MXPA01009889A - Thiadiazolyl urea or thiourea derivatives for antiviral treatment - Google Patents

Abstract

A pharmaceutical composition that inhibits or slows the growth of viruses in animals, particularly in mammals, is disclosed. This same composition can be used to treat viral infections, particularly hepatitis C, herpes simplex, Kaposi's sarcoma and HIV. The composition preferably comprises from about10 mg to about 6000 mg of a (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or (5-aryl-1,2, 4,-thiadiazol)-3-yl urea derivative of formula (I), wherein X is oxygen or sulfur, R is hydrogen or alkyl having from 1-3 carbons, n is 0-4, R1 is independently selected from the group consisting of hydrogen, alkyl having from 1 to 7 carbon atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the formula -O(CH2)yCH3 wherein y is from 1 to 6, or a pharmaceutically acceptable acid addition salt or prodrug thereof. The preferred compound is (5-phenyl-1,2,4-thiadazol-3-yl) thiourea.

Description

DERIVATIVES OF TIADIAZOLIL UREA OR TIOUREA FOR ANTIVIRAL TREATMENT VIRAL TREATMENT This application is a continuation in part of the request of J.B. Camden, serial number 09 / 281,896 filed on March 31, 1999.

TECHNICAL FIELD This invention is a pharmaceutical composition that is effective against the treatment of viruses. The composition can be used to treat viral infections, especially hepatitis, including hepatitis C virus (HCV), hepatitis B virus (HBV), Human Immunodeficiency Syndrome (HIV) and Kaposi sarcoma.

(HHV8). The composition comprises one or more derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl urea or (5-aryl-1,2-thiadiazole) -3-yl thiourea. Methods for treating viral infections are also discussed.

BACKGROUND DB THE INVENTION HIV and other viral infections such as hepatitis are some of the leading causes of death.

HIV is the virus that is known to cause acquired immune deficiency syndrome (AIDS) in humans. HIV is a disease in which a virus replicates in the organism or in host cells. Viruses attack the body's immune system. Several medications have been approved for the treatment of this devastating disease, including azidovudine (AZT), didanosine (dideoxyinosine, ddl), d4T, zalcitabine (dideoxycytosine, ddC), nevirapine, lamivudine (epivir, 3TC), saquinavir (Invirasa), ritonavir (Norvir), indinavir (Crixivan) and delaviridina (Rescriptor). See M.I. Johnston & D.F. Hoth, Science, 260 (5112), 1286-1293 (1993) and D.D. Richman, Science, 272 (5270), 1886-1888 (1996). A vaccine against AIDS (Salk vaccine) has been tried and it has been discovered that several proteins that are chemokines of CD8 act as suppressors of HIV. In addition to the analogs of synthetic nucleosides, proteins and foregoing antibodies, it has been found that various plants and substances derived therefrom have anti-HIV activity in vi tro. However, the HIV virus is not easily destroyed nor is there a good mechanism to protect the host cells from the replication of the virus. Thus, medical professionals continue to search for medicines that can prevent HIV infections, treat carriers of HIV virus to prevent their diseases from progressing to deadly AIDS and treat patients with AIDS.

Herpes simplex (HSV) viruses type 1 and 2 are persistent viruses that usually infect humans; They cause a variety of worrisome diseases. HSV type 1 causes oral "fever bubbles" (recurrent cold sores) and HSV type 2 causes genital herpes, which has become the main venereal disease in many parts of the world. At present, there is no totally satisfactory treatment for genital herpes. In addition, although it is rare, HSV can also cause encephalitis, a life-threatening infection of the brain. (The Merck Manual, Holvey, Ed., 1972, hitley, Herpes Simplex Viruses, in: Virology, 2nd Ed., Raven Press (1990)). The most serious disorder caused by HSV is dendritic keratitis, an ocular infection that produces a branched lesion in the cornea, which in turn can lead to permanent scarring and loss of sight. Eye infections with HSV are one of the main causes of blindness. HSV is also a virus that is difficult to cure and even impossible. Hepatitis is a disease of the liver in humans. It is manifested by 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 ultimately death. It is known that several viruses such as hepatitis A, B, C, D, E and G cause several types of viral hepatitis. Among these the most serious are HBV and HCV. HBV is a DNA virus with a virion size of 42 nm. HCV is an RNA virus with a virion size of 30 to 60 nm. See D.S. Chen, J__, Formos. Med. Assoc., 95 (1), 6-12 (1996). Hepatitis C infects a number of people 4 to 5 times more than 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 worldwide (approximately 15 times more than those infected with HIV). Currently there is no effective immunization and only hepatitis C can be controlled by other preventive measures such as improving hygiene and sanitary conditions and interrupting the route of transmission. At the moment 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 patients. people. However, treatment with interferon with or without ribavarin has limited long-term efficacy, with a response rate of approximately 25%. Infection with hepatitis B virus results in a broad spectrum of liver damage. In addition, chronic hepatitis B infection has been linked to the subsequent development of hepatocellular carcinoma, a very important cause of mortality. The current prevention of hepatitis B infection is vaccination, which is safe and effective. However, vaccination is not effective in treating already infected people (ie, carriers and patients). Many medications have been used to treat chronic hepatitis B and none has been shown to be effective, except interferon. The treatment of HCV and HBV with interferon has limited success and has often been associated with adverse side effects, eg, fatigue, fever, chills, headache, myalgias, arthralgias, moderate 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 is necessary. In the present invention it has been found that the compounds described above are useful for the treatment of hepatitis C virus, hepatitis B virus, herpes simplex and the treatment of HIV infection and other viral infections.

