected cells to their ability to inhibit retroviral functions (i.e., the activity of reverse transcriptase enzyme) more efficiently than they inhibit host cell functions (i.e., the activity of DNA polymerase). The use of such nucleoside analogs is limited due to their narrow spectrum of activity and their toxic side- effects when administered systemically to a host organism over long periods of time. Furthermore, long-term use of these drugs increases the likelihood of development of resistant mutants. A member of the retroviral family, the Human Im¬ munodeficiency Virus (HIV), is currently being spread in epidemic proportions in the U.S. and around the world. HIV is now believed to be the causative agent of Acquired Immune Deficiency Syndrome (AIDS). Two different serotypes of the virus have been identified to date: HIV-1 and HIV-2. Current estimates are that approximately 1.5 million people have been infected with HIV at thiε time in the United States alone. It is believed that the vast majority of individuals infected with the virus eventually will develop AIDS and are likely to succumb to opportunistic infections and/or malignancies. The drug currently used against HIV infection is AZT. However, because of the toxicity of AZT and because its effectiveness is also otherwise limited, alternative antiviral agents (or at least agents of relatively low toxicity that could be used in conjunction with AZT therapy) are needed. Moreover, because of its toxicity, AZT is inappropriate for use prophylactically and therefore less toxic alternatives suitable for prophylactic use are desired. In addition, AZT-resistant strains of HIV have been recently reported. Copending U.S. Patent Application Serial No. 082,700 of D. Lavie et al. filed August 7, 1987, discloses the antiviral activity of two aromatic polycyclic dione compounds: hypericin (Hy) and pseudohypericin (Ps). Copending U.S. Patent Application Serial No. 084,008 of D. Lavie et al. filed August 10, 1987 expands upon the dis¬ closure of U.S. Application Serial No. 82,700, focusing on the use of Hy and Ps as effective anti-retroviral agents. Copending U.S. Patent Application Serial No. 172,064 filed March 23, 1988 of D. Meruelo et al. discloses anti- retroviral compositions comprising effective amounts of Hy and Ps in combination with nucleoside analogs such as AZT and methods for treating retroviral infections. In addition, copending U.S. patent application of Daniel Meruelo and Gad Lavie Serial No. 299,971, filed January 19, 1989 entitled Blood Purification System discloses composi¬ tions and methods for inactivating viruses and retroviruses present in blood, other body fluids and, more generally biological fluids, and articles used in the practice of such methods. The compositions comprised hypericin, pseudo¬ hypericin, isomers, analogs, homologs, and derivatives of aromatic polycyclic diones and mixtures of these compounds, all of which are also used in the present invention. The present invention is directed to use of a variety of compounds structurally related to hypericin as therapeutic (or prophylactic) antiviral and antiretroviral agents in vivo. Therefore, it is an object of the present invention to provide novel therapeutic agents for the treatment (or preven¬ tion) of viral infections. (Henceforth, the terms "virus" and "viral" will include "retrovirus" and "retroviral" unless explicitly stated otherwise. ) Another object of the present invention is to provide methods for treating mammals suffering from (or potentially exposed to) infections caused by viruses, especially HIV. A further object of the present invention is to provide pharmaceutical formulations for treating individuals suffering from (or potentially exposed to) viral infections. These and other objects of the present invention will be apparent to those of ordinary skill in the art in light of the present description accompanying drawings and appended claims. SUMMARY OF THE INVENTION The present inventors have discovered that certain compounds are effective for treating or preventing viral infections in mammals. Furthermore, the present inventors have devised compositions (comprising such compounds) suitable for therapeutic or prophylactic use in vivo. These compounds are related to hypericin and comprise monomers or dimers of anthracenes, anthraguinones and anthrones, as well as homologs, isomers, derivatives, salts and analogs of any of the foregoing and mixtures thereof. (Hereafter, these compounds will be referred to as "antiviral anthraquinone- or anthracene- or anthrone-based compounds" abbreviated as "AAB".) In addition, within the scope of the present invention are various aromatic polycyclic dione compounds as well as homologs, isomers, derivatives, salts and analogs of such polycyclic compounds and mixtures thereof. Hereafter, all the compounds of the present invention including those which are not "AAB compounds" will be referred to collectively as "polycyclic antiviral compounds" or "PAC". In this context, "polycyclic" means having at least three rings. In one aspect, the present invention comprises a method for preventing or treating a viral infection in a mammal comprising administering to such a mammal an effective amount of a compound selected from the group consisting of PAC compounds and mixtures thereof wherein said PAC compounds or mixtures are used as the sole antivirally active ingredients or in conjunction with other antiviral agents (or in conjunction with stabilizers and/or potentiators of PAC compounds and/or other antiviral agents). Another aspect of the present invention comprises pharmaceutical compositions and formulations for treating or preventing viral infections in mammals, said compositions and formulations comprising an effective amount of an antiviral agent selected from the group consisting of PAC compounds and mixtures thereof and a pharmaceutically acceptable carrier or diluent. DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and literature references referred to in this specification are hereby incorporated by reference in their entirety. However, the meaning specifically ascribed herein to defined terms shall prevail (in case of discrepancy with definitions in the prior patent applications incorporated by reference herein). The present inventors have discovered that PAC com¬ pounds are useful for the treatment (or prevention) of infec¬ tions caused by viruses. The structure of the AAB compounds and many PAC compounds falls within the general Formula I wherein: n is an integer selected from 1 and 2; each of A, C, D, E, F, H, I, J is independently selected from the group consisting of hydrogen, hydroxy, lower (C-^ - C4) alkyl, aryl, arylalkyl, arylamino, lower alkenyl, alkoxy, hydroxyalkyl, halogen, carboxy, acyl (aromatic or aliphatic), amino, acyloxy, alkoxycarbohyl, aryloxycarbonyl (each of which may be substituted or unsubstituted), and a dimer-forming bond; each of B and G are independently selected from the group consisting of (a) oxygen forming a keto group with the ring carbon to which the oxygen is appended; (b) two hydrogen atoms; (c) one hydrogen atom and one peroxy group; (d) aryl; (e) alkenylcarbonylalkyl; (f) alkenyloxycarbonylalkyl; (g) cyanoalkenyl; (h) arylalkenyl; (i) lower alkyl; (j) alkenyl; (k) acyl; each of which may be substituted or unsubstituted; and (1) a double or single dimer-forming bond; wherein one or more of A and B, B and C, A and J, C and D, D and E, E and F, F and G, G and H, H and I, and I and J can be combined to form aromatic, alicyclic or heterocyclic rings having 5-7 carbon atoms, said rings optionally being further substituted; wherein the three rings in said formula are aromatic except that the particular bonds formed by one or more of the ring carbon atoms adjacent to A, B, C, H, G or F can be saturated; provided that, when n=2, at least one of H, G and F or at least one of A, B and C is a bond and either or both of (i) D and E and (ii) J and I optionally form aromatic or alicyclic or heterocyclic rings having 5-7 atoms with the adjacent carbon atoms. Several of the compounds encompassed by the above formula can be considered monomers or dimers of substituted or unsubstituted anthracenes, anthraquinones, or anthrones. For example, hypericin and substituted hypericins (such as hypericin hexaacetate) can be considered as dimers of anthraquinone (and substituted anthraquinones) with all the intermediate rings fused (i.e. wherein both H and F are single, dimer-forming, bonds and simultaneously G is a double, dimer- forming, bond). See compounds 7-10 (Series C) in Example 2 as well as compounds XI, XIV, XV, XVII. For example, compound XX in Example 2 described in Brockmann in Tetrahedron Letters, infra, is a dimer of 1, 3, 8 trihydroxy-6-hydroxyethyl-9 anthrone wherein H G and F are all bonds; compound XXII is a dimer of 1, 3, 8 trihydroxy-6-methyl- 9-anthrone wherein E has formed an extra ring with the cor¬ responding side-chain of the second anthrone monomer. Also within the definition of the PAC compounds are isomers, homologs, analogs, derivatives and salts of the compounds of Formula I. "Homologs" shall mean compounds with structural formulas that differ from the compounds of Formula I (or from another PAC compound) by one or more carbon atoms and one or more hydrogen atoms or pairs of hydrogen atoms (see by way of non-limiting example, compounds XV and XVI of Example 2 below; see also the three pairs of compounds in the table of compounds synthesized according to U.S. Patent No. 2,707,704 of Brockmann et al. issued May 3, 1955 of Example 2 below and visualize their homologs wherein one or more of the R groups will have been replaced by C2-C4 alkyl groups; and compare the structure of hypericin with that of protohypericin in Example 2 (Series C) below, etc. ) . "Isomers" shall mean compounds having the same molecular formula as the compounds of Formula I (or another PAC compound) and shall include, without limitation, structural isomers, enantio ers, position isomers, optical isomers and