MXPA00011360A - Compositions for the treatment of hiv and other viral infections - Google Patents

Abstract

A pharmaceutical composition that can be used to treat viral infections, particularly HIV. The composition comprises from about 250 mg to about 6000 mg of a benzimidazole derivative of formula (I) or a pharmaceutically acceptable organic or inorganic addition salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms;n is a positive integer of less than 4;Y is hydrogen, chlorine, nitro, oxychloro, methyl or ethyl;R is hydrogen or an alkyl group having from 1 to 8 carbon atoms;and R2 is 4-thiazolyl. The preferred compound is thiabendazole. In the present invention it has been discovered that the compounds described above are useful for the inhibition of HIV and the treatment of HIV infection when used alone or in combination with other anti-viral agents. These compositions can prevent replication of the HIV virus, prevent creation of virus strains that are resistant to treatment with benzimidazoles, prevent or delay infection of cells with HIV virus and delay reappearance of the virus in the treated cells. These compositions are also effective against hepatitis and viruses such as herpes, influenza and rhinoviruses.

Description

COMPOSITIONS FOR THE TREATMENT OF VIRUS DB HUMAN IMMUNODEFICIENCY AND OTHER VIRAL INFECTIONS TECHNICAL FIELD This invention is a method to treat viral infections, especially the human immunodeficiency virus (HIV). The pharmaceutical composition contains one or more benz midazole derivatives, especially a thiabendazole compound.

BACKGROUND OF THE INVENTION HIV infections and other viral infections are a leading cause of death. HIV is a disease in which a virus that attacks the body's immune system replicates in the body. The HIV virus is not easily destroyed nor is there a good mechanism to defend the host cells from virus replication. Several drugs have been approved for the treatment of this devastating disease, including zidovudine (AZT, Retrovir®, didanosine (dideoxinosine, ddl, Videx®), stavudine (d4T, Zerit®), zalcitabine (dideoxycytosine, ddC, Hivid®), nev rapina (Viramune®), lamivudine (Epivir®, 3TC), protease inhibitors, saquinavir (Invirase®), Fortovase®), ritonavir (Norvir®), nelfinavir (Viracept®), efavirenz (Sustiva®), abacavir (Ziagen®), amprenavir (Agenerase®) indinavir (Crixivan®), ganciclovir, AzDU, delavirdine (Rescriptor®), erythropoietic , colony stimulation factors (G-CSF and GM-CSF), non-nucleoside inhibitors and nucleoside inhibitors. See M.I. Johnston & DF Hoth, Science, 260 (5112), 1286-1293 (1993) and DD Richman, Science, 272 (5270), 1886-1888 (1996. A vaccine against AIDS has been tried (Salk vaccine, and has been discovered that several proteins that are chemokines from CD8 act as suppressors of HIV.In addition to the nucleoside analogs, proteins and synthetic antibodies above, it has been found that several plants and substances derived from plants have anti-HIV activity in vi tro. However, the HIV virus is not easily destroyed, nor is there a good mechanism to defend the host cells from virus replication, so medical professionals continue to look for drugs that can prevent HIV infections, treat carriers of HIV to prevent it from progressing to fatal, developed AIDS, and to treat the patient with AIDS.Therefore, a material that is targeted is highly desirable. to the HIV virus and inhibits viral replication. Herpes simplex is another viral infection that is difficult to cure. Herpes simplex virus (HSV) types 1 and 2 are persistent viruses that commonly infect humans. HSV type 1 causes oral "fever blisters" (recurrent herpes labialis), and type 2 HV causes genital herpes, which has become a major venereal disease in many parts of the world. There is currently no completely satisfactory treatment for genital herpes. In addition, although it is not common, HSV can also cause encephalitis, a life-threatening brain infection (The Merck Manual, Holvey, Ed., 1972, hitley, Herpes Simplex Viruses, In: Virology, 2 'Ed., Raven Press (1990)). A more serious disorder caused by HSV is dendritic keratitis, an ocular infection that produces a branched lesion of the cornea, which can in turn lead to permanent scarring and loss of vision. Eye infections with HSV are a leading cause of blindness. Hepatitis is a disease of the human liver. It manifests with inflammation of the liver and is usually caused by viral infections and sometimes by toxic agents. Hepatitis can progress to liver cirrhosis, liver cancer and eventually death. Several viruses are known such as hepatitis A, B, C, D, E and G that cause several types of viral hepatitis. Among these, HBV and HCV are the most serious. HBV is a DNA virus with a virion size of 42 nm. HCV is an RNA virus with a virion size of 30-60 nm. See, D. S. Chen, J. Formos, Med. Assoc, 95 (1), 6-12 (1996). Hepatitis C infects 4-5 times the number of people infected with HIV. Hepatitis C is difficult to treat and it is estimated that there are 500 million people infected with it around the world (approximately 15 times those infected with HIV). Currently, effective immunization is not available and hepatitis C can only be controlled by other preventive measures such as improvement in hygiene and sanitary conditions and by the interruption of the route of transmission. Currently, the only acceptable treatment for chronic hepatitis C is interferon that requires at least six (6) months of treatment and / or ribavarin that can inhibit viral replication in infected cells and also improve liver function in some people . The treatment with interferon with or without ribavapna, however, has an efficacy limited in the long term with a response rate of approximately 25%. Infection with the hepatitis B virus leads to a broad spectrum of liver injury. In addition, chronic infection with hepatitis B has been linked to the subsequent development of hepatocellular carcinoma, a leading cause of death. Currently the prevention of HBV infection is a vaccination with hepatitis B that is therapeutically effective. However, vaccination is not effective in the treatment of those already infected (ie, carriers and patients). Many drugs have been used in the treatment of chronic hepatitis B and none have proven effective except interferon. The treatment of HCV and HBV with interferon has limited success and has frequently been associated with adverse side effects such as fatigue, fever, chills, migraine, myalgias, arthralgias, benign alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction. Because interferon therapy has limited efficacy and frequent adverse effects, a more effective regimen for the treatment of these viral infections is necessary. Lovett (Diss, Abstr. Int. (Sci.) (1979), 39 (11), p. 5315-5316) describes the use of thiabendazole for the treatment of cancer. Edlind et al., (Chemical Abstr. (1994), 121.175012x), Brown et al., (J. Am. Chem. Soc. (1961), 83, pg 1764-1765) and Aur (J. Pediatr. 1971), 78 (1), pp. 129-131) describe the use of thiabendazole for the treatment of helminthic infections. Wagner et al., (U.S. 3 / 370,957) describes anti-fungal compositions of thiabendazole. To date, there is no description or suggestion of the use of thiabendazole for the treatment of viral infections. However, because of the many disadvantages exposed to the treatment of viral infections, there is a continuing need for new improved methods for the treatment of viral infections. viral infections.

