JPH07504170A - Ion pair of hypericin compounds with antiviral activity - Google Patents

Abstract

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

Description

[Detailed description of the invention] Ionization of hypericin compounds with antiviral activity The present invention describes hypericin ion pairs and their use in inhibiting viral growth. Concerning business.

Main body weight Hibericin, a plant component of the genus H. ericum, is 2491 (1957)).

The 11th edition of the Merck Index, 4799.1989, has the following structure for hibericin: Furthermore, it has been reported that this has pyridine + methanolic HCI gives solvated blue-black needle-like crystals that decompose at 320°C; Dissolves freely in organic bases to produce a bright red solution with red fluorescence; in most other organic solvents. Virtually insoluble; soluble in alkaline aqueous solutions; and pH below 11.5 It is red in a solution of poii, and green with red fluorescence in a solution of poii or more. It has been reported that

Hypericin, both plant-derived and synthetic, can be used to treat viruses and especially Retroviruses, such as human immunodeficiency virus (HIV), AIDS and other diseases A broad-spectrum, potent inhibitor of DNA and RNA, including drugs that are presumed to cause was found to be a tar.

U.S. Patent No. 4,898,891, issued February 6, 1990, describes hibericin. , an antiviral pharmaceutical composition comprising pseudohyvericin or a pharmaceutically acceptable salt thereof and methods of using these compositions to treat viral infections. There is.

Muruelo et al., Proc, Na order, Acad, Sci, tlsA, 85 : 5230-5234 (1988), and U.S. Patent 5,047.435 is an antihypericin and pseudohypericin antibody in vitro and in vitro. Retroviral activity was reported. The authors also found that these aromatic polycyclic diones also reported that it was possible to prevent HIV from infecting individual cells.

Harlem, touch!” Tsujiri Niji no Kadan 1 degree, 332 217-218 (197B) and Binozaki, JPO63254 announced on October 29, 1984 is Hericu Discloses the extraction and use of antiviral agents from MS.

U.S. Patent No. 5.149.718, issued September 22, 1992, is body fluids and, more generally, viruses and retroviruses present in biological fluids. describes compositions and methods for inactivating gases. This composition is an anti-viral Rustic compounds hibericin, pseudohyvericin, derivatives, analogues, isomers, congeners, salts and mixtures thereof.

PCT patent publications W O89/Q9055 and 89109056 contain hibericin, A mixture of pseudohyvericin, salt, and nucleoside analogues such as AZT can be used to 5 discloses a composition for treating a virus infection.

However, hypereri obtained from plants of the genus Ncue or prepared synthetically It was noted that different formulations of Syn have varying biological activity. Also hypericin The formulation has a number of physical properties, including solubility in organic solvents and dispersibility in water. Drying is different. This change is clearly due to the extraction and purification method of hibericin. Ta.

Therefore, it provides consistent antiviral and antiretroviral activity. A need arose to find compounds with a pericin moiety. It also has antiviral activity. hypericin or related moieties whose physical properties are suitable for biological functions It is necessary to obtain a compound that

Highlight Ω base! The present invention discloses a novel virus containing a hibericin moiety consisting of an ion pair with antiviral activity. Concerning the compound. These ion pairs bind to organic or inorganic cationic species. It consists of negatively charged hibericin ions and is highly effective against human and animal viruses and especially It is useful in the treatment of various diseases caused by toroviruses, and in vitro. Useful to negate the virus's contagiousness. The ion pair was initially hyvericin. Free hibericin can be generated by treatment with acid. Disperse in organic or inorganic salts to form ion pairs.

Hyvericin ion pair is used to prevent or prevent people who are infected or suspected to have been infected with the virus. can be used therapeutically. In addition, the hypericin ion pair is Can be used to inhibit the growth of russ or to sterilize liquids and substances .

Concave dish Figure 1 shows the projections of hypericin-sodium ion pairs and hypericin-lysine ion pairs. A graph plotting the inhibition rate of Friend virus-induced spleen tumors in mice as a function of dose. It's rough.

Figure 2 shows the dosage of hibericin-sodium ion pair and hibericin tris ion pair. Graph plotting the inhibition rate of Friend virus-induced spleen in mice as a function of It is.

Figure 3 shows the hypericin-sodium ion pair and hypericin-ammonium ion pair. The inhibition rate of Friend virus-induced spleen in mice was plotted as a function of dose. It is a graph.

Figure 4 shows that mouse The direct inactivation of radiation leukemia virus was monitored and various hypothermic ion pairs were tested. 1 is a graph plotting the antiretroviral activity of .

・The amount of this day The form of hypericin that has been isolated from plants to date has a certain amount of sodium ion. It has been found that it contains Conventional method for isolating hibericin from plant materials is extracted using a polar solvent such as ethanol, methanol, or acetone, and then extracted using silica. Use gel chromatography. The form of hibericin obtained is always sodium Contains sodium ions resulting from ion-containing silica gel.

Sodium ion in pure hibericin obtained by chromatography on silica gel The relative amount of Varies depending on elution rate. In addition, hypericin prepared by chemical synthesis is Since silica gel chromatography is generally used for its purification, sodium It was found that it contains ions.

Another way to obtain Hibericin in pure form as described in the above Merck Index and in the literature The method of crystallization or precipitation from pyridine solutions in the absence or presence of hydrogen chloride . These crystals are only slightly soluble in organic solvents and especially insoluble in water. These are Piperazine can also be converted to a soluble form by chromatography on silica gel.

We have determined by X-ray diffraction that such pipera precipitated from pyridine solution A 0-diffraction pattern that discovered that gin crystals contain two molecules of pyridine and one molecule of water. According to One of the hydrogen atoms of the hydroxyl group is contained between two pyridine molecules. This is these Is the piperazine crystal a negatively charged piperazine and a positively charged pyridinium part? This shows that it consists of

The implication of this finding is that piperazine is already ionic at slightly alkaline or low pH. This shows that the situation is changing. This discovery is based on the UV-visible absorption spectrum The pKa value of piperazine is approximately 2.5, and the above hydroxyl group is confirmed by the measurement of The same spectral measurements show that the first ionization of pipera occurs at that pH. The second pKa value of gin is about 11, and above this pH value two hydroxyl groups are removed. Indicates that it is to be turned on. Therefore, under conditions greater than pH 2.5, only hydroxyl groups tend to form ion pairs with bases, but at pH greater than 11, both One hydroxyl group ionizes to form a salt with two cations.

physical properties, including solubility, and whether isolated from plants or chemically synthesized. However, varying batches of piperazine have been shown to show variability in biological activity. Some differences may be due to the uneven amount of sodium bound to the piperazine molecule or This is due to the complete lack of sodium. Both hydroxyl groups are ionized To distinguish between the piperazine form and the form in which only − hydroxyl groups are ionized, , hereinafter, the former will be referred to as a salt and the latter as an ion pair.