stereoisomers (e.g. cis and trans, + and -, d and 1) (see, by way of non-limiting example, compound 17 in Example 2 below of Banks et al. infra and its isomer wherein, e.g. the hydrogen atoms in the center would be oriented both below or above the plane of the paper and compound 25 in Example 2 below of Weiss, U. et al., infra which has several asymmetric carbon atoms and its various optical isomers) . "Analogs" shall include polycyclic aromatic compounds having the same activity as Hy and Ps (e.g., compounds referenced to Weiss, U. et al. infra, and compounds selected among compounds 1-36 of Example 1). "Derivatives" shall include compounds bearing a strong structural similarity to a compound of Formula I or to another PAC compound but having one or more substitute groups in one or more positions (see, e.g. compounds 7 and 9 of Banks et al. in Example 2; benzoic acid derivatives of the XIX compound of Brockmann, et al., infra in Example 2 (series A) below and hydroxylated, esterified, alkyl-substituted and otherwise substituted derivatives of the compounds specifically disclosed herein) . A non-limiting list of the compounds used in the present invention iε set forth in Examples 1 and 2 below. Salts (of the above compounds) soluble in aqueous media and physiologically acceptable are particularly preferred. "Salts" shall mean both complex salts (such as compound 26 of Weiss et al. infra of Example 2 below) and ionic salts. The AAB dimer compounds can be synthesized using for example one of the synthetic schemes set forth below: (Scheme I) (Scheme II) dimethyl εulfate (i) (ϋ) IB*. R—CEU π__.„R-_-H This scheme also applies when the starting material is an anthracene or an anthrone. The protecting/deprotecting step in Scheme I can be used or not depending on the starting material and the desired product (e.g. if the starting material is a fully alkoxylated emodin derivative such as compound 1 of the Brockmann patent, infra, and the end product is compound 7 of the same reference then no protection would be necessary) . The various sub¬ stitutes of the ultimate dimer can thus be appended either on the starting tricyclic (or other) material or can be con¬ stricted by modification of the dimeric structure itself, depending on the reactivity of each particular site, as is well-known in the art. A third general reaction scheme is the following: (Scheme III) (m-cresol ) 3 j 5-dimethoxy- 2-(2'<4ιydroxy« '<_oethyl-benzoyl) • 3:5 c-phtl lic anhydride dimetboxy- cnzoic acid halogenating agent Z = halogen The starting monomers can be synthesized according to well-known techniques or can be purchased from commercial sources. For example, anthrone can be synthesized as described in Org. Syn. Coll. .1: 60, 1941, or purchased from Aldrich Chemical Co., Milwaukee, WI (Cat # A9,120-5). Anthrone derivatives can be synthesized from anthrone as described in Anal. Bioche . 68.:332, 1975. Anthracene can be synthesized according to the method described in E. Clar, Chem. Ber. 72: 1645, 1957 and E. Clar, Polycyclic Diones. Academic Press, N.Y. 1964 or purchased from Aldrich Chemical Co, Cat. # A8, 922-0. Anthracene derivatives (such as anthracene dione) can be synthesized from phthalic acid and benzene in AICI3 via Friedel-Crafts reaction as described in Ind. Eng. Chem. 18: 1327, 1926. 11 In addition, PAC compounds can be advantageously combined (as therapeutic or prophylactic agents) with nucleoside analogs such as AZT when treating retroviral infection. That is, one or more PAC compounds can be adminis- tered in conjunction with one or more of AZT or another nucleoside analog. "In conjunction" includes co-administra¬ tion, contemporaneous administration of different preparations (each preparation containing one type of active ingredient or ingredients — nucleoside(s) or PAC compound(s) — or alternat- ing administration of nucleoside therapy and PAC compound therapy. Advantages of such conjunctive therapy include at least additive enhanced therapeutic (or prophylactic) effect — nucleoside therapy does not interfere with PAC therapy — and diminished risk of undersirable side-effects of either active ingredient. Preferred conjunctive therapy includes use of AZT and hypericin. AZT is currently being employed to treat patients with AIDS and/or ARC (AIDS Related Complex, a prodrome of AIDS). AZT has been shown to improve immunologic functions, to reverse, at least partially, HIV-induced neurological disfunc¬ tion in some patients and to improve certain other clinical abnormalities associated with AIDS. However, a dose-dependent suppression of bone marrow, resulting in anemia and leukopenia (an abnormally low number of leukocytes in the circulating blood) has been found to occur with its use. This has limited the effectiveness of AZT for the treatment of AIDS. Because of • the displayed additive therapeutic or prophylactic effect of AAB and other PAC compounds administered in conjunction with AZT it is anticipated that it will be possible to use smaller doses of AZT for antiviral therapy when AZT is used in combina¬ tion with the present compounds (most notably in AIDS therapy) which will decrease or eliminate the undersirable side-effects of AZT. The combined effect of AZT and the compounds of the present invention iε shown in Example 1 below. As illustrated in Example 1, the activity of AZT does not interfere with that of PAC compounds. Accordingly, the present invention includes the use of effective amounts of PAC compounds (as disclosed below) in combination with AZT or other nucleoside analogs for treating viral (especially retrovival) infections. Non-limiting examples of nucleoside analogs useful in the present invention are 2', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine, 2' , 3'- dideoxythymidine and preferably azidothymidine (AZT, commer¬ cially available from Burroughs Welcome Research Triangle Park, NC). 2', 3'-dideoxycytidine and 2', 3'-dideoxyadenosine are commercially available from Calbiochem-Behring (San Diego, CA) ; 2', 3'-dideoxythymidine is commercially available from Phar÷ macia Fine Chemicals (Piscataway, NJ) . The PAC compounds of the present invention (even when used by themselves, i.e., not in conjunction with nucleoside analogs) have a wide spectrum of effectiveness in inhibiting viruses and are especially effective in inhibiting enveloped viruses. Enveloped viruses are defined herein as viruses (both RNA- and DNA-containing) having a lipid-containing membrane. The lipid is derived from the host cell whereas the membrane proteins and glycoproteins are virally encoded. Non-limiting examples of the enveloped viruses which are inhibited by the compounds of the present invention are cytomegalovirus, Herpes Simplex Virus (HSV), vaccinia virus, influenza virus. Vesicular Stomatitis Virus (VSV) , Hepatitis B virus and retroviruses. Retroviruses are viruses containing an RNA genome and RNA-dependent DNA polymerase (reverse transcriptase) enzymatic activity. All retroviruses have common morphological, biochemical and physical properties that justify their in¬ clusion into a single virus family. These parameters are summarized in Table I below (RNA Tumor Viruses. Weiss, R. et al. eds., p.28, Cold Spring Harbor Press, New York, 1984). Most preferred among the AAB compounds are hypericin, pseudohypericin, hypericin hexaacetate, and protohypericin, with hypericin being the most active. For prophylactic administration the AAB compounds having low toxicity (by comparison to AZT) are preferred, with hypericin, pseudo¬ hypericin and protohypericin being again most preferred. In general, a compound is considered to have low toxicity if it has a therapeutic index greater than 5, i.e. it is effective at doses five times smaller than the dose at which it causes severe toxicity. TABLE I GENERAL PHYSICAL PROPERTIES OF KNOWN RETROVIRUSES Nucleic acid linear positive-sense single-stranded RNA (60S-70S) composed of identical subunits (30S-35S); 5' structure (m 7 G 5 ppp 5 NmpNp) ; polyadenylated 3' end; repeated sequences at 3' and 5' ends; tRNA base-paired to genome complex Protein above 60% by weight; gagr, internal structural proteins; pol, reverse transcriptase; env, envelope proteins Lipid about 35% by weight; derived from cell membrane Carbohydrate about 4% by weight; associated with envelope proteins Physicochemical density 1.16-1.18 g/ml in sucrose, 1.16-1.21 properties g/ml in cesium chloride; sensitive to lipid solvents, detergents, and heat inactivation (56°C, 30 min); highly resistant to UV- and X-irradiation Morphology spherical enveloped v.irions (80-120-nm diameter), variable surface projections (8-nm diameter), icosahedral capsid containing a ribonucleoprotein complex with a core shell (nucleoid) In addition, the genome of HIV encodes at least 5 other proteins in addition to those normally found in other retroviruses. These additional genes are designated TAT, ART/TRS, 3'-ORF, SOR and R. HTLV I also contains an additional gene, the pX gene, which may encode up to four proteins (Yarchoan, R. et al.. New England J. Med. 316: 557-564, 1987; Seiki et al.. Science 228: 1532-1534, 1985). All retroviruses have similar overall chemical composi¬ tions. In general, they comprise about 60-70% protein, 30-40% lipid, 2-4% carbohydrate, and about 1% RNA. Retroviruses are enveloped. The envelope of retroviral particles is derived from the cell-surface membrane, and most, if not all, of the lipids in the retroviral particles are located in the unit- 14 membrane envelope of the virion. Non-limiting examples of retroviruses include Friend Leukemia Virus (FV) , Radiation Leukemia Virus (RadLV), Bovine Leukemia Virus, Feline Leukemia virus, Avian Myeloblastosis Virus, and the human T-cell ly photropic virus family (HTLV I, II, III and IV; HTLV III is also known as Human Immunodeficiency Virus or HIV in turn encompassing two serotypes designated as HIV-1 and HIV-2). HTLV I is believed to cause adult T-cell leukemia and certain neurological illnesses and HTLV II is believed responsible for hairy cell leukemia in humans. HTLV