STATEMENT OF THE INVENTION A pharmaceutical composition for administering to animals under treatment and, in particular to warm-blooded animals and to humans, that are infected with a virus. The composition comprises a therapeutically effective amount of an antiviral compound and, optionally, a pharmaceutical carrier. The antiviral compound is selected from the group consisting of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea derivative or (5-aryl-1, 2,4-thiadiazole) -3-yl derivative. urea that have the formula: wherein X is oxygen or sulfur, R is hydrogen or alkyl having 1 to 3 carbon atoms, n is 0 to 4, Ri is independently selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms , chlorine, bromine or fluorine, oxychlor, alkoxy having the formula -0 (CH2) and CH3, wherein y is from 1 to 6 or a pharmaceutical addition salt or a prodrug thereof. Preferred antiviral compositions comprise a therapeutically effective amount of an antiviral compound having the formula: The compositions can be used to treat hepatitis C, hepatitis B, herpes simplex and other viral infections. More specifically, the invention provides an antiviral composition comprising a pharmaceutical carrier and a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative of (5-aryl-1, 2, 4 -thiadiazole) -3-yl urea, as defined herein, together with a method to treat viral infections, for example: hepatitis C, hepatitis B, other hepatitis infections, HIV, influenza and rhinovirus, Kaposi's sarcoma, herpes simplex, and the like. The derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl urea or the corresponding urea derivatives are also fungicides and can be used to treat certain fungal infections. The same composition can be used against some fungi, particularly those that are common in patients with HIV. In addition, the compounds are effective in the treatment of bovine diarrhea virus and can be used in the veterinary treatment of these diseases. The present invention also provides methods for the treatment of HIV infection, which comprises administering to the host infected with HIV, a therapeutically or pharmaceutically effective amount or an acceptable amount of the compound described above. This invention also comprises the use of a combination therapy in the treatment of viral infections. The compositions can be used in conjunction with other treatments. The route of administration is the same as that used with other medical treatments. The drug can be administered daily or one to four times a week.

DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without exhibiting excessive adverse side effects (such as toxicity, irritation and allergic response) provided with a risk relationship. / benefit when used according to this invention. As used herein, the term "safe and effective amount" refers to the amount of the component that is sufficient to provide a P13S3 ded therapeutic response in the absence of undue adverse side effects (such as toxicity, irritation or allergic response) commensurate with a reasonable risk / benefit ratio, when used in the manner described in the invention. As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present invention effective to provide a ded therapeutic response. For example, to inhibit HIV infection or treat symptoms of infection in a host, or in an effective amount to treat hepatitis. The therapeutically effective specific amount will obviously vary with factors such as: the particular condition of the patient being treated, the physical condition of the patient, the type of mammal or animal being treated, the duration of the treatment, the nature of the concurrent therapy (if any) and the specific formulations used and the structure of the compounds or their derivatives. As used herein a "pharmaceutical addition salt" is an arylthiazolyl thiourea or urea salt which is modified to form an acidic or basic salt of the compounds. Examples of pharmaceutical addition salts include, unrestrictedly, salts of mineral or organic acids from basic waste such as amines, alkalis or P1363 Organic salts of acidic residues such as carboxylic acids. Preferably, the salts are prepared using an organic or inorganic acid. These preferred acid addition salts are: chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formations, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like. As used herein, the term "pharmaceutical carrier" is a solvent, a suspending agent or a pharmaceutically acceptable carrier for the administration of the antiviral agent to the animal or to the human. The carrier can be liquid or solid and is selected according to the form of administration that is kept in mind. As used herein, the term "antiviral compounds" are the derivatives of (5-aryl-l, 2,4-thiadiazole) -3-yl thiourea or the derivative of (5-aryl-l, 2,4-thiadiazole) -3-yl urea and the pharmaceutical addition salts or the prodrugs thereof. The preferred antiviral compound is 5-phenyl-3-thioureido-1,2,4-thiadiazole. As used here, the term "derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or (5-aryl-l, 2,4-thiadiazole) -3-yl urea or "arylthiadiazolyl thiourea or urea derivatives" includes compounds that include the formula: P1363 wherein X is oxygen or sulfur, R is hydrogen or alkyl having 1 to 3 carbon atoms, n is 0 to 4, R_. it is independently selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine or fluoro, oxychlor, alkoxy having the formula -0 (CH2) and CH3, wherein y is from 1 to 6 or their pharmaceutical addition salts or their prodrugs. As used herein, "Alkyl" can be any branched, straight-chain or cyclic alkene or alkane, generally having less than 8 carbon atoms. As used herein, "Aryl" refers to a substituted phenyl compound and which itself includes phenyl wherein R is hydrogen and n is 5. As used herein, the term "prodrug" is considered as referring to any carrier covalently linked which releases the active matrix drug according to the formula of the derivatives described above, irz vivo, when the prodrug is administered to a patient or mammal in need of treatment. The prodrugs of the arylthiadiazolyl thiourea or urea derivatives are prepared by modifying the functional groups present in the compounds, so that the P1363 modifications are cleaved, either in routine manipulation or in vivo, to form the parent compounds. Prodrugs include compounds wherein the free hydroxyl, sulfhydryl or amine groups are attached to any group which, when administered to a mammal, is cleaved to form a free hydroxyl, amino or sulfhydryl, respectively. Examples of prodrugs include, unrestrictedly, acetate, formate or benzoate derivatives of alcohol and amine functional groups in the arylthiazolyl thiourea or arylthiazolyl urea derivatives; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of the alcohol and phenol functional groups or the aminoalkylbenzyl amides, aminoalkyl amides and carboxyalkyl amides of the amino functional group in the arylthiazolyl thiourea derivatives or ariltizolyl urea, and the like. As used herein, the term "virus" includes viruses that infect animals or mammals, including humans. The viruses include HIV, influenza virus, poliovirus, herpes simplex, hepatitis B virus, hepatitis C virus and other strains of hepatitis virus, Kaposi's sarcoma, rhinovirus and the like. As used herein, the term "combination therapy" refers to the patient in need of the drug being treated or receiving administration of the drug for the disease, together with arylthiazolyl thiourea or arylthiazolylurea derivatives. This combination therapy can be a sequential therapy wherein the patient is first treated with one or more drugs and then with the other, two or more drugs are administered simultaneously.

B. ANTIVIRAL COMPOUNDS The antiviral material is a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl. urea or its pharmaceutical addition salts or prodrugs having the formula: wherein X is oxygen or sulfur, R is hydrogen or alkyl having 1 to 3 carbon atoms, n is 0 to 4, R_. it is independently selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine or fluorine, oxychlor, alkoxy having the formula -0 (CH2) and CH3, wherein y is from 0 to 6, preferably from 2 to 4. Preferably the derivative of (5-aryl-1,2,4-thiadiazol) -3-yl urea or of (5-aryl-l, 2,4-thiadiazole) -3-yl thiourea it is substituted with an alkyl of less than 4 carbon atoms, P1363 a halogen, preferably a chlorine in the 7 or 8 position and the remaining substituents of the benzene ring are hydrogens. The most preferred antiviral is (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea. The pharmaceutical addition salts of the arylthiazolyl thiourea or arylthiazolyl urea derivatives include the conventional non-toxic salt or the quaternary ammonium salt of arylthiazolyl thiourea or arylthiazolylurea, formed, for example, from non-toxic organic or inorganic acids. For example, these non-toxic conventional salts include those which are derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sultonic, phosphoric, nitric acid and the like; and prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic , methanesulfonic, ethanesulfonic, oxalic, isethionic and the like.