To reduce the problem of solubility and biological activity variables between different batches of piperazine , the hydroxyl group is not ionized and the pyridine or pyridine paired with the molecule during finishing The compound is combined to form free piperazine (1) from which sodium is removed. make it acidic.

Free piperazine is acidic and different from that obtained from the initial form of piperazine It has IR, UV-visible and fluorescent spectral properties.

Once the free piperazine is formed, the organic or inorganic salt can be removed at a pH below about 11.5. negative groups and bonded to organic or inorganic cationic species as piperazine ion pairs. It becomes a compound consisting of a piperazine moiety charged with . The piperazine ion pair is pipera Gin salt, the green substance mentioned above, is characterized by its solubility in organic polar solvents, its color and its Differs by extremely low electrical conductivity. Therefore, ion pairs are organic compounds in all respects. and can be defined as such, but cannot be defined as a salt.

Free piperazine is first acidified and then reacted with predetermined amounts and basic pH. As a result, compounds with improved, predictable and reproducible structures have improved solubility and biological properties. are produced with improved predictability and reproducibility regarding the nature of their activity.

The piperazine ion pair of the present invention has the following general formula: on and n is 1, or X is a divalent cation and n is 2 , X is not a sodium or pyridinium cation.

Therefore, the present invention provides that as long as the pH is not such as to produce a divalent salt of piperazine, As the cation in the ion pair, any organic or Including the use of inorganic salts. Preferred inorganic cation species are alkali and alkaline earth golds. cations such as potassium, lithium, calcium and magnesium; Preferred organic cations include ammonium in the general formula NR'R''R3R4. It is a rotonated nitrogen group moiety, and Rl-R4 in the formula are the same or different, Hydrogen; - one or more hydroxyl, alkoxy, phenoxy, amino or or alkyl, alkenyl or cyclo optionally substituted by a carboxy group alkyl; or phenyl, phenylalkyl, and alkyl, alkoxy, Aryl, such as phenyl, substituted by hydroxy or halogen alkyl or alkaryl group; or on one or more nitrogen or oxygen atoms thus or interrupted by one or more nitrogen or oxygen atoms an alkyl or an alkyl-substituted nitrogen atom It's a kill. By appropriately selecting R'-R', the cation can be made into any basic type. It may be an amino acid.

Two of the R groups, together with the nitrogen atom that binds them, are pyrrolidine, piperidine, moly forming a ruforine, piperazine or N-alkyl substituted piperazine ring, or R Three of the groups together with the nitrogen atoms that connect them form an alkyl-substituted pyridine ring be able to.

The various ion pairs of the present invention have varying solubility in water depending on the cation selected. .

Preferred organic cation species are those of the general 2NHR'R'R', in which RI All R'' are ethyl or 2-hydroxyethyl, R1 and R2 are hydrogen and R3 is octyl, 2-hydroxyethyl, 2-aminoethyl, 5-aminoethyl Nor-5-carboxypentyl (lysine) or 1,3-dihydroxy-2-hydro roxymethyl-2-propyl, R1 is hydrogen and R2 and R''4 are 2- hydroxyethyl or 2-hydroxypropyl; or R1 is hydrogen; R2 is methyl and R3 is 1-desoxy-1-sorbityl.

Compounds in which X is an inorganic monovalent or divalent cation Aqueous solutions or suspensions of corresponding inorganic salts such as carbonates, bicarbonates, hydroxides, phosphates, etc. For example, if X is ammonium, lithium or is a potassium cation, free piperazine, ammonium hydroxide, Prepared by adding each to an aqueous solution of lithium hydroxide or potassium hydroxide. , preferably using 1 equivalent and then freeze-drying to dry the resulting solution. do. X is an inorganic divalent cation, such as a calcium or magnesium cation When the ion pair is a calcium hydroxide or It can be prepared by adding each to an aqueous solution of nesium, preferably in equal amounts. Use half and then lyophilize the resulting solution to dryness.

An organic cation in which X is derived from a nitrogen base bonded to a hydrogen of the structural formula NH'R"R" The piperazine ion pair, which is a It can be prepared by processing free piperazine dissolved in a polar solvent. Alright The aqueous suspension of free piperazine can be treated with nitrogen base.

For example, if X is NHR, 'R''R3r, where R'=H, R''=CHt and R ”=(Jlt(C110)ri-CIIzOH), the hibericin ion pair is N-methane. Adding free hypericin to an aqueous solution of tilglucamine and then freezing the resulting solution 0 formula, which can be prepared by drying, RI = R! ＝　R’　　　CHzC In other examples, where the hypericin ion pair is H-poor OH, the hypericin ion pair triates free hibericin. It can be prepared by adding it to an ethanolic solution of nolamine and evaporating it to dryness. Wear.

A quaternary ammonium cation with a structure in which X is N" (R', R1, R3, Ra) The hyvericin ion pair, which is a sodium Inorganic monovalent cation species including potassium, ammonium or lithium cations are preferred. Preferably, it is prepared by treating the contained hibericin ion pair with each quaternary ammonium salt. can be manufactured.

For example, X in the formula is Nゝ(R', R'', R3, R') and RI = R'-R' =R'=CH, the hibericin ion pair is the hibericin ammonium ion pair. to an aqueous solution of tetramethylammonium chloride and then freeze the resulting solution. It can be prepared dry. The resulting dry material is then heated in vacuo. another In the example, X is N" (R', R", R3, R') and R""R"=R3=C The hyperinine ion pair with 1l+ and R'=(CHz)+s is Add thorium ion pair to cetyltrimethylammonium bromide water, then obtain It can be prepared by lyophilizing the solution. The resulting dry substance is then treated with an organic solvent. , preferably those in which sodium bromide is insoluble, toluene, acetonitrile, etc. Extract using When the solvent is evaporated and dried, each quaternary ammonium ion pair is can get.

The quaternary hibericin ion pair behaves in all respects as an organic compound and as a salt. cannot be defined.

The hypericin ion pair of the present invention is characterized by its solubility in organic solvents. . Some of these derivatives can be dispersed in water and monomers can be prepared by adding organic solvents. A loosely bound polymer containing occluded water that can be broken down into hypericin of form a polymer structure.