IV is related to simian immunodeficiency virus and has been found in African natives• suffering from AIDS; its relationship to HTLV III is currently under investigation. The present invention provides a method for treating mammals suffering from infections caused by viruses (or retroviruses) comprising administering to mammals in need of such treatment a therapeutically (or prophylactically) effec¬ tive amount of a compound selected from the group consisting of PAC compounds and mixtures thereof. Effective inhibition of a given virus may be achieved by using a single one of such compounds, or a combination of two or more of such compounds. Naturally, it is desirable to employ the smallest possible quantity of the PAC compound or compounds that will provide a significant inhibition of the target virus. What constitutes "significant inhibition" varies from virus to virus. For example, significant inhibition of Fried Leukemia Virus-induced splenomegaly is at least 15% (inhibition being calculated according to the formula given in Example 2, below). Significant inhibition of HIV is defined as at least one log reduction in the infectivity of free virus preparations. In addition, one, two or more of the compounds can be employed together. Moreover, the PAC compounds or mixtures may constitute the sole active ingredient of the composition of the present invention or may be employed in conjunction with other antiviral agents and/or other in¬ gredients active in inhibiting viral replication and/or otherwise diminishing or abolishing viral infectivity (e.g. by inactivating the virus directly). When treating mammals suffering from infections caused by viruses according to the present invention, the determina¬ tion of the most effective compound or mixture of compounds for treatment of the particular virus or retrovirus responsible for the infection can be ascertained by routine experimentation using suitable experimental models, such as that described in Example 5 for HIV in vitro or in Example 1 for Friend Leukemia Virus in experimental animals. When employed in vivo to treat AIDS, viremia (i.e. the presence of virus in the blood stream) or sepsis (viral contamination of bodily fluids) caused by viruses, the PAC compounds may be administered orally, topically or preferably parenterally, and most preferably intravenously at dosages which can be broadly defined by reference to hypericin as follows: Antiviral compositions containing hypercin as the sole active ingredient can be used at dosages containing from about 0.002 to about 100,000 micrograms per kilogram bodyweight per treatment, preferably between about 2 micrograms and about 5 x 10^ micrograms per kilogram bodyweight per treatment, and most preferably between about 200 micrograms and 5 x 10^ micrograms per kilogram bodyweight per treatment. When one or more other PAC compounds are used as the active ingredient, the broad dosages will generally be the same as with hypericin. It iε understood, however, that if a given PAC compound haε e.g. twice the activity of hypericin, the minimum effective dosage will be one-half that of hypericin. Moreover, when more than one active (antiviral) ingredient (i.e., at least one non-PAC antiviral agent is induced) is used in a therapeutic or prophylactic regimen according to the invention, the minimum dosage of the PAC component (i.e., the PAC compound or compounds) of this regimen may be decreased if desired or appropriate. Finally, when more than one active ingredient is used and there is synergis between the PAC component and the other antiviral ingredient or ingredients (or between two or more PAC compounds, even in single active- ingredient regimens, i.e., in regimens where the only antiviral agent or agents are PAC compounds), the minimum effective dosages will be even smaller. It should be also understood that analogous minimum dosage modifications apply when a stabilizing or potentiating agent is used in conjunction with a PAC compound. To illustrate the foregoing, consider a therapeutic or prophylactic regimen that involves administration of a PAC compound in conjunction with an antivirally active nucleoside analog, as an example of use of more than one active in¬ gredient. (It should be understood that "in conjunction" means coadministered or administered sequentially but as part of the same treatment regimen) . When one or more nucleoside analogs are used in combination with the compounds of the present invention, the nucleoside analog may be administered in conjunction with the PAC compound(s) at doses broadly ranging between about 0.001 and about 20,000 micrograms/kg body weight of said mammal per treatment (again based on hypericin). A preferred minimum dose under these circumstances is 1 microgram and a most preferred minimum dose is 100 micrograms all per kg body weight. The duration and number of doses or treatments required to control the disease will vary from subject to subject, depending upon the severity and stage of the illness and the subject's general condition and will also depend on the specific antiviral activity of each PAC compound, as well as its toxicity (if any). The total dose required for each treat¬ ment may be administered in divided doses or in a single dose. The antiviral treatment may be adminiεtered daily, more than once daily, one or two times a week, or as determined by the subject's condition and the stage of the disease. The present inventors have also discovered that the an¬ tiviral activity of hypericin is a function of the frequency of treatment. For example, in mouse studies, a single dose of ten micrograms per mouse was less effective than a single dose of 100 micrograms per mouse, as expected. However, administration of 10 micrograms every day for ten days was less effective than even a single 10-microgram dose. By contrast, administration of 10 micrograms once a week was as effective as the single 10- microgram dose. This indicates that the frequency of treatment effects its efficacy. While the foregoing observations in mice may not be applicable to other mammals or humans, those skilled in the art will appreciate that the frequency of treatment is subject to optimization, which can be determined by routine experimentation according to methods well known in the art, e.g. by establishing a matrix of dosage and frequency and assigning a group of experimental subjects to each point of the matrix. Design of this experiment should preferably also take into account the tissue accumulation properties of PAC com¬ pounds. The present invention also provides pharmaceutical compositions and formulations for treating viral infections. The PAC compounds of the present invention can be incorporated in conventional, solid and liquid pharmaceutical formulations (e.g. tablets, capsules, caplets, injectable and orally administrable solutions) for use in treating mammals that are afflicted with viral infections. The pharmaceutical formula¬ tions of the invention comprise an effective amount of the PAC compounds of the present invention (as disclosed above) as the active ingredients (alone or in combination with other active or inert agents as discuεsed above). For example, a parenteral therapeutic composition may comprise a sterile isotonic saline solution containing between about 0.001 micrograms and about 100,000 micrograms of the polycyclic compounds of the present invention and between about 100 and 50,000 micrograms of the nucleoside as described above. It will be appreciated that the unit content of active ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of capsules, tablets, injections or combinations thereof. Each formulation according to the present invention may additionally comprise inert constituents including phar- maceutically-acceptable carriers, diluents, fillers, salts, and other materials well-known in the art the selection of which depends upon the dosage form utilized and the particular purpose to be achieved according to the determination of the ordinarily skilled artisan in the field. For example, tablets may be formulated in accordance with conventional procedures employing solid carriers well known in the art. Examples of solid carriers include, starch, sugar, bentonite, silica and other commonly used carriers. Propylene glycol, benzyl alcohol, isopropanol, ethanol, dimethylsulfoxide (DMSO) dimethylacetamide or other biologically acceptable organic solvents or aqueous solutions (e.g. water with a pH higher than 7 and preferably about 8) may be used as diluents, carriers or solvents in the preparation of solid and liquid pharmaceutical formulations containing the anti-retroviral compositions of the present invention. Further nonlimiting examples of carriers and diluentε include carbohydrates, albumin and/or other plasma protein components such as low density lipoproteins, high density lipoproteins and the lipids with which these serum proteins are associated. Such lipids include phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine and neutral lipids such as triglycerides. Additional lipid carriers include without limitation tocopherol, retinoic acid and cyclodextranes. Semisolid formulations such as those well- known in the art (e.g. suppositories) are also contemplated. Preferred parenteral dosage forms may comprise for example an isotonic saline solution, containing between about 0.1 micrograms and about 100,000 micrograms of the polycyclic compounds of the present invention. Capsules employed in the present invention may be made from any pharmaceutically acceptable material, such as gelatin or cellulose derivatives. Sustained release oral and transdermal delivery εyεtems are also contemplated. The antiviral polycyclic compounds of the present invention may additionally be incorporated into liposomes for use as specific drug carriers. Such liposomes may also comprise other active agents e.g., specific anti-HIV antibodies directed against viral proteins expressed by virally infected cells such as HIV pl20, p41 and p24 (as well as glycosylated forms thereof) to act as specific targeting agents. The present invention is described below and specific working examples which are intended to illustrate the invention without limiting the scope thereof. EXAMPLE 1; ANTI-RETROVIRAL EFFECT OF THE POLYCYCLIC COMPOUNDS OF THE PRESENT INVENTION (a) Effects of PAC Compounds Used Alone. The effects of compositions according to the present invention on infection of mammals with Friend Leukemia Virus (FV) were examined. Friend Leukemia Virus is an aggressive retrovirus which induces an acute erythroleukemia in sensitive strains of mice such as BALB/c and NIH swiss mice as described in Friend, C.J., Exp. Med. 105: 307-324, 1957; Friend, C. et al. Proc. Natl. Acad. Sci. USA 68: 378-383, 1971; Friend, C. et al. Natl. Cancer Inst. Mongr. 