SUMMARY OF THE INVENTION A pharmaceutical composition for the treatment of animals, and in particular, animals of hot and human blood, comprising a pharmaceutical carrier and an effective amount of an anti-viral compound of Formula I: *** ^ ** & ^ ']. wherein: X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl R is hydrogen, or an alkyl group of 1 to 8 carbon atoms; and R2 is 4-thiazolyl as claimed. Preferably, the benzimidazole is substituted with either a chloro (C1-) or oxychloro (C10-) at the 5 or 7 position (meta to the benzene ring bridge carbons) and the substituents remaining on the ring of benzene are hydrogen. The preferred compounds are those of the Formula III: ^ ¡^ ¡¡^^^^ ¿g (III) wherein R3 is hydrogen or an alkyl of 1 to 8 carbon atoms or the pharmaceutically acceptable, non-toxic acid addition salts thereof, with either organic and inorganic acids. The most preferred compound is 2- (4-thiazolyl) benzimidazole. The compositions can also be used to treat HIV and other viral infections. The drug can be administered daily or 1 to 4 times a week. In the present invention, it has been discovered that the compounds described above are useful for the inhibition of HIV and the treatment of HIV infection. The present invention also provides methods for the treatment of HIV infection comprising administering to a host infected with HIV a pharmaceutically or therapeutically effective or acceptable amount of a compound as described above, particularly those wherein R is 4-thiazolyl. More specifically, this invention provides an anti-viral composition comprising a pharmaceutical carrier and a benzimidazole derivative as defined herein in conjunction with a method of treating viral infections. These compositions can prevent the replication of a virus, create resistance to the virus in the patient, prevent or delay the infection of cells with a virus, prevent the formation of viruses resistant to treatment with anti-viral agents, increase the life span of cells infected with a virus and / or delay the reappearance of a virus in the treated cells. This invention provides compositions and methods for treating viral infections such as HIV, herpes, hepatitis, influenza and / or rhinovirus with the anti-viral composition either alone or with other treatments.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions: As used herein, a component "Pharmaceutically acceptable" is one that is suitable for use with humans and / or animals without undesirable adverse side effects (such as toxicity, irritation and allergic response) in proportion to a reasonable benefit / risk ratio. As used herein, the term "therapeutically effective amount" refers to the amount of a component that is sufficient to produce a desired therapeutic response without adverse and undesirable side effects (such as toxicity, irritation or allergic response) in proportion to a reasonable benefit / risk ratio when used in the manner according to the invention. The specific "therapeutically effective amount" will generally vary with factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the aberration of the treatment, the nature of the concurrent therapy (if any) , the specific formulations used and the structure of the compounds used. Therapeutically effective amounts are generally recognized as being safe and effective amounts. As used herein, a "pharmaceutical addition salt" or "pharmaceutically acceptable salt" is a salt of the anti-viral compound with an organic or inorganic acid. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and others known to those skilled in the art. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, dispersing agent or vehicle for distributing the anti-viral agent to the animal or human. The carrier can be liquid or solid and is selected according to the proposed route of administration. The anti-viral compounds of the invention are the benzimidazoles and / or their salts. The benzimidazoles are described in detail below. The preferred anti-viral compound is the product sold by Merck under the name "thiabendazole". As used herein, "virus" includes viruses that infect animals or mammals, including humans. The viruses include HIV, influenza, poliovirus, hepatitis, herpes, rhinovirus, and others known to those skilled in the art. As used herein, "adjunctive therapy" means that the patient in need of the drug is treated or given another drug for the disease in conjunction with the benzimidazole derivatives. This adjunctive therapy can be sequential therapy where the patient is treated first with one drug and then with the other within a given period of time or it may be a concomitant therapy where the two drugs are administered in a substantially simultaneous manner.