The water dispersibility of hibericin ion pairs also has a unique influence on their bioavailability. In water dispersion, hypericin ion pairs are in an aggregated state, but they are not separated from the cell membrane or Within the viral membrane, they exist in monomeric form. Therefore, hibericin io Biosorption of a pair of molecules requires the dissociation of the aggregate into monomeric molecules. bio suction A slow down of the deposition effect will give a slow release of the active substance.

In such cases, a certain level of the active substance is retained in the body for a relatively long period of time. is expected.

Some ion pairs show slower biosorption than others; liposomes all This is a model for the membrane of High solubility in liposomes allows compounds to quickly enter cells. enters quickly, thus indicating that dosing needs to be done frequently, whereas low Solubility indicates that the compound enters cells slowly. Therefore, a considerable amount The compound remains in the body and releases the drug slowly, thus requiring frequent administration. There is no.

The solubility of hibericin ion pairs in liposomes is shown in Table 1. (10%), this solution contains various hypericin ion pairs. The maximum concentration of liposomes for the zero-order hypericin ion pair mixed with an equal volume of water is Large binding capacity was determined.

Table 1 Ion pair compound solubility (mg/a+I of 5% lecithin f4 solution) hypericinna Thorium 0.06 -Lithium 0.06 Hyperin, which acts to slowly release the vehicle to the target organ. The ability of lysine and hypericin-ethylenediamine ion pairs to indicated by their relatively low solubility (sodium and lithium ion pairs). However, all ion pairs are completely soluble in monomeric form (compared to the solubility of It is expected that the solubility will be lower than that of the salt.

The hibericin-sodium ion pair, obtained by conventional methods from isolation or synthesis, has anti-retroactive properties. made in accordance with the present invention because it has antiviral activity, including antiviral activity. All of the various ion pairs also have some degree of antiviral and antiretroviral properties. It is expected that it will have sexual activity. Of course, special viruses or retro The specific activity with respect to viruses is expected to vary from compound to compound, and Optimized for use with any given virus or retrovirus On vs. cations can be determined empirically. Against friend virus Viral activity is associated with hybelin, sodium, lysine, ethylenediamine, and gelatin. Tanolamine, N-methylglucamine, triethanolamine, Tris and It was measured using an ion pair with ammonium.

The hypericin ion pairs of the invention are advantageously used in the treatment of mammals infected by viruses. or present in biological fluids as in U.S. Pat. No. 5,149,718. Prophylactic antiviral agents to inactivate existing viruses and retroviruses It can be used as Hypericin and pseudohype on antiviral effects The effectiveness of ricin is shown in U.S. Pat. No. 4,898,891. The syn ion pair is a combination of azidothymidine (AZT) or didetine for antiviral therapy. can be combined with nucleoside analogs such as oxyinosine (DDI), When treating retroviral infections, use acyclovir or other reverse transcriptase enzymes. Can bind to inhibitors. For other viral infections, the method of the present invention Ricin ion pairs are used in antiviral drugs such as adamantine, rifampicin, or Can be used with vaccines or antibody preparations.

"In conjunction with" refers to consecutive administration, mutual administration, substantially simultaneous administration of different formulations, or multiple administrations. Includes alternating administration of cleoside analog therapy and hypericin ion pair.

Hypericin ion pairs can be used in conjunction with other biologically effective substances. can. Other known antibiotics do not affect the growth of the virus itself. An analogy that can be used in conjunction with the hibericin ion pair even if it has no effect 1 in combination to avoid opportunistic infections when administered to immunosuppressed individuals. Preferably, it contains one or more antibacterial or antimicrobial agents; The hypericin ion pair containing composition is one or more immunomodulatory chemicals. can include. Biological substances and implants may also be treated with hypericin as part of treatment. Can include ion pairs.

The hibericin ion pairs of the present invention, in their water-dispersible or water-soluble form, are It has a wide range of efficacy in inhibiting viruses and retroviruses. Compounds of the invention Non-limiting examples of viruses inhibited by cytomegalovirus, herpes Susinpres, kusuvirus (H3V), influenza virus, vesicular stomatitis Virus (VSV), Hebatitis B virus, Vapilomavirus Oyohiretro viruses such as HIV, HTLVi, HTLV■ and feline leukemia virus. Ru.

Effective inhibition of a given virus can be achieved by one of the compounds of the invention or by such a compound. It can be carried out using a combination of two or more of these. Additionally, a single hippe The lysine ion pair can constitute the only active ingredient of the compositions of the invention and is or in conjunction with other antiviral agents that act by any means. Ru.

When treating a mammal suffering from an infection caused by a virus, the present invention According to the authors, the most effective compound or mixture was determined and the specific The concentration of effective treatments for viruses or retroviruses is well known in the art. can be determined by routine experiments using appropriate experimental models. Ru.

When used to treat AIDS, viremia, or sepsis, the present invention The vericin ion pair can be administered orally, topically or parenterally, preferably approximately 0 per kilogram (Xg) of body weight of the mammal being treated per treatment. ．． static over a wide range from 0,001 micrograms to approximately 100,000 micrograms. Administer by intravenous injection. More preferably, the dosage range is within the therapeutic range per treatment. from about 0.1 to about 50,000 micrograms per IKg of body weight of the mammal be.

The hypericin ion pair of the present invention also inactivates or inhibits viruses in vitro. Can be used on a variety of surfaces to control. The surface to be treated must be medical devices, prosthetic devices, gloves, condoms, body fluid handling devices such as needles, injections The compositions of the present invention are widely used as disinfectants, including on the inside and outside surfaces of vessels, catheters, etc. and further sterilize organs, fluids, skin, tabletops, containers, equipment, etc. A thin film of the zero composition can be left on the surface.

The present invention also provides N compositions and formulations for treating viral infections. The hyvericin ion pair of the present invention can be used in conventional solid or liquid form at any desired concentration. For example, tablets, capsules, caplets, etc. that can be mixed into pharmaceutical formulations. A solution that can be administered by injection or orally to feed infants suffering from viral infections. The pharmaceutical formulation of the present invention, which can be used to treat animals, contains active ingredients and containing an effective amount of the hypericin ion pair of the present invention.

Other active or inactive ingredients can be added.

For example, parenteral therapeutic compositions may incorporate the hyvericin ion pair of the present invention into Consists of a sterile isotonic saline solution containing rum. Included in each dose of each dosage form The unit content of the active ingredient may be determined if the effective amount can be achieved by administration of multiple doses. , by itself need not constitute an effective amount.

According to the present invention, each formulation further includes pharmaceutically acceptable carriers, diluents, excipients, salts. , consisting of inert ingredients, including other materials well known in the art, and of the selection thereof. The choice depends on the dosage form used, the determination of one of ordinary skill in the art. It therefore depends on the particular purpose being served and the nature of such additions. carrier and Examples of diluents include carbohydrates and lipids, and are not limited to phosphatides. Tidylcholine, Phosphatidylserine, Phosphatidylethanolamine, Tri Glycerides, tocopherol, retinoic acid, cyclodextrin and the like Contains derivatives of.