22: 508-552, 1966. The malignant transfor¬ mation is the result of the combined activities of the Spleen Focus Forming Virus (SFFV) and the ecotropic Murine Friend Leukemia Helper Virus (F-MuLV). The acute erythroleukemia is characterized by hepatosplenomegaly (a marked increaεe in the εize of the εpleen and liver) and a εevere anemia. Friend Leukemia Virus was prepared by homogenizing the enlarged spleen of a mouse previously infected with FV, 10 days after intravenous virus injection. The spleen was homogenized in phosphate buffered saline in a volume equal to ten times the weight of the isolated spleen. The effects of compositions according to the present invention on the increase in εpleen size (splenomegaly) of BALB/c mice (Jackson Labs, Bar Harbor, ME) was examined. In these experiments, the virus (10° focus forming units - FFU) was inoculated intravenously and 100 micrograms of the com¬ pounds indicated in Table II were administered to the mice intraperitoneally 24 hours later. Each compound was ad¬ ministered once to two mice. The animals were sacrificed ten days later and their spleens weighed. Each compound listed below in Table II had five or more fused aromatic rings in any configuration and hence constitutes an analog of a Formula I compound. While the Friend virus system permits testing the activity of the compounds of the present invention, in an acute infection system several points should be noted. Transforma¬ tion of erythroid precursor cells occurs rapidly after virus inoculation. Once transformation by FV occurs, disease is likely to result. Therefore, any inhibition of viral splenomegaly caused by FV by the compounds of the present invention indicates a strong effectiveness for a rapidly- evolving disease and therefore the active compounds of the present invention will also be effective against a slowly- evolving disease. Hence, the results presented above may be extrapolated to a slower and gradually progressive disease such as that caused by HIV. The present assay has been developed from similar assays using hypericin or pseudohypericin and employing higher numbers of experimental animals per group (e.g. 4 animals). It was discovered however that the specificity and sensitivity of this assay are such that an experimental group of two animals is of more than adequate predictive value. The resultε are εhown in Table II below. •raπrπ TT Actual Average Average Tteatiπeπt Spleen Weight Spleen Weight % jj-jH h. * Hr__ PBS (ι_3ga_ive control) 0.1560 0.1495 0.1429 (positive control) 0.8316 0.8550 — 0.8799 I. Decacrycle∞ 0.3940 0.3636 57.5 0.3331 2.3,4,9,10H___yl____te___a_a__x_}yl^ d____τfcdr±-__! 0.8678 0.8439 1.3 0.8200 3. Isoyiolaπthrcne 0.5147 0.5001 41.5 0.4855 4. 16,17- 0.4194 50.9 5. Bs3Zo(__tt)_*_ryl_ene-l,2-Di^^ 0.5072 0.5101 40.5 Arih t de 0.5130 0.4796 10. ___ι____o(l,2,3-_D/l',2',3'-m)I__yl-_E 0.4809 0.4767 44.3 0.4724 12.4A,5,6,3_2C****__t___ιyd__^^ 0.4400 0.4531 47.1 (3,4**C)ptenantto_ne 0.4661 13.3,4,4A,5,6,12_-___s_-^r__q^^ 0.4719 0.4742 44.6 (3,4-C)_tenaπ___rl__-le-3,6^_ά___ne 0.4765 14. __________o(3,4-*C)_ϊteraπ_____aκ 0.5580 0.5419 36.6 0.5257 15.3,4,4A,5,6,l_C*^_x_-lιyd_x __nan_Uϊro 0.3802 0.3739 56.3 (3,4* :)ptenaπthr-n-3-o_ne 0.3677 As can be seen in Table II, PAC compounds 1, 3-5, 7, 8 and 10-15 significantly inhibited FV-induced splenomegaly. As used in Table II (and subsequent Tables of this Example 1(a) and (b), "average percent inhibition" is calculated as follows! M _ ASWE - ASWNC . - QQ ASWPC - ASWNC' wherein "ASWNC" designates "average spleen weight of negative control"; "ASWE" designates "average spleen weight of ex¬ perimental (treated) subject"; and "ASWPC" designates "average spleen weight of positive Friend Virus Friend Virus (10° FFU) (10 6 FFU)+ + PS 80 mcg/mouse 2 injections PS 80 mcg/mouse 0.2831 Spleen weight (g s) 0. .2457 Spleen weight (gms) 0.2761 Spleen weight (g s) 0, .3400 Spleen weight (gms) 0.2215 Spleen weight (gms) 0, .2938 Spleen weight (gms) 0. 810 Spleen weight (gms) o. .1956 Spleen weight (gms) x=0.2404±0.0482 x=0.2687±0.0621 Net change from control=0.0558 Net change from control=0.0841 % Inhib=93.82 % Inhib=90.70 Negative Control Mice Positive Control (Friend) Mice (PBS) (2xl0 5 FFU) 0.2094 Spleen weight (gms) 0.8911 Spleen weight (gms) 0.1834 Spleen weight (gms) 0.9211 Spleen weight (gms) 0.1790 Spleen weight (gms) 0.8004 Spleen weight (gms) _ 0.1669 Spleen weight (gms) _ 0.8662 Spleen weight (gms) χ=0.1846+0.0178 x=0.8697±0.0513 Net change from σontrol=0.6851 Friend Virus (2xl0 5 FFU) Friend Virus (2xl0 5 FFU) + PS 80 mcg/mouse 2 inject PS 80 mcg/mouse 0.3457 Spleen weight (gms) 0.4924 Spleen weight (gms) 0.2784 Spleen weight (gms) 0.2469 Spleen weight (gms) 0.2208 Spleen weight (gms) 0.2722 Spleen weight (gms) _ 0.1791 Spleen weight (gms) 0.2438 Spleen weight (gms) x=0.2560±0.0723 x=0.3138±0.1197 Net change from control=0.0714 Net change from control=0.1292 % Inhib=89.58 % Inhib=81.15 The data in Table 11(a) show the inhibition of splenomegaly, with median inhibition of 93.8%, following a single injection of 80 micrograms per mouse of Ps. A median inhibition of 89.6% in spleen enlargement was observed when 80 micrograms per mouse of Ps was administered in a single injection to mice that had previously been inoculated with 0.5ml of the virus preparation (corresponding to 2xl0 5 FFU of virus). When two daily consecutive injections of Ps, each comprising 80 micrograms per mouse of the compound were administered, the median inhibition of splenomegaly was 90.7% with a viral preparation containing 10 6 FFU and 81.7% with a viral preparation containing 2xl0 5 FFU (Table 1). The above results show a marked decrease in the spleen enlargement capacity of the Friend Leukemia Virus (as measured by decreased splenomegaly) following the intraperitoneally administration of Ps 24 hours after infection. The same type of experiment can be used to measure the antiviral activity of other PAC compounds. (2) Co-administration with Friend Leukemia Virus A different experimental design waε used involving the simultaneous intravenous co-administration of Ps with the FV complex. In this case, the viral preparation was mixed with .Ps at various concentrations and the mixture was injected into the mouse tail vein in a final volume of 0.5ml. The mice were sacrificed ten days later, their spleens weighed, and the level of inhibition of splenomegaly subsequently determined. The results are summarized in Table 11(b). TABLE 1Kb) The effect of intravenous co-administration of pseudo- hypericin (diluted in PBS with 1% EtOH) with FV, on viral- induced splenomegaly. SPleen Weights (grams) Controls Exntl Exr»t2 Exp 3 PBS PBS + l%EtOH FV ] FV+PS 5mcσ FV+PS 20 πσ FV+PS 50mcg 0.1304 0.1862 1.1499 0.3425 0.1655 0.1830 0.1490 0.1567 1.0657 0.3766 0.1426 0.1674 0.1362 0.1386 0.9597 0.4005 0.1433 0.1422 0.1515 1.1347 0,4255 0.1966 0.1365 x=0.1417 x=0.1605 x=1.0774 x=0.3862 x=0.1614 x=0.1572 ±0.0101 ±0.0240 ±0.0866 ±0.0353 ±0.0253 ±0.0217 % inhibition as compared to the group receiving Ps in PBS + 1% EtOH = 75.44% 100% 100% As shown in Table 11(b) above, 100% inhibition of splenomegaly was found when Ps was administered with the viral complex at concentrations of 20 micrograms per mouse and 50 micrograms per mouse (average mouse weight approximately 150 grams). A mean inhibition of 75.44% was found when 5 micrograms per mouse was co-administered with the virus. These results show the effectiveness of the compounds of the present invention in that as little as 5 micrograms per mouse was effective in inhibiting viral transformation by this aggressive RNA tumor virus. An expanded series of experiments was next performed in which various concentrations (i.e. 50, 100, 200 and 2X100, i.e., 100 micrograms administered twice) of a different set of PAC compounds (numbers 16-29 and 30-36 in Table III below) were administered intraperitoneally each according to the same protocol described above. Compounds 16-29 all had 3-5 fused, aromatic rings and no side groups except for oxygen or hydroxyl groups, whereas compounds 30-36 all had 3 fused aromatic rings and side chains selected from the group of oxygen, hydroxyl and methyl. When 2 doses of the compounds were given, the second dose was administered 24-48 hours after the first injection. The animals were infected and splenomegaly determined as above for the compounds in Table II. The results are presented in Table III below. In Table III, "pooled average percent inhibition" is calculated by adding the average percent inhibition for each experiment with the same compound and dividing the sum by the number of experiments (i.e. the number 4). The standard deviation was computed by pooling all the data for each compound (i.e. all concentrations of a compound employed) and therefore the large standard deviation values given reflect only the variablility of the data over the range of concentrations used for each compound. As can be seen from the spleen weight values, the PAC compounds in Table III have a definite inhibitory effect. ΈB E ΠI Average _r-_dosεge BT leϋ ■fiCtLB . ≤&lesπ Aλ≡rage Average St__n_____d Tim-na-: D^se _-E-le_n Wai±t Weicht % Trhihii-l-ifn , i I-eviaticn FJ <*_£T CF EX_S_____S HS (res ive cαiL- .) 0.1247 0.142 0.1334 1.4626 FV (positive occt_r_l) 1.7272 1.5949 0.9052 16. 