Bj. Anti-viral compounds The anti-viral benzimidazole compounds of the invention are those of Formulas (I) or (II). A preferred compound is 2- (4-thiazolyl) benzimidazole or the pharmaceutically acceptable, non-toxic acid addition salts thereof. Suitable acid addition salts are acid addition salts of organic or inorganic acids, selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates , salicylates, ascorbates and others known to those skilled in the art. Prodrugs of the benzimidazole compounds are also provided by the present invention. A "prodrug" is considered to be a compound of formulas I, II or III having one or more functional groups or carriers covalently attached to this functional groups or carriers that are removed from the compound of formulas I, II or III to form the respective compound. A prodrug of a benzimidazole compound is prepared by modifying one or more functional groups present in the compound with one or more masking groups in such a way that the masking groups can be cleaved either by routine manipulation ex vi, in vivo, in vi tro, or to form the compound of origin. Prodrugs include compounds wherein the hydroxy, amine, or sulfhydryl groups bind to any group that is cleaved to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate or benzoate derivatives of alcohol and amine functional groups in the benzimidazole derivatives; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the benzimidazole derivatives; and others known to those skilled in the art.

The pharmaceutically acceptable salts of the benzimidazole derivatives include the conventional non-toxic salts or the quaternary ammonium salts of the benzimidazole compounds formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from the acids inorganic such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzene, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention are synthesized from the benzimizadol derivatives having a basic or acid portion by conventional chemical methods. In general, these salts are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; In general, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 * ed. , Mack Publishing Company, Easton, Pa., 1985, p. 1418, the description of which is incorporated herein by reference. The ........ «toa.-.». - Descriptions of all of these references cited herein are hereby incorporated herein by reference in their entirety. The benzimidazole derivatives are prepared in various ways well known to those skilled in the art of organic synthesis. The benzimidazole derivatives are synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those compounds described below. These compounds are prepared according to the method described in U.S. Patent No. 3,738,995, issued to Adams et al., June 12, 1973. The thiazole derivatives are prepared according to the method described in Brown et al. . , J. Am. Chem. Soc. 83. 1764 (1961) and Grenda et al., J. Orq. Chem .. 30, 259 (1965). The description of each of the references cited above is incorporated herein by reference.