The hibecillin ion pair of the present invention can further be used in transdermal delivery systems or liposomes. and the latter are used as carriers for certain drugs. like this Liposomes can also contain other active agents, e.g. cells infected with viruses, e.g. Acts as a targeting agent <　)IIV　gp120, p120, gp41, P41 and p24, a specific antibody directed against the expressed viral protein. Can include HIV antibodies.

Topical use of hibericin ion pairs in suitable carriers can also be used. this is caused by viral rash, herpes simplex (type I or type ■), herpes zoster, etc. is of special importance.

Although the specification specifically refers to hypercillin as a compound formed into ion pairs, , this ion pair technology also has antiviral and antiretroviral activity, Others like hypericin have two reactive hydroxyl groups in their free acid form. It is clear to those with ordinary knowledge in the field that this can be applied to polycyclic aromatic diones. need to be understood. For example, pseudohyvericin has the formula (the two shown to the right of H hibericin except that one of the methyl groups of is replaced by C1,OH It has the same structure as . Other changes in the substituents of hibericin also indicate that such changes are ionic. Antiviral and antiretroviral properties of the compound itself without affecting its solubility As long as it has little effect on the properties of It can be carried out. These compounds are referred to herein as hypericin analogs and derivatives. will be mentioned. For example, a methyl group can be used with other alkyl, alkylamino, It can be substituted by alkoxy, and alkylaminoalkyl groups. child These two groups can be combined to form a 6-membered ring or a 7-membered ring.

The remaining four hydroxyl groups of the hypericin molecule (apart from those involved in ion-pair reactions) are removed. (H) or an ether group (OR) where R is hydrogen or alkyl or amino It can be substituted with a group (NRR).

Preferably, not all of these OH groups are removed in the same compound, The remaining four positions of the unsubstituted ring structure can be substituted with OH or alkyl. Wear. All of these compounds were ionized in the same manner as described above for Hiberin. Pairing is expected and is meant to be included within the scope of the present invention.

The hibericin used in the following examples was prepared according to the method of U.S. Pat. No. 4,898,891. It was prepared accordingly. The pharmaceutical formulations described in this patent also include the hyvericin iodine of the present invention. Can be used with a pair of links.

Example 1 - Free hypericin Free hypericin is hypericin (1 g) in acetone (150 ml)? Mixed guest appearances This was prepared by treating it with a 7% hydrochloric acid solution (5 ml). The resulting brown precipitate The lees were filtered and washed with water until neutral.

The precipitate was collected and dried in high vacuum at 70°C.

IR spectrum (KBr) is 3400.1625.1598.1473.1 426.1399.1369.1330.1300.1224.1188.11 53.1116.1090.844.806.794.673 cwr-' It showed an absorption band.

UV-visible absorption spectrum (ELOH) λ+eax 572. , 531.461 rnNMl? (DMSO) δ2.69.6.51.7.35.14.04.1 4.67ppm (all singlets).

Example 2-Hibericin-sodium ion pair vs. hibericin-sodium ion pair The powdered free hibericin (0.25 g) obtained in Example 1 was mixed with acetone (50 g). ml) and 5% aqueous sodium bicarbonate (168n+l, 2mM). It was prepared by adding slowly. After about 0.5 hours, the resulting solution was filtered and the filtrate was evaporated. Once dried, the ion pair was dried at 70° C. in high vacuum.

II? The spectrum (XBr) is 3400.1615.1590.1559. 1500.1465.1422,. 1353.1386.1337.1260. 1187.1114.843.805.685.604.567.538.52 It showed an absorption band at 7 cm-'.

UV-visible absorption spectrum (EtOH) λ, 589.545.470.38 2.325nmNMR(D)'130) 18.40.14.7.14.1. 7.4.6.5.2.7p, Dai (all singlets).

Example 3 - Hibericin Potassium Ion vs. Hibericin Potassium Ion Pair The powdered free hibericin (0.25 g) obtained in Example 1 was mixed with acetone (50 ml). Slowly add to a stirred solution of 2% aqueous potassium hydroxide (5.6ml 1.2sM). It was prepared using

After about 0.5 hours, the resulting solution was filtered and the filtrate was evaporated to dryness. Furthermore, ion pairs was dried at 70°C in high vacuum.

IR spectrum (KBr) is 3400.161B, 1586.1557.1 499.1458.1386.1368.1333.1299.1183.11 It showed an absorption band at 14.851.804 cm-'.

UV-visible absorption spectrum (EtOH) λ, 590.547.509.47 4 nap.

? 1MR (DMSO) δ18.26.14.63.1401.7.29.6. 41.2.63ppm (all singlets).

Example 4 - Hibericin lithium ion vs. hibericin lithium ion pair The powdered free hibericin (0.25 g) obtained in Example 1 was mixed with acetone (50 ml). 0.31 to a stirred solution of 3% aqueous lithium hydroxide-hydrate salt (2M). It was prepared by adding After about 0.5 hours, the resulting solution was filtered and the filtrate was evaporated to dryness. . The ion pair was further dried at 70° C. in high vacuum.

■R spectrum (KBr) is 3400.1590.1558.1501.14 An absorption band was observed at 65.1422.603.567.528c.

UV-visible absorption spectrum/L, (EtOH)λ, 589.545.470. 382.325 nsNMR (DMSO) δ18.3.14.65.14.0 2.7.31.6゜43.2.641) I) Im (all singlets).

Example a - Hibericin ammonium ion pair vs. Hibericin ammonium ion pair The powdered free hypericin (0.25 g) obtained in Example 1 was mixed with acetone (5 g). and 0.32 ml of a stirred solution of 5% ammonium bicarbonate (2 mM). It was prepared by adding slowly. After about 0.5 hours, the resulting solution was filtered and the filtrate was evaporated. I let it dry. The ion pair was further dried at 70° C. in high vacuum.

IR spectrum (KBr) is 3400.3200.1620.1585.15 56.1499.1461.141B, 1365.1334.1260.118 3.1114.893.850.831.804.671.624cm+-' The absorption band was shown in .

UV-visible absorption spectrum: λ, 590.547.509.474 nmN MR (DMSO) δ14.65.14.02.7.15.6.44.2.60 ppm (all singlets).