0.9508 44 24 16 100 1.5907 1.6057 — • 1.2007 200 1.2948 1.2478 24 1.161 2X100 1.2072 1.1867 28 1.06 17. S_SΩπ _hr_ne 50 1.21 1.1350 31 26 8 1.3626 100 1.2101 1.2864 21 1.4602 200 1.24 1.3501 17 1.0704 250.00 1.0662 1.0683 36 1.1141 18. Hierylaπthraσene 50 1.2464 1.1803 28 19 10 1.6206 100 1.4902 1.5554 3 1.3797 200 1.2794 1.3296 18 1.4116 2X100 1.0222 1.2169 26 1.0961 19. -TTT hgylgB 50 1.0036 1.0499 37 17 12 1.5971 100 1.4719 1.5345 4 1.3636 200 1.4352 1.3994 13 1.246 2X100 1.5665 1.4063 13 1.3209 20. 1.2758 22 3 19 100 1.9626 2.0019 — 1.4003 200 1.4626 1.4315 11 1.4929 2X100 1.5117 1.5023 6 1.4102 27 (ccπt'd) Average _*e__ sage Bxilsd A ual Splee Average Average Sta daxd Wa ftt _fc TrMW-Hrri 8c TirMMHm 21. 1,4,5,8,9,10- 50 1.3969 1.4036 13 17 1.4907 100 1.3334 1.4121 13 1.4772 200 1.1121 1.2947 21 1.3242 2X100 1.2006 1.2624 23 0.9242 100 6226 1.5171 5 5997 200 5828 1.5913 0 4611 2X100 3629 1.4120 13 1.1961 23. 100 1.4147 1.5131 6 1.0303 200 1.1618 1.0961 34 1.0119 2X100 1.2443 1.1281 32 1.3016 24. _tet--3E_hgylcyc3o pa±adisxne 50 1.2902 1.2959 20 16 1.3774 100 1.4106 1.3940 14 1.61 200 1.404 1.5070 6 1.2876 2X100 1.1998 1.2437 24 1.2062 25. 2*4_3t-γlaπt_ xacεne 50 1.2145 1.2104 26 30 1.0062 100 1.1149 1.0606 37 1.2106 200 1.1702 1.1904 28 1.19 2X100 1.1616 1.1758 29 1.2003 28 (σcπt'd) Stardaid 26. I,2,3,4**_t3t__ϊ-___5a-l, 3-*cy lqpa .Lrfli as 50 1.1967 1.1985 27 25 15 0.9898 100 1.0662 1.0280 39 1.0779 200 1.1482 1.1131 33 2161 2X100 977 1.5966 0 2226 27. B_ryla_e 50 407 1.3148 19 5572 100 4982 1.5277 5 5066 200 7022 1.6044 1 496 2X100 1.3723 1.4342 11 1.2351 28. __π__cεre 50 1.3209 1.2780 22 12 1.4996 100 1.5772 1.5384 ■ 4 1.4806 200 1.3749 1.4278 11 1.4208 2X100 3996 1.4102 13 6182 29. 9-Vi-y_anL ranene 50 6851 1.6517 4 14 11 1792 100 2606 1.2199 26 2933 200 1.2933 1.2933 21 1.3747 2X100 1.3747 1.3747 15 ΕES (negative ocπtrol) 0.2061 0.1551 0.1806 IV (positive ccπtmL) 2.0462 2.1004 2.0733 Hy (h^Rriπi ) 15Cπg 0.7245 0.8169 0.7707 63 30. A-±-Xl 50 1.4837 1.4953 31 53 13 1.5069 100 0.8623 0.8790 63 0.8957 200 0.9567 0.9092 62 0.8616 2X100 0.9799 0.9878 57 0.9956 29 (ccπt'd) Average Eterdosage Bxtted Artual j-pleen Average Average Stardard TteaϋiB± D__3e __pLeen ^feid_ t Ws ζ S Tr* . * j> * fi * ir * n 3. Ty * frj)τi * l * -jrr. Dgyjgtiα 31. XaπOxze 50 0.965 1.0006 57 59 1.0362 100 0.9708 0.9806 58 0.9903 200 0.9866 0.9431 60 0.8996 2X100 0.8744 0.9003 62 0.9262 32. A_rt±ιraf_lavdc acid 50 1.7072 1.5718 26 50 15 1.4363 100 1.1367 1.1542 49 1.1717 200 0.8236 0.8593 64 0.8949 2X100 0.961 0.9325 60 0.904 33. 2-{_haτyl-l,2, inacl ne 50 0.9376 0.9410 60 51 21 0.9444 100 1.8237 1.7763 16 1.7288 200 0.7737 0.7938 68 0.8138 2X100 0.9522 0.9127 61 0.8732 34. Bτoϋ_n 99% 50 1.3341 1.2914 41 38 11 1.2487 100 1.1661 1.1333 50 1.1005 200 1.7441 1.6902 20 1.6363 2X100 1.2635 1.2834 42 1.3033 35. 2-0^d_r_§_redyl)- 50 0.8845 0.8921 62 70 0.8996 100 0.934 0.8615 64 0.7889 200 0.5399 0.6086 77 0.6772 2X100 0.6006 0.6575 75 0.7144 36. Biaπfchrαne 50 1.1042 1.0839 52 52 1.0636 100 1.1443 1.1575 48 1.1707 200 1.0063 0.9970 57 0.9877 2X100 1.0606 1.1353 50 1.21 As can be seen from the results in Table III compounds 30-36 (having 3 fused aromatic rings and side groups of methyl, oxygen or hydroxyl) were generally more effective than com¬ pounds 16-29 (having 3-5 fused aromatic rings and no side groups). It should be noted that all of the compounds tested in the experiments described in this Example showed at least some degree of anti-retroviral activity. The same experiment can be uεed to measure the antiviral activity of other PAC compounds. All compounds used in this Example 1(a) can be obtained from Aldrich Chemical Co., Milwaukee, WI. , and are referred to herein as Series B compounds. Their structural formulas are set forth in Example 2, below. (b) Effects of Polycyclic Compounds In Combination With Nucleoside Analogs The compounds of the present invention (100 micrograms per mouse) were also tested in combination with AZT (20 micrograms per mouse, twice a day) using otherwise the same methods as in Example 1(a) above. As representatives, compound #9 above (3-bromophenanthro (3,4-C), phenanthrene) and compound #10 (diindeno (1, 2, 3-CD/l', 2', 3' -IM) Perylene) were chosen. As shown in Table II above, compound #9 had shown weak anti-retroviral activity when administered at 100 micrograms per mouse whereas compound #10 showed significant (>40%) inhibition of FV-induced splenomegaly. The compounds were adminiεtered i.p. either once or five timeε (once per day) alone or together with AZT (20 micrograms of AZT per mouse twice a day for five days?). Thus, in experiments where AZT was administered five times, a total of 100 micrograms of AZT was received by each mouse (with a total of 500 micrograms of the PAC compound) . The results are shown in Table IV below. TABLE IV Spleen Treatment weight Average % Inhibition PBS 0.1637 0.16135 - 0.159 FV 2.2297 2.1586 - 2.0875 IX #9 2.0831 2.1074 3 2.1317 5X #9 1.6262 1.68125 24 1.7363 IX #10 1.7816 1.724 22 1.6664 5X #10 1.5771 1.2358 46 0.8945 5X AZT 1.3744 1.3895 39 (20 micrograms per mouse) 1.4046 5X (AZT + #9) 0.9097 0.9358 61 (20 micrograms 0.9619 +100 _αicrograms of #9 per mouse) 5X (AZT + #10) 0.9787 1.0199 57 (20 miciograms 1.0611 +100 micrograms of #10 per mouse) Aε εhown in Table IV above, although compound #9 εhowed weak anti-retroviral activity when adminiεtered once (3%) or five ti eε over a period of five days (24%). When the same compound was co-administered with AZT, substantial inhibition of FV-induced splenomegaly (61%) was found. This increase in inhibitory activity is not attributable to AZT alone, since the same amount of AZT alone caused only 39% inhibition. Hence, the co-administration of the preεent compounds and AZT con¬ stitutes a regimen of at least additive effectiveness compared to the administration of either active ingredient alone. Administration of compound #10 (which demonstrated significant anti-retroviral activity when administered alone) in conjunction with AZT not only led to substantial retroviral inhibition (57%) but thiε inhibition waε also greater than the inhibition found when each drug was administered alone. Based on the above testε involving PAC compounds and/or tests of hypericin and pseudohypericin combined with AZT, it iε anticipated that other PAC compoundε will have at leaεt additive activity when uεed therapeutically or preventively in conjunction with AZT or another nucleoside analog. Therefore, the above data in Table IV show the enhanced efficacy of the PAC compounds when combined with nucleoside analogs such as AZT when treating a retroviral infection. The results of a similar experiment using hypericin and pseudo- hypericin together with AZT show that hypericin-containing compositions and also containing AZT have antiviral activity (and splenomegaly-inhibitory activity) that is higher than the activity of either the PAC compound or the nucleoside. EXAMPLE 2 : Listed below are a series of PAC compounds (Series A) . Due to their structural similarity with hypericin, they are expected to be active against viruseε and retroviruses. Theεe compounds are available upon request from the National Cancer Institute, Bethesda, MD and their properties have been described in Weiss, U. et al. Progress in Chemistry of Organic Natural Products £2:1-71, 1987. Al. CAS Registry No. 14343921 A2. CAS Registry No. 6336841 A3. CAS Registry No. 14642729 A4. CAS Registry No. 6336874 A5. CAS Registry No. 6941475 A6. CAS Registry No. 4478766 A7. CAS Registry No. 2013583 A8. CAS Registry No. 667914 A9. CAS Registry No. 434855 A10. CAS Registry No. 3438082 All. CAS Registry No. 24541193 A12. CAS Registry No. 10395025 A13. [NSC No. 123399-N] A14. CAS Registry No. 69544850 A15. CAS Registry No. 55043419 A16. CAS Registry No. 71205384 A17. CAS Registry No. 52236541 A18. [NSC No. 231579-Y] A19. [NSC No. 241039-1] A20. CAS Regiεtry No. 27575468 A21. [NSC No. 308787-V] A22 . [NSC No. 308805-Q] A23. [NSC No. 308814-Z] A24. CAS Registry No. 14343954 A25. Rondomycin, 2-Naphthacenecarboxamide, NSC No. 356465-U A26. CAS Registry No. 81092844 A27. CAS Registry No. 81092855 A28. [NSC No. 507458-S] Liεted below are a εeries of compounds (Series B) which are PAC compounds (including AAB compounds and analogs or derivatives of AAB compounds) . Due to their structural similarity with hypericin, they are expected to be active againεt viruses and retroviruses. These compounds are avail¬ able from Aldrich Chemical Co. The names of these compounds are in Tables II and III of Example 1. Series B - Compounds 1-4 1. 3< 4. Series B (cont'd) - Compounds 5-11 5. 6. 7. 8. 9. 10. 11. Series B (cont'd) - Compounds 12-21 12. 13. 14. 15. 16. 17 18. 19, 20. 21. Series B (cont'd. - Compounds 22-29 22. 23. 24. 25. 26. 27, 28. 29. Series B (cont'd) - Compounds 30 - 36 30. 31. 32. 33. 3.4. 35. 36, o The properties of the following AAB compounds, 1-25 (Serieε C) have been described in Bankε, H.J. et al., Aust. J. Chem. 29: 1509-1521, 1976. Series C - Compounds 1-19 (13) Me Me W Me Me (14) Ml CO j H (II) Me COΛ (iS) COjH OV- G»> CO_H co,κ >) M< H}0H Series C (cont'd) - Compounds 20-25 The synthesis and/or isolation of compounds 1-25 (Series C) listed above are specifically described in the following references: 1. Emodin. Commercially available from Aldrich. Synthesis from 3,5 dimethoxy-o-phthalic anhydride and m-cresol U.S. Pat. No. 2,707,704 of Brockmann et al, alεo from Ahmed, S.A. et al -J^ Chem. Soc. Chem. Commun. 1987, pp. 883-884 which alεo diεcloεeε synthesis for various hydroxyemodins. 2. 7-hydroxyemodin. Bankε, H.J. et al., Aust. J. Chem.. 29:1509-1521, 1976. 3. Omega-hydroxyemodin. Banks, supra. 4. alaternin (2-hydroxyemodin) . Banks, supra. 5. Emodic Acid. Synthesis from emodin: Anslow, W.K. et al. Biochem. J. 34: 159, 1940. 6. Skyrin: Auterhoff, H. et al. Arch. Pharm. 295: 850, 1962; also Bankε, εupra from emodin bianthrone by O2, OH followed by HCl, thin-layer chromatography, and gel filtration. 7. Hypericin: Brockmann, εupra, alεo Anεlow, supra. 