C. Dosage and. forms of dose distribution The identity of the anti-viral compound, the iMabaiMatiBie ^ pharmaceutical carrier and the amount of the compound administered will vary widely depending on the species and body weight of the mammal and the viral infection or virus being treated. The dose administered will vary depending on known factors such as the pharmacodynamic characteristics of a specific antiviral compound and its mode and route of administration; age, sex, metabolic rate, absorptive efficiency, health and patient's weight; the nature and degree of the symptoms; the kind of concurrent treatment that is administered; the frequency of treatment with a compound of Formulas I, II or III; and the desired therapeutic effect. The benzimidazole is preferably micronized or powdered so that it is more easily dispersed and solubilized by the body. The processes for grinding or spraying the drugs are well known in the art. For example, a hammer mill or similar mill mill is used. The preferred particle size is less than about 100 μ and preferably less than 50 μ. Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligrams to about 5000 milligrams of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.05-95% by weight based on the total weight of the composition. Based on the patient's body weight, the dose can be administered in one or more doses several times per day or per week. Multiple dosage units may be required to achieve a therapeutically effective amount. For example, if the dosage form is 1000 mg and if the patient weighs 40 kg a pill will provide a dose of 25 mg per kg for that patient. A dose of only 12.5 mg / kg will be provided for an 80 kg patient. The anti-viral compounds of the invention have an efficacy exhibited against viruses and cancers in mice at doses of approximately 500 mg / kg, 2,500 mg / kg, 3,500 mg / kg, 4,000 mg / kg, 5,000 mg / kg and 6,000 mg / kg. In general, an effective dose in mice is approximately 12 times the expected effective dose in humans. As a general guide, for humans a dose of as little as 30 milligrams (mg) per kilogram (kg) of body weight and up to about 10,000 mg per kg of body weight is suitable as a therapeutically effective dose. Preferably, from about 250 mg / kg to about 5,000 mg / kg of weight is used bodily. Other preferred doses vary between 100 mg / kg to about 3,000 mg / kg of body weight. However, a dose of between about 2 milligrams (mg) per 5 kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some viral infections. Intravenously, the most preferred administration rates may vary from about 1 to about 1,000 mg / kg / minute during an infusion at constant speed. Benzimidazole derivatives can be administered in an individual daily dose, or the total daily dose can be administered in divided doses of two, three or four times daily. The benzimidazole derivatives are given in one or more doses on a daily basis or from one to three times a week. The anti-viral compounds (active ingredients) of this invention are administered to inhibit The growth of viruses or viral infections by any means that produces contact of the active ingredient with the site of action of the agent in the body of a mammal or animal. They can be administered by any conventional means available for use with other pharmaceutical products, either as agents - ^ - ^ - 6a & - - - * »- * • ._,",. ",,, ^,.,., .. .jp¡ g¿ ^ ff ~ individual therapeutic or in combination with other therapeutic agents. A dose unit may comprise a single compound or mixtures thereof with other compounds, other viral inhibiting compounds or other anti-viral compounds. The benzimizadol derivatives can be administered in oral dosage forms such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The benzimizadol derivatives can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms well known to those skilled in the pharmaceutical arts are used. The compounds described herein form in detail the active ingredient, and are typically administered in admixture with suitable diluents, excipients, excipients or pharmaceutical carriers (collectively referred to herein as a carrier or pharmaceutically acceptable carrier materials) appropriately selected from regarding the proposed form of administration and how it is consistent with conventional pharmaceutical practices. The unit will be in a liquid form suitable for oral, rectal, topical injection, intravenous or parenteral administration. The benzimizadol derivatives can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is chosen in general based on the type of administration used. The tablets may contain binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and suitable melting agents. For example, for oral administration in the unit dosage form of a tablet or capsule, the active drug component will be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia gum, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these forms of '- * • ^ -s * - "» - Doses include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The benzimizadol derivatives can also be administered in the form of a liposome distribution system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidyl cholines. The benzimizadol derivatives can also be coupled with soluble polymers as selectable drug carriers. These polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic acid copolymers and . ~ A * ~ M-. polyglycolide, poly-epsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in liquid, sterile dosage forms. The gelatin capsules may contain the active ingredient and the powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide continuous release of the drug over a period of hours. The compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. ** ° ~ - * > * "- -ta '*'" * •• '" For oral administration in the liquid dosage form, the components of the oral drugs are combined with any inert, pharmaceutically acceptable, non-toxic, oral carrier, such as ethanol, glycerol, and water. Examples of suitable liquid dosage forms include pharmaceutically acceptable solutions or suspensions in water, fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules. and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, dispersing agents, diluents, sweeteners, thickeners and melting agents. Liquid dosage forms for oral administration may contain coloration and taste to increase patient acceptance. In general, water, a suitable oil, saline solution, aqueous dextrose (glucose) related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. The solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The benzimizadol derivatives can also be administered in intranasal form via the use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the administration of the dose will generally be continuous rather than intermittent throughout the dose regimen. Parenteral and intravenous forms may also include materials and other materials to ^^ g ^ -rTT " make them compatible with the type of infection or distribution system chosen. The pharmaceutical dosage forms useful for the administration of the compounds of this invention are illustrated as follows: Capsules: A large number of unit capsules are prepared by filling two-piece hard gelatin capsules, normal each with 100 to 500 milligrams of active ingredient powder, 5-150 milligrams of lactose, 5-50 milligrams of cellulose and 6 milligrams of magnesium stearate.

Soft Gelatin Capsules: A mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement gum in gelatin to form soft gelatine capsules containing 100 -500 milligrams of the active ingredient. The capsules are washed and dried.

Tablets: A large number of tablets are prepared per conventional procedures so that the dosage unit was 100-500 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase the good taste or delay absorption.

Injectable Solution: A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension: An aqueous suspension is prepared for oral administration so that every 5 ml contains 100 mg of the finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of USP sorbitol solution, and 0.025 ml vanilla .