Example 6 - Hypericin calcium ion vs. hypericin calcium ion pair is The powdered free hibericin (0.25 g) obtained in Example 1 was dissolved in acetone (50 g). l) and 1 liter of 2% aqueous calcium hydroxide by adding slowly to a stirred solution of Prepared. After about 0.5 hours, the resulting solution was filtered and the filtrate was evaporated to dryness.

The ion pair was further dried at 70° C. in high vacuum.

IR spectrum (KBr) is 3500.1620.1585.1563.1 490.1463.1418.1386.1334.1260.1180.11 Absorption bar at 16.845.806.677.625.604.571 cm-' indicated.

UV-visible absorption spectrum: (EtOFl)λ, 590.547.509 ．． 474 nmN level R (DMSO) 61B, 37.14.70.14.06. 7.38.6.51.2.70p9 cabinet (all singlets).

Example 7 - Hypericin Magnesium Ion vs. Hypericin Magnesium Ion Pair The powdered free hibericin (0.25 g) obtained in Example 1 was mixed with acetone (5 g). 0 ml) and 7111 of magnesium hydroxide in 2% aqueous basic magnesium carbonate. Prepared by slow addition to a stirred solution of pentahydrate. After about 0.5 hours, The resulting solution was filtered and the filtrate was evaporated to dryness. Furthermore, the ion pair was heated at 70°C in a high vacuum. It was dried with.

IR spectrum (KBr) is 3500.1620.1585.1563.1 490.1463.1418.1386.1334.1260.1180.11 Absorption bar at 16.845.806.677.625.604.571 cm-' indicated.

υν visible absorption spectrum: (EtOH)λ, 590.547.509. 474 nm NMR (DMSO) 18.16.14.70.13.95.7. 20.6.34.2.51ppm (all singlets).

Example g - hypericin triethylammonium ion vs. hypericin triethyl The ammonium ion pair is triethyl amine (0.05 g) and acetone (5 (1 The free hypericin powder obtained in Example 1 (0,2 5g) and then stirred at room temperature for 30 minutes. The resulting dark red solution was evaporated to dryness in vacuo.

IR spectrum (KBr) is 3500.1590.1554.1499.1 421.1392.1367.1338.1292.1185.841 cm- ’ shows an absorption band.

UV-visible absorption spectrum (EtOH): λ, 590.547.509. 474nmN)'IR(Il耶0)δ: 18.34(s), 14.67( s), 7.33 (s), 6.45 (s), 3.35 (m), 3.05 (q, J = 7Hz), 2.60 (s), 1.17 (t, J = 7Hz) Example 9 - Hype Lysine octylammonium ion pair vs. hypericin octylammonium ion pair Mix a solution of octylamine (0,065 g) and acetone (50 ml). , which was treated with the free hypericin powder (0.25 g) obtained in Example 1, and then The mixture was prepared by stirring at room temperature for 30 minutes. The resulting dark red solution was evaporated to dryness in vacuo. I set it.

UV-visible absorption spectrum: λ, 590.547.509.474nmNM R (DMSO) 18.37 (s), 7.39 (s), 5.09 (bs), 3. 45 (bs), 2.68 (s) fruit 1t4Jo -hydricine 2-hydroxyethyl ammonium ion pair The hydricine 2-hydroxyethylammonium ion pair is ethanolamine C 0.03 g) and acetone (50 ml) were mixed, and this was mixed with the free compound obtained in Example 1. Prepared by treating with hypericin powder (0,25 g) and then stirring for 30 minutes at room temperature. Ta. The resulting dark red solution was evaporated to dryness in vacuo.

IR spectrum (KBr) is 1617, 530.1552.1464.1 419.1395.1383.1364.1310.1261.1187.11 Absorption bar at 15.883.829.644.622.605.570 cm-' indicated.

UV-visible absorption spectrum: λ, 590.547.509.474 nmN MR (DMSO) δ: 7.45 (s), 6.58 (s), 2.79 (Z, J-6Hz), 3.52, (Z.

J=6Hz), 2.74 (s) Example 11-2-amino-ethylammonium ion vs. hibericin 2-aminoe The tylammonium ion pair is ethylenediamine (0,037g) and acetone ( 50 ml) and mixed it with the free hibericin powder obtained in Example 1 (0, 25g) and then stirred at room temperature for 30 minutes. The resulting dark red solution The liquid was evaporated to dryness in vacuo.

1368.1292.1258.1185.1115.940.847.807 ．． It showed an absorption band at 622 cm.

UV-visible absorption spectrum: λ, 590.547.509.474 nmN MR (OMSO) 67.44 (s), 6.58 (s), 2.74 (s), 1 ．． 01 (m) pps + real mfN12 - bis=(2-hydroxyethyl)a ammonium ion pair Hypericin bis-(2-hydroxyethyl) ammonium ion pair is Mix nolamine (0.05g) and acetone (50e+I) to obtain the mixture obtained in Example 1. free hibericin powder (0,25 g) and then stirred for 30 min at room temperature. It was prepared by The resulting dark red solution was evaporated to dryness in vacuo.

IR spectrum (KBr) is 3450.1590.1556.1551.1 421.1392.1367.1336.1290.1258.1114.10 It showed an absorption band at 66.840.624 cm-'.

UV-visible absorption spectrum: λ, 589.547.509.473 nsN MR (01150) δ7.39 (s), 6.52 (s), 3.57 (t, J = 4.4 Hz), 2.86 (t, J = 4.4 Hz), 2.7 (5) 1) I) 11 Example a Example 13 - Hibericin bis-(2-hydroxypropane) ammonia um ion pair Hibericin bis-(2-hydroxypropane) ammonium ion pair is diiso Example 1 Mix propatoolamine (0.05 g) and acetone (50 l). with the free hypericin powder (0,25 g) obtained in Prepared by stirring. The resulting dark red solution was evaporated to dryness in vacuo.

IR spectrum (KBr) is 3450.1589.1554.1464.1 420.1394.1368.1336.1291.1259.1118.11 It showed an absorption band at 14.804.623 cm-'.

UV-visible absorption spectrum: λ, 589.547.509.473nN1 IR (DMSO) 618.4 (s), 7.4 (s), 6.5 (s), 3.3 ( s+), 2.7 (s), 1.16 (d, J=6Hz) Example 14 - Tris-(2-hydroxyethyl)ammonium ion pair Hibericin tris-(2-hydroxyethyl) ammonium ion pair is Mix ethanolamine (0,075g) and acetone (50ml) and carry out Treated with free hibericin powder (0.25 g) obtained in Example 1 and stirred for 30 min at room temperature. Stirred. The resulting dark red solution was evaporated to dryness in vacuo.