8. Hypericin monocarboxylic acid: Thompson, R.H. Naturally Occurring Ouinones. 2nd Ed. Academic Preεε, London, 1971; Bankε, H.J. et al.. Insect Biochem. 3.: 139, 1973; Brown, K.S., Chem. Soc. Rev. 4.: 263, 1973; Anslow, W.K. et al., Biochem. J. 34: 159, 1940. 9. Hypericin dicarboxylic acid: Banks, H.J. et al., Aust. J-. Chem. 29: 1509-1521, 1976. 10. Pseudohypericin, Banks et al., supra. 11. Emodin Anthrone. Synthesis from reduction of emodin with hydriodic acid or stannous chloride. Brockmann, H. et al. Chem. Ber. 90: 2302, 1957. 12. Emodin Acid Anthrone. Synthesis from emodic acid reduced with hydriodic acid; Anslow, W.K. et al. supra and Brockmann, H. et al., Chem. Ber. 91: 81, 1958; Jacobsen, R.A. et al., J_ s _ Am. Chem. Soc. 46: 1312, 1924. 13. Protohypericin: Bankε et al., εupra. 14. Protohypericin monocarboxylic acid, Bankε et al., supra. 15. Protohypericin di-carboxylic acid. Banks et al.. supra, 16. Hydroxymethyl protohypericin. Banks et al., supra. 17. Emodin bianthrone: Anslow, W.K. et al., supra. 18. Emodinic acid bianthrone: Anslow, W.K. et al.. supra. 19. Emodin bianthrone dicarboxylic acid, Anslow, W.K. et al., supra. 20. Banks et al., supra. 21. Isohypericin: Steglich, W. et al., Angew. Chem. Int. Ed. Engl. 12: 79, 1973; Banks, et al., supra. 22. 10-peroxy-9-anthrone: Bedford, C.T., J^ Chem.- Soc. 23. Penicilliopsin: Banks et al., supra. 24. Hyperico-dehydrodianthrone: Banks et al., εupra. 25. Bankε et al., supra. Moreover, the AAB compoundε X-XXXII (Series D) listed below are also related to hypericin and therefore expected to possess antiviral activity. Series D - Compounds X-XVIII The synthesis of the above compoundε has been described in Brockmann, H.M., in Progress in Organic Chemistry, Vol. I, Cook, J.W. ed., p.64-82, 1952. 47 Series D (cont'd) - Compounds XIX-XXXII (XIX) (XX) OH « = C 6 H 5 C0 2 (XXII) R ■ CH3 (XXV) R' - H; R" = CH 3 (XXI) OH * CH 3 0 (XXIII) R « H (XXVI) R', R" « H (XXIV) OHCHR «■ C 2 H 5 (XXVII) R' - OH; R" **= H (XXV) OHCHR = CH3O (XXVII) R', R", OH = H (XXIX) R', R" - H (XXX) R' «= H, R" « OH (XXXI) R' - OH, R" - H (XXXII) R', R" « H and OH H at C-5 The synthesis of the above AAB compoundε XIX-XXXII has been described in Brockmann, H. et al.. Tetrahedron Letters 23; 1991-1994, 1974. geries E - Compounds 1-7 The synthesis of the above compoundε has been described in Brockmann, H. et al., U.S. Patent No. 2,707,704 issued may 3, 1955. EXAMPLE 3: ANTIVIRAL ACTIVITY OF PROTOHYPERICIN The antiviral activity of the hypericin homolog protohypericin was tested as follows. Protohypericin was synthesized by the method of Banks, H.J. et al., Aust. J. Chem. 29: 1509-1571, 1975. The material was purified by chromatography using silica gel 60 (mesh 0.4 - 0.6) and stored in the dark until use. Supernatants (10 ml/tube) from B10.T(6R) cellε (Meruelo et al. J_ s _ Exp. Med. 147: 470-487, 1978) chronically infected with Radiation Leukemia Viruε (RadLV) were obtained by centrifugation of cellε in culture at 4 β C, 3500 rpm for 15 minuteε. The top 2/3 of the εupernatant were removed and aliquotε were incubated for 30 minuteε on ice with the indi¬ cated amounts of hypericin or protohypericin. The procedure was carried out in the absence of light because protohypericin converts to hypericin upon exposure to light. Thereafter, supernatantε were centrifuged at 100,000 x g uεing a TI70 rotor (Beckman Instruments) for 1 hour at 4°C. The pellet was decanted and analyzed for reverse transcriptase activity as follows. The reverse transcriptaεe asεay waε performed in a volume of 100 microliterε containing the following componentε: Final Microliters of Concentration Reagent Stock Stock per assay per assay Sol'n A: 0.50M Tris/HCl pH 7.8 10 50 mM 0.6M KC1 60 mM Sol'n B: 2.0mM Mn Acetate 10 0.2 mM Sol'n C: 40 mM dithiothreitol 5 2 mM Triton X-100 (10%) 1 0.1% poly (rA). * (dT) 12 *- 10 A 260 units / ml ) 1 4 0.4 A p 2er60m U l nlts dTTP (2X10 _4 M) 10 2X10 --5- D M, [ 3 H]-TTP (500 micro Ci/ml) 2 10 5 micro Ci 50 •** Obtained from Pharmacia Fine Chemical Co., (Piscataway, NJ) 2 Obtained from New England Nuclear (Boston, MA) The reverse tranεcriptaεe assay provides a measure of the antiviral activity of the compounds tested by reference to the observed decrease in activity of this enzyme. The results of these assays are shown in Table V below. In Table V, "CPM" is "counts per minute", "Average" is the numerical average of CPM values within each group of animalε. TABLE V Antiretroviral Activitv of Protohvoericin Addition CPM Average Average percent (micrograms) inhibition None (negative 195,554 control) 222,846 209,200 100 hypericin 1,502 2,158 1,830 99.0 50 hypericin 5,434 3,716 4,575 97.8 10 hypericin 8,912 9,102 9,007 95.7 5 hypericin 12,224 11,332 11,778 94.4 1 hypericin 4,504 3,690 4,097 98.0 0.5 hypericin 3,190 3,667 3,428.5 98.4 0.1 hypericin 1,668 2,998 2,333 98.9 0.05 hypericin 2,882 3,067 98.5 3,252 100 protohypericin 8,818 11,744 10,281 95.1 50 protohypericin 75,816 67,466 71,641 65.8 10 protohypericin 202,656 168,422 185,539 11.3 5 protohypericin 12,358 12,908 12,633 94.0 1 protohypericin 192,184 263,044 227,614 0.5 protohypericin 264,710 251,048 257,879 .—_ 0.1 protohypericin 216,824 305,342 261,083 52 (cont'd) Addition CPM Average Average percent (micrograms) inhibition 0.05 protohypericin 310,952 307,254 309,103 Aε can be seen from the data in Table V, protohypericin significantly inhibited the reverse transcriptase activity of RadLV, although 10 to 100 fold higher concentrations of protohypericin were required to obtain the same degree of inhibition as that obtained with hypericin. Similarly, the activity of other AAB compounds can be tested by the same assay. EXAMPLE 4: Antiviral Activity of Hypericin Hexaacetate The antiviral activity of hypericin hexaacetate (HHA) was tested as follows: Hypericin hexaacetate can be synthesized by warming hypercin in the presence of excess acetic anhydride with the addition of an acid catalyst, such as εulfuric acid or boron fluoride. Alternatively a basic catalyst can be used such aε fuεed sodium acetate, pyridine or triethylamine. See alεo Brockmann. H.. et al.. 90:2480-2491, 1957. The antiviral activity of HHA waε teεted using AQR (Bach and Meruelo, i. Exp. Med. 160:270-285. 1984) cells chronically infected with Radiation Leukemia Virus in the reverse transcriptase assay as described in Example 3 above. The results are shown in Table VI below. 53 TABLE VI Anti-retroviral Activity of Hypericin Hexaacetate Average Addition CPM Average Percent (micrograms) Inhibition None 477,218 448,251 (Negative 419,284 control) 100 Hy 28,946 31,347 93.0 33,748 50 Hy 33,948 31,818 92.9 29,688 10 Hy 9,288 11,588 97.4 13,888 2 Hy 14,474 9,986 97.8 5,498 0.4 Hy 1,700 2,489 99.4 3,278 100 HHA 2,750 2,545 99.4 2,340 50 HHA 5,236 5,305 98.8 5,374 10 HHA 96,654 91,440 79.6 86,226 5 HHA 221,098 205,891 54.1 190,604 1 HHA 401,306 451,634 501,962 0.5 HHA 518,336 501,386 484,356 0.1 HHA 208,882 202,454 54.8 196,026 0.05 HHA 441,410 466,981 492,552 As can be seen from the results shown in Table VI, HHA was about as active a protohypericin in inhibiting the RadLV reverse transcriptase activity. EXAMPLE 5: INHIBITION OF HIV BY THE COMPOSITIONS OF THE PRESENT INVENTION The activity of the AAB compounds of the present invention against human immunodeficiency virus (HIV) may be investigated in the following manner. HIV-infected cells, such as OKT4+ lymphoblastoid cells, e.g. clone H9 (described in Popovic, M., et al. Science 221:497-500, 1984) or HUT 78 cells (Gazdar, AF et al. Blood 55:409, 1980) or Molt-78 (available as ATCC CRL 1582 from the American Type Culture Collection, Rockville, MD) are maintained in RPMI-1640 medium (GIBCO, Grand Island, New York) containing 20% fetal calf serum (Flow • Laboratories, Inglewood, CA) . Triplicate cultures of cells, seeded at a concentration of about 4X10 * ** 1 cells per ml, are exposed to polybrene (2 micrograms per ml, Sigma Chemical Co., St. Louis, MO), infected with 2X10 8 HIV particles per 4X10 5 cells, and cultured in the presence or absence of the compounds of the present invention as in Examples 1 and 2 above. The antiviral activity of the compounds of the present invention is determined by monitoring the reverse transcriptase activity and the expression of HIV proteins p24 and pl7, aε deεcribed in Sarin, P.S. et al., (J. Nat. Cancer Inεt. 78:663- 665, 1987), and aε deεcribed below. EXPRESSION OF HIV GAG PROTEINS P24 AND P17. HUT-78, Molt-4 or H9 cellε (2X10 5 ), either uninfected or HIV infected, are continuouεly exposed to various concentra- tionε of the compoundε of the present invention at concentra¬ tions between 5 and 200 micrograms per ml for 4 days. The percentage of cells expresεing p24 and pl7 proteins of HIV is determined by indirect immunofluorescence microεcopy with the uεe of mouεe monoclonal antibodieε to HIV pl7 and p24 (avail¬ able from numerous commercial sources such as those in HIV εerum antibody detection kits from Abbott Labs, North Chicago, IL, and from DuPont, Wilmington, DE). The positive cells are visualized by treatment with fluorescein-labeled goat anti- mouse IgG (Cappell Laboratories, Cochranville, PA). The experiments are performed in duplicate and repeated at leaεt three timeε. DETERMINATION OF REVERSE TRANSCRIPTASE ACTIVITY H9, HUT-78 or MOLT-4 cells infected with HIV are exposed to various concentrations of the compounds of the present invention as above. At day 4, supernatantε of the cultures are collected and virus particles are precipitated with polyethylene glycol and obtained by centrifugation as described above and asεayed for reverεe transcriptase activity as follows. The virus pellet is suεpended in 300 microliters of buffer containing 50 mM Tris-HCl (pH 7.5), 5mM dithiothreitol, 250 mM KC1, and 0.25% Triton X-100. Reverse transcriptase activity in these samples are analyzed in a 50 microliter reaction mixture containing 50 mM Tris/HCl (pH 7.5), 5mM dithiothreitol, 100 mM KC1, 0.1% Triton X-100, 10 microliters dT*L5rA n as template primer, 10 mM MgCl 2 , 15 micromolar [ 3 