The present invention also includes equipment pharmaceuticals useful for example for the treatment of HIV infection, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a benzimizadol derivative. These kits may additionally, if desired, include one or more of the various conventional components of the pharmaceutical equipment, such as, for example, containers with or one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. in the technique. The printed instructions, either as instructional sheets or as labels, indicating the quantities of the components to be administered, the guidelines for administration and / or guides for mixing the components can also be included in the equipment. It should be understood that although the specified materials and conditions are important in the practice of the invention, the unspecified materials and conditions are not excluded as long as they do not prevent the benefits of the invention from being realized.

D. Attached Therapy One or more benzimized can be used in a individual treatment. One or more benzimizadol derivatives can be combined with other antiviral agents or enhancers. Enhancers are materials that affect the body's response to the anti-viral agent. In the case of HIV, an adjunctive therapy with AZT, TC-3 or protease inhibitors in general will be effective. In the case of hepatitis, acyclovir, famciclovir or valaciclovir, Ribavipna, interferon or combinations of Ribavirin and interferon or beta-globulin can be administered as adjunctive therapy. For herpes, a recombinant alpha-interferon can be used. In some embodiments of the invention, thiabendazole is used in combination with one or more anti-inflammatory, anti-viral, anti-fungal, amoebicidal, trichomonocidal, analgesic, antineoplastic, anti-hypertensive, anti-microbial and / or steroidal drugs. treat antiviral infections. In some preferred embodiments, viral infections are treated with a combination of thiabendazole with one or more of beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, nitrofurazone, nalidixic acid, cortisone, hydrocortisone, betamethasone, dexamethasone , fluocortolone, prednisolone, tpamcinolone, indomethacin, sulindac, acyclovir, amantadine, rimantadine, recombinant soluble CD4 (rsCD4), anti-receptor antibodies (for rhinoviruses), nevirapine, cidofovir (Vistide®), trisodium phosphonoformate (Foscarnet®), famciclovir, penciclovir, valaciclovir, acid inhibitors nucleic acid / replication, interferon, zidovudine (AZT, Retrovir®), didanosine (dideoxinosine, ddl, Videx®), stavudine (d4T, Zerit®), zalcitabine (dideoxycytosine, ddC, Hivid®), nevirapine (Viramune®), lamivudine ( Epivir®, 3TC), protease inhibitors, saquinavir (Invirase®, Fortovase®), ritonavir (Norvir®), nelfinavir (Viracept®), efavirenz (Sustiva®), abacavir (Ziagen®), amprenavir (Agenerase®), indinavir (Crixivan®), ganciclovir, AzDU, delavirdine (Rescriptor®), rifampin, clatiromycin, erythropoietin, colony stimulating factor (G-CSF and GM-CSF), nucleoside reverse transcriptase inhibitors, nucleoside inhibitors, adriamycin, fluorouracil, methotrexate, aspar aginasa and combinations thereof. When thiabendazole is used in combination with other therapeutic agents, the ratio of thiabendazole to the other therapeutic agent will be varied as needed and according to the desired therapeutic effect, the side effects observed from the combination or other considerations such as those known to those skilled in the medical arts. In general, the ratio of thiabendazole to the other therapeutic agent will vary from about 0.5%: 99.95% by weight to about 99.5%: 0.5% by weight. When the thiabendazole is administered before or after other therapeutic agents to treat viral infections, the respective dose and dosage regimen of thiabendazole and the other therapeutic agent may vary. The adjunctive therapy can be sequential, this is the treatment with an agent first and then the second agent, or it can be concomitant treatment, where one or more agent is administered sequentially at the same time. Sequential therapy may be within a reasonable time after the completion of the first therapy before starting the second therapy. The treatment with both agents at the same time can be in the same daily dose or in separate doses. For example, treatment with one agent on day 1 and the other on day 2. The exact regimen will depend on the disease being treated, the severity of the infection and the response to treatment. For example, a total dosing regimen of thiabendazole can be administered either before or after a complete dosage regimen of the other therapeutic agent, or alternative doses of thiabend-azole and the other therapeutic agent can be administered. As a further example, thiabendazole can be administered concomitantly with the other therapeutic agent.