IR spectrum (KBr) is 3350.1591.1558.1500.1 487.1465.1423.1407.1336.1291.1259.11 87.1117.1097.1094.1065.1031.917.841. It showed an absorption band at 825 cm-'.

UV-visible absorption spectrum (EtOll): λ1. . 590.547.509. 473 nwNMR (D gate So) 18.3 (s), 14.64 (s), 14. 02 (s), 7.28 (s), 6.41 (s), 3.71 (t=5Hz), 3 ．． 22 (t, J=5Hz), 2.63 (s) Example 15-Hypericinridi lysine ion pair and hibericin lysinium ion pair is lysine (0.08g) and water ( Free hypericin powder (0.25 g) obtained in Example 1 by mixing and stirred at room temperature overnight. The resulting solution was freeze dried until dry.

+R spectrum (KBr) is 3500.3100.3000.1618.1 585.1502.1482.1419.1386.1335.1259.11 82.1114.839.804.675.666 Absorption band at cs+-' showed that.

UV-visible absorption spectrum (EtOH>:λ, 589.547.510. 474.383.328n cod NMR (DMSO) 618.4 (s), 14.07 (s), 7.43 (s), 6.77 (s), 2.81 (m), 2.73 (s), 1.54 (m) ppmX Example 16 - Hibelin N-methylglucammonium ion pair Hibericin N-methylglucammonium ion counter, N-methylglucamine Free hypericin powder obtained in Example 1 by mixing (0.2 g) and water (20 μl) (0.25 g) and stirred at room temperature overnight. Until the resulting solution is dry Lyophilized.

IR spectrum (KBr) is 1590.1557.1502.1464.1 421.1393.1336.1259.1187.1113.1084.10 It showed an absorption band at 31.841.624.603.526 cs-'.

UV-visible absorption spectrum: (EtO)I)λ, 589.547.510 ．． 474.383, 28 nm +111R (DMSO) δ1.8.4 (s), 7.43 (s), 6.57 (s ), 3.31 (m), 2.73 (s) pp+m Example 17 - Hibericint Lis ion pair hypericin Tris ion pair is 2-amino-2-hydroxymethyl -1,3-propanediol Tris (0.06g) and water (20μl) were mixed, It was treated with the free hypericin powder obtained in Example 1 and stirred at room temperature overnight. obtained The solution was lyophilized until dry.

IR spectrum (KBr) is 3500.1589.1557.1463.1 421.1389.1367.1335.1259.1185.1114.10 57.843.624.603C False-1 showed absorption hand.

uv-visible absorption spectrum) Ii: (EtO) 1) λ, , 1589.547. 510.474.383, 28 nm lnm1t (D? l5O) 618.36 (s), 7.4 (s), 5.09 ( m), 3.45 (M), 2.68 (s) Example 18: Hypericin-tetramethyl Ammonium ion vs. tetramethylammonium chloride (0.2 g > water (50 I ll) The solution was treated with hyvericin-ammonium ion pair (0.5 g). profit The resulting dark red solution was lyophilized and the resulting dry powder was heated to 80°C under vacuum to give the standard The title compound was obtained.

Example 19: Hibericin-cetyltrimethylammonium ion vs. cetyl bromide Limethylammonium (0.5g) in water (100ml) and tg solution in Hibericin. Treated with sodium ion pair (0.5 g). The resulting dark red solution was lyophilized. The resulting dry powder was dissolved in acetonitrile (100 ml). dry and evaporate The title compound was obtained.

Real jH1120: selected hibericin compounds with soluble seeding of hibericin ion pairs The concentration of the aqueous dispersion of the substance was measured. The following data were found.

Compound solubility (envious g/ugly I) Hypericin-sodium 1-3.5 Hypericin-Lysine 11 Hypericin-Ethylenediamine 0.13 Hypericin-N-methylglucamine 9.1 Hypericin-triethanolamine 4.7 Free hypericin 0.05 Hypericin-Viridin 0.05 Example 21: Hibe against murine Friend virus in BALB/c mice Antiretroviral activity of lysine-lysine ion pair Infected with Friend virus Mice showed virus-induced erythroleukemia with 100% of animals dying within 25-45 days. develop a disease. If the infection appears early, the lungs will increase in size (splenia). lungs The size increased 4 to 8 times within 10 days after infection with the virus. spleen Inhibition is therefore assayed for the antiviral activity of various drugs in vitro. Can be used for weighing. In this experiment, mice (3 groups) were 1.10.50 and 15 within 1 hour of infection. Administering the hyvericin-lysine ion pair at a single dose of 0 micrograms/mouse did.

0.5 al of a solution of compound and PBS was administered. Standard hypericin (silica gel) obtained by a process involving chromatography and is therefore a sodium ion pair) was solubilized in 0.5% aqueous benzyl alcohol and administered at the same concentration, and in PBS. It was used as a control along with infected normal control mice. vinegar All mice were sacrificed after 10 days and the lung weights were analyzed.The results shown in Figure 1 are as follows: Both hypericin-lysine and hypericin-sodium are Approximately 70-80% of the lungs of Friend virus-infected mice were affected within the dosage range of mice/mouse. It shows that it has been suppressed.

Example 22 - Hibe against murine Friend virus in BALB/c mice Antiretroviral activity of ricin tris ion pair Experiments were conducted as described in Example 21, but using the hypericin tris ion pair. Ta. The results are shown in FIG.

Example 23 - Hibe against murine Friend virus in BALB/c mice Antiretroviral activity of ricin-ammonium ion pair Experiments were conducted as described in Example 21, but with hypericin-ammonium (fl y-NH4') ion pair was used. The results are shown in FIG.

Example 24 - As measured by inhibition of viral particle-induced reverse transcriptase activity In addition, various studies were conducted by monitoring the direct inactivation of the Radiation Leukemia Virus. Determination of antiretroviral activity of hyvericin ion pair Infection generated with RadLν Viral particles released into the growth medium of At1lRIJ blastocytes were treated with hypericin. -Ethylenediamine (EDA), Hiberin triethanolamine (TEA) , hypericin-diisopropanolamine (dpa) and hypericin-n-methane Reacted with tilglucamine (nmg) ion pair. In addition, hypericin sodium (bv and pf #4) and two bunches of sodium titration batch (Na) Tested. Incubate the virus and compounds on ice for 30 minutes, then The viruses were ultracentrifuged in a Beckman Zhao centrifuge at 40,000 RP for 1 hour. Stephenson et al. Nson H.R., Reynolds R.K. and Aaronson Niss. ・A, Vitrl'y, 48: 749-756.1972). Shown in Figure 4 The results were expressed as counts per minute of 3H-thymidine mixing. These are the smallest 0 showing significant inhibition of virus-particle-induced reverse transcriptase using potent eda. See Figure 4.