H]dTTP (New England Nuclear, Boston, MA) , and 10 microliters of disrupted virus suspension. After incubation for 1 hour at 37°C and subsequent addition of 50 micrograms of yeast tRNA (Sigma Chemical, St. Louis, MO), the incorporation of radioac- tivity into the cold trichloroacetic acid-insoluble fraction is assayed. - Assays are performed in duplicate and repeated three times. EXAMPLE 6: THE EFFECT OF THE COMPOSITION OF THE PRESENT INVENTION ON THE REPLICATION OF FELINE LEUKEMIA VIRUS Cats which test positive for feline leukemia virus (FeLV) viremia will be inoculated with the compounds of the present invention (as shown in Examples 1 and 2 above), with and without nucleoside analogs, at 5-20mg/kg twice a day for various intervals of time. Serum levels of FeLV will then be followed and treatment will be resumed using the same regimens or adjusted with respect to the levels of viremia suppression obtained. The length of follow up will be determined by experimental considerations. A minimum of six months follow-up will be undertaken. EXAMPLE 7: CHEMICAL SYNTHESIS OF AAB COMPOUNDS. The following AAB compounds, referred to as WIS-1 - WIS-6 were synthesized as follows below. WIS-1-Hypericin-dicarboxylic acid. Thiε compound has been described by Bankε, H.J. et al., Aust. J. Chem. 29: 1509-1521, 1976. Its chemical structure and synthesis are shown below. Hypericin-hexa¬ Hypericin dicarboxylie acetate acid 200 mg hypericin hexaacetate (Brockmann, H. et al.. Tetrahedron Letters: 2: 37-40, 1975) and whoεe εynthesiε iε alεo described above in Example 4 was dissolved in 4 ml acetic acid and treated dropwise with a εolution of 720 mg of chromium trioxide in 0.3 ml water and 3 ml acetic acid. After incuba¬ tion for 1 hour at 55 β C, the reaction mixture waε poured into 50 ml of water, incubated overnight at room temperature and then filtered (Whatman qualitative No. 1 filter). The yellow solid obtained was dissolved in 400 ml of 0.2 M potassium hydroxide solution, heated with 0.2 ml piperidine, and the solution warmed to 60°C for 10 minutes. The solution was then acidified to pH 1 with a 5% hydrochloric acid solution and the black precipitate obtained was filtered (Whatman qualitative No. 1 filter) to give the desired product. m^v (MeOH) 600 ( 35 , 000 ) , 555 ( 17 , 000 ) , 518 ( 10 , 000 ) nm. 1 (KBr) 1590 , 1700 3000 cm -1 . 2 1 H NMR (CD 3 SO ) 7 .72 , 6.42 ppm. 3 WIS-2-Tetrahydroxy-dibenzoperylene-dione 1,3-dihydroxy Tetrahydroxy- anthraquinone dibenzoperylene-dione This compound has been described in Rodewald, G. et al., Angew. Chem. Int. Ed. 16: 46-47, 1977. 5 g of 1, 3-dihydroxyanthraquinone (Perkin, A.G. et al., J. Chem. Soc. 1929:1399-1411) was diεεolved in 92 ml water containing 5 g of potassium tert-butoxide, and treated with 3 g hydroquinone. The resulting dark red solution was introduced into a glass ampule, purged with argon gas and then sealed. The sealed glasε ampule waε heated in an oil bath at 120°C for 20 days. The contentε of the ampule were then acidified with a max = wavelength absorption peak in MeOH ( = molar extinction coefficient). 2 = frequency, cm""*. 3 = chemical shift ppm (partε per million) as described in Spectroscopic Methods in Organic Chemistry. Williams, D.A. et al. (eds) pp. 40-129, McGraw-Hill Ltd., London, 1966. solution of hydrochloric acid (1%) to pH 1, extracted with a εolution of butanol and ethyl acetate (1:1), washed with distilled water until neutral and evaporated to dryness. The residue obtained was chromatograph on a column of silica gel and eluted with a mixture of ethyl acetate:butanol (100:5) to yield 350 mg of the product which did not change upon irradia¬ tion. The physical data (lambda- j ^x, ** * H NMR) were identical to those reported in the above-cited Rodewald et al. publication. WIS-3-Desmethylhypericin 1,3,6-trihydroxy- Des-methylhypericin anthraquinone Thiε compound haε been previously described and characterized (Cameron, D.W. et al., Aust. J. Chem. 29:1523- 1533, 1976). 1, 3, 8-Trihydroxyanthraquinone (300 mg) (prepared as described in Lovie, J.C. et al., J. Chem. Soc. 1961:485-486) was dissolved in 10 ml water containing 0.5 g of potassium tert-butoxide, and treated with 0.3 g hydroquinone. The resulting dark red solution waε introduced into a glasε ampule which waε purged with argon gaε, and then εealed. The sealed glass ampule was incubated in an oil bath at 140°C for 21 days. The contents were then acidified with a solution of hydrochloric acid (1%) to pH 1, extracted with a εolution of butanol and ethyl acetate (1:1), washed with distilled water until neutral and evaporated to dryness. The residue was chromatographed on a column of silica gel and eluted with a mixture of ethyl acetate:methanol (100:5) yielding a desmethyl analog of protohypericin in the amount of 50 mg. This material was.disεolved in ethyl acetate and irradiated with visible light for one hour. The solvent was evaporated to dryness resulting in desmethylhypericin in a yield of 44 mg. The compound was a dark red amorphous solid. ra=v (in MeOH): 580 (45,000), 537 (25,000), 502 (15,000), 468 (30,000) nm. „__,„ (KBr): 3400, 1620, 1590, 1550. - ■ E NMR (CD 3 SO) 8.48 (d, J=8H) , 7.15(d, J=8HZ), 6.57 (s) ppm WIS-4-Desoxohypericin-hexacetate Hypericin Desoxo-hypericin hexa-acetate This compound has been previously disclosed in Brock¬ mann, H. et al., Chem. Ber. 90: 2481-2491, 1957. 200 mg hypericin and 200 mg sodium acetate were heated over reflux for 10 minutes and treated with 4 g zinc powder, added in small portions. The residue was filtered (Whatman qualitative No. 1 filter) dried, dissolved in 50 ml benzene and filtered again. The solution thus obtained was treated with 275 mg chloranil, boiled under reflux for 30 minutes and incubated for 2 days at room temperature. The dark blue εolution was filtered through a column containing 50 g of silica gel. The reaction product was eluted with a mixture of benzene and acetone (100:2) yielding 55 mg of desoxohypericin- hexaacetate. UV (in MeOH) 621 (45,000), 567 (24,000), 310 (91,000) nm. - ■ E NMR (CDC1 3 ) 2.36, 2.40, 2.45, 2.46, 8.3, 7.44, 7.39 ppm. WIS-5-Desoxohypericin Desoxohypericin Desoxohypericin hexa-acetate This iε a new compound not previously described in the literature which was prepared by hydrolysis of desoxoyhypericin-hexaacetate (WIS-4) . 20 mg of deεoxoyhypericin-hexaacetate (synthesized as described above) was disεolved in 8 ml ethanol containing 20 mg sodium hydroxide. The solution was incubated at room tempera¬ ture for 24 hours. After this period, all of the acetate groups were hydrolyzed yielding the sodium salt of desoxyhypericin. The material was not isolated from solutions since it decomposses readily in neutral or acetic pH. UV (ethanol, pH 10) max >800, 755, 438 nm. WIS-6-Hypericin Diacetate Hypericin Hypericin diacetate This compound has been described in Brockmann, H. et al., Chem. Ber. 84: 865-867, 1951. 200 mg hypericin waε diεsolved in 50 ml acetic an- hydrive and incubated at room temperature for 48 hours. It was then poured over ice and extracted with 100 ml ethyl acetate. The organic extract was washed with 50 ml of a dilute hydrochloric acid solution (1%) and 500 ml sodium bicarbonate (3%). The residue, after evaporation of the organic solvent, was chromatographed over silica gel. The fraction eluted with ethyl acetate and comprised orange crystals of hypericin diacetate with a melting point higher than 360°C. max (MeOH) 586 (35,000), 573 (25,000), 544 (20,000), 458 (28,000), 434 (18000) nm. -*R NMR (in CDCI3) 2.39, 2.82, 7.28 ppm. EXAMPLE 8: BIOLOGICAL ACTIVITY The AAB compounds whose synthesis iε deεcribed above were assayed for antiviral activity. WIS-2, -3, -4, -5 and -6 were tested to determine their biological effects on Friend Virus-induced splenomegaly using the procedure and technique set forth in Example 1 above. The asεay reεultε (three mice per group were tested each at different concentrationsε of the active composition except for the PBS-negative control wherein two animals per group were used) are reported in Table VII below. TABLE VII TREATMENT Actual Spleen Average Spleen Average % Weight Weight Inhibition PBS (negative control) 0.1947 0.1754 0.1460 FV (positive control) 0.9484 0.9661 ——— 0.9826 0.9673 WIS-2 (150 micrograms) 0.4075 0.4416 66.3 0.4656 0.4517 WIS-2 (50 micrograms) 0.4818 0.4603 64.0 0.4925 0.4066 WIS-2 (10 micrograms) 0.4263 0.4701 62.7 0.4868 0.4972 WIS-2 (1 microgram) 0.6615 0.7015 53.9 0.7519 0.6912 WIS-3 (150 micrograms) 0.2967 0.3290 79.7 0.3518 0.3384 WIS-3 (50 micrograms) 0.6998 0.6921 34.7 0.6723 0.7041 WIS-3 (10 micrograms) 0.7727 0.7759 24.1 0.8108 0.7413 TREATMENT Actual Spleen Average Spleen Average % Weight Weight Inhibition WIS-3 (1 microgram) 0.7527 0.7737 24.3 0.8048 0.7277 WIS-4 (150 micrograms) 0.6214 0.6012 46.1 0.6663 0.5159 WIS-4 (50 micrograms) 0.7368 0.7384 28.8 0.7744 0.7041 WIS-4 (10 micrograms) 0.8118 0.7921 22.0 0.8625 0.7019 WIS-4 (1 microgram) 0.7790 0.8480 14.9 0.8852 0.8797 WIS-5 (150 micrograms) 0.6919 0.6879 35.2 0.6790 0.6927 WIS-5 (50 micrograms) 0.7817 0.8134 19.3 0.8389 0.8196 WIS-5 (10 micrograms) 0.9126 0.9147 6.5 0.8898 0.9417 WIS-5 (1 microgram) 0.9062 0.9197 5.9 0.9528 0.9001 WIS-6 (150 microgramε) 0.7921 0.8187 18.6 0.8013 0.8626 WIS-6 (50 micrograms) 0.9012 0.9407 3.2 0.9969 0.9241 WIS-6 (10 micrograms) 0.8387 0.8930 9.2 0.8529 0.9874 WIS-6 (1 microgram) 0.9291 0.8210 18.4 0.8017 0.7323 Referring to Table VII above, it can be seen that all of the analogs demonstrated antiviral activity. WIS-2, 3, and 4 were the most active compounds of the group in the splenomegaly assay. EXAMPLE 9: RADIATION LEUKEMIA VIRUS REVERSE TRANSCRIPTASE ASSAY The same group of analog compounds used in Example 8 were tested to determine their ability to directly inhibit the reverεe tranεcriptase of Radiation Leukemia Virus. The assays were conducted using the same procedure as in Example 3 above, using supernatants from infected AQR cells. The results of the assay are reported below in Table VIII. TABLE VIII Average % Treatment CPM Average Inhibition None ( [negative control) 829,640 816,568 803,496 WIS-2 (10 micrograms) 4,158 4,156 99.5 4,154 WIS-2 (5 micrograms) 4,278 3,922 99.5 3,566 WIS-2 (2 micrograms) 4,100 4,343 99.5 4,586 WIS-2 (1 microgram) 11,576 10,503 98.7 9,430 WIS-2 (0.5 micrograms) 16,602 15,306 98.1 14,010 WIS-2 (0.1 micrograms) 212,984 238,201 70.8 263,418 WIS-2 (0.05 micrograms) 455,360 476,704 41.6 498,048 Average % Treatment CPM Average Inhibition WIS-3 10 micrograms) 57,512 119,248 85.4 61,736 WIS-3 5 micrograms) 75,776 76,907 90.6 78,038 WIS-3 2 micrograms) 14,020 15,467 98.1 16,914 WIS-3 1 microgram) 21,896 24,606 97.0 27,316 WIS-3 0.5 micrograms) 2,630 2,799 99 * 7 2,968 WIS-3 0.1 micrograms) 19,322 20,893 97.4 22,464 WIS-3 0.05 micrograms) 89,170 78,424 90.4 67,678 WIS-4 10 micrograms) 186,168 184,852 77.4 183,536 WIS-4 5 micrograms) 164,780 164,440 79.9 164,100 WIS-4 2 micrograms) 236,374 237,365 70.9 238,356 WIS-4 1 microgram) 179,312 180,180 77.9 181,048 WIS-4 0.5 micrograms) 196,740 208,119 74.5 219,498 WIS-4 0.1 micrograms) 100,504 144,512 82.3 188,520 WIS-4 0.05 micrograms) 156,830 164,212 79.9 171,594 Average % Treatment CPM Average Inhibition WIS-5 ( 10 micrograms) 168,008 177,364 78.3 186,720 WIS-5 ( 5 micrograms) 220,588 236,878 71.0 253,168 WIS-5 ( 2 micrograms) 216,764 205,469 74.8 194,174 WIS-5 ( 1 microgram) 238,782 251,168 69.2 263,554 WIS-5 ( 0.5 micrograms) 240,372 249,351 69 * 5 258,330 WIS-5 . 