E. Treatment method The treatment method can be any suitable method that is effective in treating the particular type of virus being treated. The treatment may be by oral, rectal, topical, parenteral or intravenous route of administration and the like. The method to apply an effective amount also varies depending on the virus or viral infection being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of benzimizadol compounds, formulated with an appropriate carrier, compound of additional viral inhibition or compounds or diluent to facilitate application will be the preferred method of administering the compounds to animals. of warm blood. The method for treating viral infections can also be by oral, rectal, topical, parenteral or intravenous administration. The time and dose actual will depend on the virus in question and the desired blood levels. The following examples are illustrative and are not intended to be limiting of the invention. The following examples illustrate the effectiveness of thiabendazole, 2- (4-thiazolyl) -lH-benzimidazole, against HIV and its derivatives of benzimizadol against several viruses. Thiabendazole is effective in suppressing the production of the HIV virus in chronically infected cells. The additional cellular viral count effectively goes to zero or undetectable levels. Thiabendazole does not kill chronically affected cells but reduces the proliferation rate of infected cells to therapeutically effective concentrations. Thiabendazole does not affect the expression of CD4 in uninfected cells. The effective concentrations, thiabendazole decreases but does not alter the cellular, normal RNA or protein synthesis of either infected or uninfected cells. Thiabendazole is effective in a variety of chronically infected cell types (this effect does not appear to be cell-type specific). Thiabendazole is effective against a variety ^ ^ ^^^^ of strains of HIV virus. (It is not effective for the strain of the virus, although some variation per strain is observed, SK-1> IIIB> RF). Thiabendazole does not appear to be effective in SIV in vi tro or in vivo under the test conditions used. After 20 months of administration of the agent, no strains of thiabendazole-resistant virus have been developed in tests designed to promote this development. The resistance developed in six months or less in the test used for existing HIV drugs, with resistant strains for protease inhibitors that develop in approximately 3-4 months. Thiabendazole does not adversely affect the activity of existing HIV drugs, AZT, 3TC, ddC, ddl or protease inhibitors (saquinavir and indinavir) in truly infected cells, nor does any of these existing drugs interfere with the efficacy of thiabendazole in chronically infected cells. Thiabendazole is also effective against viruses resistant to the protease inhibitor. Thiabendazole confers temporary suppression of viral HIV production from 4 to 80 days after stopping treatment.

The results of these studies are summarized in detail below: EXAMPLE 1 5 HIV TEST HIV Replication Study Thiabendazole was tested on chronically infected HIV virus. These cell populations contain integrated copies of the HIV genome and constitutively produce HIV at relatively high levels (CEM-SK1, U937-SK1 and H9-SK1 from Fredepck Research Center, Maryland) or are latently infected and only produce viruses after stimulation with porbol-esters, tumor necrosis factor or IL6 (Ul and ACH2). When treated with a compound of Formula II, virus products are reduced in all tested cell lines and the compounds do not stimulate virus production from latently infected cells. The reductions in Virus production was observed when the inverted transcriptase supernatant, the p24 supernatant as well as the intracellular p24 were quantified, indicating that the compound inhibits the production of the virus at a replication step prior to the production of the virus. production of intracellular proteins. íá e? s ißmti * ~ - SÉSMÉ.

The quantification of the infectivity of the virions produced from the infected cells demonstrates reductions in the number of infectious virions in parallel with reductions in the RT or p24 supernatant, indicating that the compounds reduce the amount of virus produced, but not the quality of the virus. the virions. Inhibition of virus production from chronically infected cells was observed at concentrations that were non-toxic to the target cells. Thiabendazole inhibited virus production or concentrations greater than 1-10 μg / ml. The toxicity to chronically infected cells was similar to that observed with uninfected cells. The evaluation of thiabendazole in chronically infected cells was performed by evaluating the incorporation of thymidine (DNA) uridine (RNA) and leucine (protein) into cellular macromolecules. Inhibition of the synthesis of cellular macromolecules paralleled the toxicity of the two compounds as would be expected and did not occur at lower non-toxic concentrations found to inhibit virus production in chronically infected cells. After 28 days of treatment with these compounds in chronically infected cells, the toxicity of the compounds to the target cells appeared to be similar in both uninfected and chronically infected cells. Compounds do not preferentially annihilate cells infected with HIV. Reductions in the level of virus production were stable and were observed at concentrations greater than 10 μg / ml for thiabendazole. These results suggest that thiabendazole can rapidly reduce the level of virus production from cellular formations chronically infected with HIV-1 and the antiviral effect is maintained with prolonged exposure to the compound. This reduction in virus production occurs at concentrations that are substantially non-toxic to the host cell and that have no substantial effect on the synthesis of DNA, RNA and cellular protein.

Virus Resistance Studies Cultured chronically infected HIV cells were cultured in the presence of thiabendazole at 1 μg / ml for the first month, 5 μg / ml during the second month, 10 μg / ml for the third month, 20 and 40 μg / ml. ml for the fourth month and 80 μg / ml for the fifth and sixth months. At the end of each month, the cells were evaluated for production of the virus compared to chronically infected cells, not treated with the compounds. For each of the six months of the treatment experience, there was no change in the antiviral effect and the toxicity of thiabendazole remained identical and remained active against HIV, and resistance to thiabendazole was not quickly achieved via the selection of resistant virus. or adaptation of the cells to prevent the toxicity induced by the compound. The production of the virus remained completely suppressed from the cultures treated with thiabendazole at 40 and 80 μg / ml.