Example 25 - Hyperici against murine cytomegalovirus (MCMV) In vitro assay of ion and its two ion pairs The antiviral activity of the test compound was determined at the final concentration of 32.10.3.2.1.0.0.3 2 and 0.1 μg/+ml. The stock solution contains the planned weight of the test compound. were dissolved in dimethyl sulfoxide (DMSO) and then adjusted to a final stock concentration of 1 m It was prepared by adjusting the volume with a medium so that it was g/+wl.

The stock solution, and all diluted solutions made from the stock solution, were mixed with 2% fetal bovine serum (2% %MM) in Earle's) 18M medium.

Antiviral activity was demonstrated in mouse mammary tumors grown in 24-well tissue culture plates. was evaluated in tumor fibroblasts (CI27L). 4 wells for each test article at each concentration used against. &1lVa After aspirating the medium from the culture plate, 3 wells contains 0.5 al of virus inoculum; the fourth well contains 0.5 al of virus inoculum; I put in % goods. Incubate the plate for 1 hour at 37°C in 5% CO2 with continuous agitation. I bet.

After incubation, the virus inoculum was removed and the agar overlay was added. minutes Separate overlays were created for each concentration of test compound. Each overlay is 3al of test compound (prepared as a 2x solution) plus 31 agar overlay Consists of. After mixing, add a formulation overlay of lll+ to each of the four wells. and the fourth well serves as a toxicity control for the test compound. cell control wells and virus control wells were incubated on each plate.

Acyclovir, positive antiviral control, and viral titration tested I went at the same time. Plates were incubated at 37°C in 5% CO□ for 6 days, Afterwards, remove the overlay, fix the plate, and add 1% crystal violet to the plate. Stained. Read the plaques using an inverted microscope and record the number of plugs in each well. Ta.

Average plaque forming units (PFU) per al from this in vitro assay and percentage conversions are shown in Table 2, and plaque counts for each well are shown in Table 3. vinegar. 5 in plaque count compared to virus control (≦44 PFU/ml) Test compound concentrations that result in a decrease of 0% or more are indicative of good antiviral activity. It is a sign. Hibericin is toxic at concentrations of 32 and 10 μg/wIl; , 2 μg/+l showed a 51% reduction in plaque compared to any of the other concentrations tested. There was no decrease either. Both hibericin ion pairs are toxic at 32 μg/al and 10 There was moderate toxicity at a concentration of μg/m+. N-methylglucamine derivative is 1 0 μg/ml was moderately toxic, but showed an 88% reduction in plaque, compared to other concentrations. There was no decrease in plaque at any time. Lysine derivative is 10μg/ml showed a 100% reduction in plaque. Only 25% of the cell sheet is up These cells were still attached when reading the plaque, but these cells were normal and no plaque was present. I didn't. Other concentrations tested showed no signs of reduction. Ashi Kurovir, a positive antiviral control, showed complete control at all concentrations tested. showed defense.

In conclusion, in vitroa, sei, hibericin is 32 and ]Oμg/l It was toxic at a concentration of aj, but at a concentration of 3.2 μg/ml, it caused a 51% reduction in plaque. showed that. Both hibericin derivatives are toxic at a concentration of 32 μg/ml; Although Qfl at 10 μg/ml was moderately toxic, N-methyl glycol Kamin derivatives showed 88% plaque conversion and lysine derivatives showed 100% plaque conversion. The calculation was shown.

Example 2626-11c 4y Vives of Hibericin and its Two Ion Pairs Orasosei ! For in vitro evaluation of three test articles against '1clIV, dose concentration 5 0.25 and LO mg/kg body weight (mpk) were used. Has virus antibodies Four-week-old female CDI mice were collected at the Charles River Breeding Laboratory. Retrieved from (Voltage, Michigan). This animal is highly recommended for general activity and agility. After a rough test, five animals were randomly housed per cage. Before dosing this mouse After 12 days of isolation, they were given food and water ad libitum between every gIM and throughout the study. dosage Three days before the start, the animals in each group of 10 mice were weighed and the body weight Allocated to groups according to defined doses. Specify the group as follows: Tani Group 1 Hypericin-IQmpk Group 2 Hibaricin-25pk Group 3 Hibericin-50+*pk Group 4 Hibericin N-methylg Lucamine ion pair - IQlapk group 5 hypericin N-methylglucami ion pair-251Ipk group 6 Hiba 11sin N-methylglucamine On pair 50 arpk group 7 hyperin lysine ion pair -10 Ilpk group Group 8 hypericin lysine ion pair -25Ilpk group 9 hypericin lysine pair ion pair - 50 spk group 10 Acyclovir - 25 faith ρ to group 1 1 Ala-A-25mpk Group 12 Vehicle Control All dosing solutions are concentrated so that the desired dose of compound can be administered in a volume of 0.2 ml. Prepared. For 50 mpk dosing solution, the three test compounds were tested against hypericin. 5.75mg/ml 5.75mg/ml for N-methylglucamine derivative , and lysine derivatives at a concentration of 5.5 mg/a+l in sterile water.

Dosing solutions for 25 and 10+ opk are prepared by diluting with sterile water from a 50+ pk concentration. did. Positive control compounds, acyclovir and adenine-9-BD -Arabinocyto (Ara-A) was dissolved in 0.25% methylcellulose.

Dosing solutions were prepared fresh daily. The test product was intraperitoneally injected into mice once a day at 0.2 ml volume for 8 consecutive days. Vehicle control group 0.2 daily An injection of ml of sterile water was given. On day 2, received a second dose of test compound. Approximately 5 hours later, all mice were challenged with 0.2 ml of MCFIV by intraperitoneal injection. received the dose. Mice were observed for mortality for 21 days after virus challenge. death Percent mortality and mean survival time (MST) were calculated for each group.

The results of this experiment are summarized in Table 4. In this experiment, the vehicle control group 60% mortality rate, ? lST showed 11.9 days.