0.1 micrograms) 172,984 171,635 79.0 170,286 WIS-5 0.05 micrograms) 183,654 193,017 76.4 202,380 WIS-6 10 micrograms) 178,026 146,588 82.0 115,150 WIS-6 5 micrograms) 86,850 90,273 88.9 93,696 WIS-6 2 micrograms) 96,562 94,199 88.5 91,836 WIS-6 [ 1 microgram) 124,996 153,363 81.2 181,730 WIS-6 [0.5 micrograms) 116,590 161,570 80.2 206,550 WIS-6 0.1 micrograms) 188,378 389,388 52.3 590,398 WIS-6 [0.05 micrograms) 195,374 190,506 76.7 185,638 The assay results in Table VIII above showed that all of the compounds tested were found to inhibit the reverεe transcriptase activity of Radiation Leukemia Virus. Compoundε WIS-2 and WIS-3 had the higheεt level of antiviral activity of the compoundε that were teεted in thiε assay. EXAMPLE 10 : In order to investigate the structural features of hypericin which are essential for antiretroviral activity, numerous analogs and precursorε of hypericin were examined for activity in two in vitro and one in vivo biological assay. The assays employed were: (1) Direct inactivation of retroviruses in vitro, performed as in Example 3 above; (2) In vitro inhibition of a virus budding, performed as deεcribed in Meruelo, D. et al. (Proc. Natl. Acad. Sci. USA 85: 5230-5234, 1988 and Lavie G. et al. (Proc. Natl. Acad. Sci. USA 86: 5963-5967, 1989). Briefly, tissue culture adapted, virus-producing cells were incubated with various amounts of compounds for 30 minutes at 37°C. After 30 minutes the cells were washed three times with Dulbecco's Modified Eagle Medium (DMEM) supplemented with fetal calf serum, growth factors and antibiotics and cultured for 24 to 48 hours. The cells were then harvested and the culture supernatants were assayed for reverse transcriptaεe activity as described above in Example 3; (3) In vivo inhibition of Friend Leukemia Virus Splenomegaly performed as described in Example 1 above except that the compounds were administered intravenously 1-2 hours post infection. The syntheεis and/or isolation of these compounds is described above. The results of these assays are presented in Table IX below. EC 50 (uM) FOR EC 50 (uM) FOR DIRECT ' PRODUCTION EC 50 (uM) FOR INACTIVATION OF DEFECTIVE FV-INDUCED COMPOUND OF VIRIONS BUDDED VIRIONS SPLENOMEGALY HYPERICIN 0.06 0.2 0.12 PROTOHYPERICIN 7.90 — 98 PSEUDOHYPERICIN __ 3.8 HYPERICIN-DICARBOXYLIC -ACID (WIS-1) >100 HYPERICIN -DIACETATE (WIS-6) 0.85 >255 HYPERICIN -HEXAACETATE 12.90 >199 DESMETHYL -HYPERICIN (WIS-3) 0.07 174 DESOXOHYPERICIN (WIS-5) >21 >316 DESOXOHYPERICIN -HEXAACETATE (WIS-4) 6.90 >242 EMODIN >37 HYDROXYMETHYL- ANTHRAQUINONE >41 145 ANTHRONE >51 267 BIANTHRONE >26 >100 98 The resultε presented above in Table IV are presented as EC50 concentrations. These are the effective concentrations which inhibit 50% of the viruses in micromolar concentrations. As can be seen rom the results presented in Table IX above, different analogs varied in their levels of effective¬ ness. Only hypericin, pseudohypericin and desmethyl hypericin showed a high degree of activity in a more than one assay. Removal of the carbonyl groups from hypericin (e.g., desoxohypericin) resulted in a significant loss of in vivo reverse transcriptase inhibitory activity. This loss of activity was also evident when the activities of the hexaacetate derivative of hypericin are compared with those of the desoxo-hexaacetate derivative. These observationε suggest that the quinone structure was important for the antiviral activity of aromatic polycyclic diones, preferably when structured on a naphthodianthrone backbone. In addition, replacement of the methyl side chains by a more polar group such as a carboxylic, acetoxy, or hydroxy side group diminished the antiviral activity aε εeen above in hypericin dicarboxylic acid and the di-and hexaacetate derivativeε of hypericin

Claims: WHAT IS CLAIMED IS: 1. A method for treating a mammal suffering from a viral infection comprising administering to a mammal in need of such treatment an effective amount of a compound selected from the group consisting of a compound of the Formula I wherein: n is an integer selected from 1 and 2; each of A, C, D, E, F, H, I, J is independently selected from the group consisting of hydrogen, hydroxy, lower (C^ - C ) alkyl, aryl, arylalkyl, arylamino, lower alkenyl, alkoxy, hydroxyalkyl, halogen, carboxy, acyl (aromatic or aliphatic), amino, acyloxy, alkoxycarbohyl, aryloxycarbonyl (each of which may be substituted or unsubstituted), and a dimer-forming bond; each of B and G are independently selected from the group consisting of (a) oxygen forming a keto group with the ring carbon to which the oxygen is appended; (b) two hydrogen atoms; (c) one hydrogen atom and one peroxy group; (d) aryl; (e) alkenylcarbonylalkyl; (f) alkenyloxycarbonylalkyl; (g) cyanoalkenyl; (h) arylalkenyl; (i) lower alkyl; (j) alkenyl; (k) acyl; each of which may be subεtituted or unεubεtituted; and (1) a double or single dimer-forming bond; wherein one or more of A and B, B and C, A and J, C and D, D and E, E and F, F and G, G and H, H and I, and I and J can be combined to form aromatic, alicyclic or heterocyclic rings having 5-7 carbon atoms, said rings optionally being further substituted; wherein the three rings in said formula are aromatic except that the particular bonds formed by one or more of the ring carbon atoms adjacent to A, B, C, H, G or F can be saturated; provided that, when n=2, at least one of H, G and F or at least one of A, B and C is a bond and either or both of (i) D and E and (ii) J and I optionally form aromatic or alicyclic or heterocyclic rings having 5-7 atoms with the adjacent carbon atoms. 2. The method of claim 1 comprising administering said compound parenterally. 3. The method of claim 1 comprising administering said compound orally. 4. The method of claim 1 wherein said virus is human immunodeficiency virus. 5. The method of claim 1 further comprising adminis- tering an effective amount of a nucleoεide analog with said compound. 6. The method of claim 6 wherein said nucleoside analog is azidothymidine. 7. A pharmaceutical formulation for treating mammals suffering from viral infections comprising an effective amount of a compound selected from the group consisting of a compound of the Formula I wherein: n is an integer selected from 1 and 2; each of A, C, D, E, F, H, I, J is independently selected from the group consisting of hydrogen, hydroxy, lower (C j C4) alkyl, aryl, arylalkyl, arylamino, lower alkenyl. alkoxy, hydroxyalkyl, halogen, carboxy, acyl (aromatic or aliphatic), amino, acyloxy, alkoxycarbohyl, aryloxycarbonyl (each of which may be εubεtituted or unsubstituted), and a dimer-forming bond; each of B and G are independently selected from the group consisting of (a) oxygen forming a keto group with the ring carbon to which the oxygen is appended; (b) two hydrogen atoms; (c) one hydrogen atom and one peroxy group; (d) aryl; (e) alkenylcarbonylalkyl; (f) alkenyloxycarbonylalkyl; (g) cyanoalkenyl; (h) arylalkenyl; (i) lower alkyl; (j) alkenyl; (k) acyl; each of which may be substituted or unsubstituted; and (1) a double or single dimer-forming bond; wherein one or more of A and B, B and C, A and J, C and D, D and E, E and F, F and G, G and H, H and I, and I and J can be combined to form aromatic, alicyclic or heterocyclic rings having 5-7 carbon atoms, said rings optionally being further subεtituted; wherein the ' three ringε in said formula are aromatic except that the particular bonds formed by one or more of the ring carbon atoms adjacent to A, B, C, H, G or F can be saturated; provided that, when n=2, at least one of H, G and F or at least one of A, B and C is a bond and either or both of (i) D and E and (ii) J and I optionally form aromatic or alicyclic or heterocyclic rings having 5-7 atomε with the adjacent carbon atomε; and analogs, isomers, homologs, derivatives and saltε of εaid compound and mixtureε thereof and a pharmaceutically acceptable carrier or diluent. 8. The pharmaceutical formulation of claim 7 compris- ing a parenteral dosage form. 9. The pharmaceutical formulation of claim 7 compris- ing an oral dosage form. 10. The formulation of claim 7 further comprising an effective amount of a nucleoside analog. 11. The formulation of claim 10 wherein said nucleoside analog is azidothymidine. 12. A composition of matter comprising desoxohypericin.

Inventors: LAVIE GAD, MAZUR YEHUDA, MERUELO DANIEL, LAVIE, GAD, MAZUR, YEHUDA, MERUELO, DANIEL
Applicants: UNIV NEW YORK, YEDA RES & DEV, NEW YORK UNIVERSITY, YEDA RESEARCH AND DEVELOPMENT COMPANY, LTD.
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61P31, A61P43, C07C39, C07C50, C07D221, C07D471, C07D493