Reappearance of Virus Production from Chronically Infected Cells. Previously Treated Chronically infected cells treated with a compound of Formula II for extended periods were washed free of the compound and cultured to determine if, and when, the virus production is resumed. The cultures from which the treatment resulted in the total elimination of virus production were used in these assays. These cultures included chronically infected cells cultured in the presence of 20, 40 and 80 μg / ml thiabendazole. Within 4 days the Virus production was resumed from cultured cells in the presence of lower concentrations of each compound (20 μg / ml and 4 μg / ml). Virus production was summarized by day 12 in the cells cultured at 40 μg / ml thiabendazole concentrations. For cells cultured at the highest concentrations of thiabendazole, virus production was first observed at approximately day 70.

Inability of Tiabendazole-treated Cells The cells that were pre-treated with thiabendazole for a prolonged period of time were washed free of the compound and used as a white cell population. The cells were divided into three populations and labeled Group 1, 2 or 3. Group 1 was treated with the compound for 24 hours (at the same concentration used in the prolonged treatment phase) were washed free of the compound and cultured in the presence of infectious virus and fresh compound. Group 2 was pre-treated for 24 hours, washed free of the compound and cultured in the presence of the infectious virus only. Group 3 was cultured both for the pre-treatment and for the infection phases in the fresh medium only (neither virus nor compound). The virus production of the cell populations was identical despite the culture conditions. These results indicate that chronically infected cells, treated for prolonged periods, were not overinfected with HIV.

Additional Studies with HIV Chronic Ul cells infected with chronic HIV-1 were derived from an acute HIV-1 infection of the promonocitic cell line, U937. The chronic HIV-1 infected cells, ACH-2, were derived from an acute HIV-1 infection of the T cell line, A3.01. These cells were cultured in the medium in the presence of the porbolyl ester, PMA. The PMA that causes the cells (both Ul and ACH-2) to activate and not divide. This causes the U-l cells to differentiate. This results in fewer cells in the cultures treated with PMA than the cultures alone with the medium. Cell viability was measured when these cell lines were treated with the test compound. Both cell lines constitutively produce a small amount of HIV-1. The ACH-2 cell lines tend to produce more HIV-1 than Ul cells as shown by ELISA p-24. When any cell line is grown in the presence of PMA, there is an increase in the amount of HIV-1 produced as measured by p-24 antigen ELISA. In addition, the number of cells expressing HIV positive mRNA per microscopic field is measured. Comparisons can be made from these numbers since the same number of cells adhered to the slides for each drug concentration (approximately 10 x 10 6 cells / ml). These cells were treated with test samples. Thiabendazole at 60 μg / ml suppressed replication in HIV monocytes by 74% and HIV replication of T cells was increased by 26%. The positive control was interferon that suppresses the replication of HIV monocytes by 80%. AZT showed no activity in this model. 2- (methoxycarbonylamino) benzimidazole suppressed replication in HIV monocytes by 9% and replication of HIV in T cells was increased by 44%. The positive control was interferon that suppressed the replication of HIV monocytes by 80% and suppressed HIV replication of T cells by 60%.

Acute HIV Test In an acute in vitro model for HIV, 2- (4-thiazolyl) -lH-benzimizadol inhibited viral replication by 98% at 60 μg / ml, AZT inhibited viral replication by 98% at 1 μg / ml. The therapeutic index (TI), the ratio of the toxic dose of the drug to the effective dose of the drug for 2- (4-thiazolyl) -lH-benzimidazole is 2.8 against 12,500 for AZT.

EXAMPLE 2 HERPES In a herpes in vi screening test for 2 - (4-thiazolyl) -lH-benzimizadol at a dose of 200 mg / kg dose, 10% of the mice survived with an average death date of 10.4 days; At 100 mg / kg dose, 50% of the mice survived with an average death date of 9.2 days. The positive control was acyclovir at 75 mg / kg dose where 60% of the mice survived with an average death date of 17.2 days. 2- (4-thiazolyl) -lH-benzimizadol was tested in a herpes in vi tro model and showed no activity.

EXAMPLE 3 INFLUENZA 2- (4-thiazolyl) -lH-benzimizadol was tested in an influenza in vi tro model and showed no activity. In an in vivo model for influenza, 2- (4-thiazolyl) -lH-benzimizadol was tested at 200 mg / kg, 67% of the mice survived with an average death date of 8 days; at 100 mg / kg, 62% survived with an average death date of 8.7 days. The positive control was amantadma (75 mg / kg) with 100% of the mice that survived for 21 days.

EXAMPLE 4 RINOVI? S 2- (4-thiazolyl) -lH-benzimizadol was tested in a rhinovirus model in vivo and A-36683 was compared. The therapeutic index (TI), the ratio between the toxic dose of the drug and the effective dose of the drug for 2- (4-thiazolyl) -lH-benzimidazole is 1-2 against 1000-3200 for A-36683.