Both hibericin, and its derivatives, when compared to vehicle control Mean survival times for treated animals were statistically increased. 25 and 50mp When treated with hibericin in K, the mortality rate decreased to 10% and 0%, respectively. The mean survival time increased from 19.7 days to 21 days. Hibericin with lo+mpk Survival of animals treated with this drug was not significantly different from the vehicle control group. won. Does the N-methylglucamine ion pair derivative reduce mortality at all three concentrations? IST increased. 10.25, and the concentration of 50*pk is 18.21 and 2 The average survival time was 1 day, and the mortality rates were 20%, 0%, and 0%, respectively. . Lysine ion pair derivatives were 20% and 20% at concentrations of 25 and 50 pk, respectively. MST increased to 18 and 21 days. 10mpk glue The survival rate of the group was not significantly different from that of the vehicle control group. Yang Acyclovir treatment at 25 npk compared to the sex control compound at 19. The mortality rate was 10% with MST of 4 days, but with MST of 25 npk with MST of 21 days. There was a 0% mortality rate in MST.

deep red Mice treated by intraperitoneal route and challenged with murine cytomegalovirus. Survival time and mortality rate 1'JLt-7" 1") Mi9ru""" ■μ Hayaday "1 Hypericin 10 13 ．． 5 5/10 502 Hypericin 25 19.7” 1/10 103 Hypericin 50 21.0" O/lo O4 glucamine ion pair 10 1 8.0" 2/10 205 Glucamine ion pair 25 2L, O" O/1 0 O6 glucamine ion pair 50 21.0” O/10 .07 Lysine On vs. 10 15.4. 4/10 408 Lysine ion pair 25 18. 0” 2/1.0 209 Lysine ion pair 50 21.00 0/10 0 10 Acyclowill 25 19.4” 1/10 1011 Ara-A 2 5 21.0" 0/10 012 Vehicle Control - 11.9 6/ 1060a Mice were dosed once a day for 8 consecutive days. Second virus attack This occurred 5 hours after administration of .

b MST, average survival days Number of dead mice per total number of C attacks * MSTO difference is Dunnehu analysis of variation It is statistically significant (p≦0.05).

In conclusion, in Vive or Sei, Hibericin at 25 and 5Q++ pk. , N-methylglucamine ion pair derivative at 10.25 and 5Qa+pk, and At 25 and 50 npk, the lysine ion pair derivatives were treated with only the vehicle of administration. Compared to treated animals, mean survival time was significantly increased and mortality was decreased.

The specific preferred embodiments described above are indicative of the general nature of the invention, so that existing knowledge may not be applied. The use of such specific preferred embodiments in various can be easily modified and/or adapted for applications and therefore Any adaptations or modifications thereof are intended to be included within the scope of the disclosed spirit and preferred embodiments. intend. The expressions or terminology employed herein are for descriptive purposes only and are not intended to be limiting. do not have.

All publications and pending patent applications mentioned in this specification are incorporated by reference. It will be done.

-11% suppression rate for each item! -IM □% inhibition rate HY-lysine IG 2 pg/ml pg/ml FIG.4 4+q/ml August 12, 1994

Claims (19)

[Claims] 1. Free hypericin is combined with a predetermined amount of an organic or inorganic base of about 11.5 or more. hypericin, which consists of reacting at a pH below to form an ion pair with the base. How to generate ion pairs. 2. The organic or inorganic base has an alkali or alkaline earth metal cation. 2. The method according to claim 1, wherein the base is on. 3. According to claim 1, the organic or inorganic base is a protonated nitrogen base. Method. 4. The hypericin ion pair produced by the method of claim 1 is treated with an excess of quaternary anion. The hypericin phase consists of reacting with a monium salt at a pH below about 11.5. A method for producing quaternary ammonium ion pairs. 5. Claim 1, wherein the organic or inorganic base is other than sodium or pyridine. Hypericin ion pair produced by the method of 6. A hypericin ion pair produced by the method of claims 1-4. 7. General formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (X in the formula is a monovalent cation, n is 1, or X is a divalent cation) and n is 2 and X is not sodium or viridinium) The ion pair of hypericin is represented by . 8. An effective amount of hypericin ion pair according to claim 7 and a pharmaceutically acceptable carrier. An antiviral pharmaceutical composition comprising Riya. 9. Claim 7, wherein X is an alkali or alkaline earth metal other than sodium. ion pair of hypericin. 10. X is potassium, lithium, calcium, magnesium or ammonium The hypericin ion pair according to claim 7. 11. X is the protonated nitrogen base moiety of the single-stage NR1R2R3R4, and the formula R1-R4 are the same or different, hydrogen; one or more hydroxyl groups, atom optionally substituted with alkoxy, phenoxy, amino or carboxy groups alkyl, alkenyl or cycloalkyl; aryl, aralkyl or alkaryl; or by one or more nitrogen or oxygen atoms; is an alkyl or an alkyl group interrupted by one or more nitrogen or oxygen atoms. is an alkyl interrupted by a nitrogen atom substituted by an alkyl, Or two of R1-R4 together with the nitrogen atoms bonding them are pyrrolidine, pyrrolidine, Forms a peridine, morpholine, piperazine or N-alkyl substituted piperazine ring or three of R1-R4 are alkyl substituted together with the nitrogen atom bonding them. Ion pair of hypericin according to claim 7, forming a pyridine ring. 12. R1-R3 in the formula are all ethyl or 2-hydroxyethyl; R 1 and R2 are hydrogen, R3 is octyl, 2-hydroxyethyl, 2-amino Noethyl, 5-amino-5-carboxypentyl (lysine) or 1,3-dihydrogen droxy-2-hydroxymethyl-2-propyl; R1 is hydrogen and R2 and R3 is 2-hydroxyethyl or 2-hydroxypropyl; and is hydrogen, R2 is methyl, and R3 is 1-desoxy-1-sorbitol. 12. Ion pair according to claim 11 of general formula NHR1R2R3, which is chill. 13. In the formula, R1=R2=R3=CH3, and R4=CH3 or cetyl. 12. The ion pair of hypericin according to claim 11. 14. General formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (X in the formula is a monovalent cation, n is 1, or X is a divalent cation and n is 2 and X is not a sodium or pyridinium cation) An ion pair of hypericin or an analogue or derivative of hypericin represented by 15. General formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (R5 and R6 in the formula are the same or different, an alkyl group, an alkylamino group, alkoxy group, hydroxyalkyl group or alkylaminoalkyl group. or combine to form a 6-membered ring or 7-membered ring; R7-R10 are the same or are different and are H, OR or NRR, where R is hydrogen or alkyl ; and R11-R14 are H, OH or alkyl. ) Claims expressed in 14. The ion pair described in 14. 16. A virus-containing substance in an effective amount of ions according to claim 7 or 9-15. A method for inactivating viruses consisting of contacting them with 17. Administering an effective amount of the ion pair according to claim 7 or 9-15 to a subject in need of treatment. A method of treating viral diseases consisting of giving. 18. 18. The method of claim 17, wherein the viral disease is a retroviral disease. 19. When the base is monovalent, the predetermined amount is about 1 molar equivalent. and when the base is divalent, the predetermined amount is about 1/2 mole. 2. The method of claim 1, wherein the method is ole equivalent.