B? ÁüMl? MÉÍ-:

Claims (19)

1. CLAIMS 1. An effective pharmaceutical composition for treating viral infections comprising a pharmaceutical carrier and a therapeutically effective amount of a benzimidazole of Formula I:

   I or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms, n is a positive integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.
2. 2. A pharmaceutical composition according to claim 1, comprising a pharmaceutical carrier and from about 25 mg to about 6000 mg of a benzimidazole of Formula II:

   I or a pharmaceutically acceptable organic or inorganic acid addition salt thereof, wherein R is hydrogen or an alkyl having from 1 to 8 carbon atoms; and R2 is 4-thiazole? lo.
3. 3. A pharmaceutical composition according to claim 2, wherein the benzimizadol is 2- (4-thiazolyl) benzimidazole present in an amount of about 250 mg to about 5,000 mg.
4. 4. A pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt is an organic or inorganic acid addition salt selected from the group consisting of chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate salts, maleate, malate, citrate, benzoate, salicylate, ascorbate and mixtures thereof.
5. 5. An effective pharmaceutical composition for suppressing viral proliferation in a viral infection comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a benzimidazole of Formula I

   or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms; or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.
6. 6. A composition according to claim 5, comprising from about 25 mg to about 5,000 mg of a benzimidazole of Formula II:
7. or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.
8. 8. A composition according to claim 7, wherein the benzimizadol is 2- (4-thiazolyl) -

   benzimizadol, or a pharmaceutically acceptable salt thereof and the composition comprises from about 100 mg to about 6,000 mg of the benzimizadol.
9. 9. An effective pharmaceutical composition for preventing the development of a virus strain that is resistant to viral infection treatment, which comprises a pharmaceutical carrier and a therapeutically effective amount of a benzimidazole of Formula I:

   a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is an integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl. 9. A composition according to claim 8, comprising a pharmaceutically acceptable carrier and

   20 from about 25 mg to about 5,000 mg of a benzimidazole.
10. 10. An effective pharmaceutical composition for

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    treating a viral infection that is resistant to treatment with a protease inhibitor, which comprises a pharmaceutical carrier and a therapeutically effective amount of a benzimidazole of Formula I:

    or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazole? lo.
11. 11. An effective pharmaceutical composition for reducing the rate of RNA or protein synthesis in a cell having a viral infection, which comprises a pharmaceutical carrier and a therapeutically effective amount of a benzidazole of Formula I:

    i or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms; or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.
12. 12. An effective pharmaceutical composition for increasing the life span of a mammal having a viral infection which comprises a pharmaceutical carrier and a therapeutically effective amount of a benzimidazole of Formula I:

    or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4;

    And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.
13. 13. A composition according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 which also comprises adjunctive therapy.
14. 14. A composition according to claim 13, wherein the adjunctive therapy is an antiviral agent.
15. 15. A composition according to claim 10, wherein the adjunctive therapy comprises an element selected from the group consisting of: acyclovir, amantadine, rimantadine, soluble recombinant CD4 (rsCD4), anti-receptor antibodies, nevirapine, cidofovir, trisodium phosphonoformate, famciclovir,

    15 penciclovir, valaciclovir, nucleic acid inhibitors / replication, interferon, zidovudine (AZT), didanosine (ddl), stavudine (d4T), zalcitabine (ddC), nevirapine, lamivudine (3TC), protease inhibitors, saquinavir, ritonavir, nelfinavir , efavirenz, abacavir,

    20 amprenavir indinavir, ganciclovir, AzDU, delavirdine, rifampin, clatiromycin, erythropoietin, colony stimulation factors, nucleoside reverse transcriptase inhibitors and nucleoside inhibitors.
16. 16. A composition according to claim 1, 25 2, 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14 and 15, in

    '•' «-" * "- * -. • •

    where the infection of the virus is caused by one or more of: HIV, influenza virus, hepatitis virus and rhinovirus.
17. 17. A composition according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the composition is in the liquid dosage form aqueous selected from the group consisting of a solution, emulsion, suspension, solution, and reconstituted suspension from an effervescent or non-effervescent preparation.
18. 18. A composition according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the composition is in a dosage form that it comprises a carrier selected from the group consisting of lactose, sucrose, gelatin and agar. A method for reducing the rate of RNA or protein synthesis in a cell having a viral infection which comprises treating the cell with an effective amount of a benzimidazole of Formula I

    or a salt thereof, wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of

    less than 7 carbon atoms; n is a positive integer of less than 4; And it is hydrogen, chlorine, nitro, oxychlor, methyl or ethyl; R is hydrogen or an alkyl group having from 1 to 8 carbon atoms; and R2 is 4-thiazolyl.

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