C. SYNTHESIS The arylthiazolyl thiourea or arylthiazolyl urea derivatives can be prepared in various forms well known to those skilled in the art from organic synthesis. The arylthiazolyl thiourea or arylthiazolyl urea derivatives can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereof, as will be appreciated by those skilled in the art. Preferred methods include in an unrestricted manner the methods described below. Each of the references cited below is incorporated herein by reference. The compounds can be synthesized by desulphurisation of aromatic thioureas or urea compounds using hydrogen peroxide in alkali or by reacting 3-amino-5-aryl-l, 2,4-thiadiazole with ethoxy carbonyl isothiocyanate to produce ethoxycarbonyl-3- (5). '-aryl-1', 2 ', 4-thiadiazol-3' -yl) thiourea or 3- (5'-aryl-1 ', 2', 4-thiadiazol-3'-yl) urea, which is then made react with sodium hydroxide in ethanol and then acidify. The (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea is prepared by the method described in Kurzer, et al. J. Chem. Soc. Perkin Trans. 1 (2), 311-314 (1985) and Kurzer, et al., J. He erocvcl. Chem., 26 (2), 355-60 (1989). (5-Phenyl-1,2,4-thiadiazole) -3-yl thiourea can be prepared by hydrolysis of 3- [N-benzoylthioureido] -5-phenyl-1,2,4-thiadiazole using 3 molar potassium hydroxide. approximately 60 ° C. The mixture cools and P1363 is then acidified with concentrated hydrochloric acid. Concentrated ammonium hydroxide is then used to basify the concentrated hydrochloric acid. Concentrated ammonium hydroxide is used to basify the resulting product. The material of this hydrolysis process is pure (approximately 99%) and the yield is high. The pharmaceutical addition salt of the present invention can be synthesized from the arylthiazolyl thiourea or arylthiazolyl urea derivatives containing a basic or acid entity, by conventional chemical methods. In general, these salts can be prepared by reacting the base or free acid forms of these compounds with a stoichiometric amount of the appropriate acid or base, in water or in an organic solvent, or in a mixture of the two. In general, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, Pa., 1985, p. 1418, the exhibition of which is incorporated here as a reference. The exhibits of all references cited herein are considered to be incorporated herein in their entirety as a reference.

P1363 D. DOSAGE The compounds can be administered in one dose, continuously or intermittently throughout the course of treatment. The methods for determining the most effective medium and the appropriate administration dose are well known to the experts. The compounds can be administered in a dose, continuously or intermittently through the treatment. The compounds can also be administered daily or one to four times per week. The compounds of the invention can be administered in one or more doses daily or one to three times a week. Dosing twice a week over a period of at least several weeks is preferred. Normally, the antiviral compounds will be administered for prolonged periods of time and can be administered for the life of the patient. Methods for determining the most effective medium and dosing administration are well known to those skilled in the art. Simple or multiple administrations can be carried out with a standard and a dose level selected by the administrator. The compounds in general are safe. The oral LD50 is greater than 6,000 mg / kg in mice and there are no special management requirements. As a general guide, a dose as small as one milligram (mg) per kilogram (kg) is adequate P1363 of body weight and preferably 10 mg / kg and up to about 10,000 mg per kilogram of body weight. Preferably 10 mg / kg to about 5,000 mg / kg body weight are used. More preferably, the doses are between 200 mg / kg to 5,000 mg / kg. In general, the dose in man is lower than for small warm-blooded mammals, such as mice. In the form of guidelines, the human dose is between about 1/12 of that of the mice. Therefore, if 25 mg / kg is effective in mice, a dose of 2 mg / kg would be used for a 60 kg person and a typical dose would be 120 mg. The dose administered will vary, of course, depending on factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and / or weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment, the frequency of treatment and the desired effect.

E. METHOD OF ADMINISTRATION AND FORMS OF DOSAGE ADMINISTRATION The compounds of the present invention can be administered by any of the suitable routes, including, but not limited to, for example, P1363 oral, rectal, nasal, topical (including transdermal, aerosol, buccal, sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal), intravesical, or injection into or around the virus. The amounts of the dosage are based on the effective inhibitory concentrations observed in antiviral studies. The preferred route will vary with (1) the condition and age of the recipient, (2) the virus being treated, (3) the nature of the infection and (4) the appropriate blood levels. It is believed that parenteral treatment by intravenous, subcutaneous or intramuscular application of the compounds of the present invention formulated with a suitable vehicle, other antiviral agents or compounds or diluents that facilitate the application, will be the preferred method for administering the compounds to animals. of warm blood. The derivatives of (5-aryl-l, 2,4-thiadiazole) -3-yl thiourea or the derivatives of (5-aryl-l, 2,4-thiadiazole) -3-yl urea are preferably micronized or pulverized , so that it is easier for them to disperse and solubilize in the body. The processes for crushing and pulverizing medicaments are well known in the technical field. For example, a hammer mill or a similar milling device can be used. The preferred particle size is less than about 100μ and P13S3 preferably lower than 50μ. These compounds are not very soluble and therefore, preferably they are administered in tablet form or as a suspension. Suitable methods for administering the compounds of the present invention and the dosage forms are presented below. The (5-aryl-1,2,4-thiadiazole) -3-yl thiourea derivatives or the (5-aryl-1,2,4-thiadiazole) -3-yl urea derivatives of this invention can be administered as treatment for viral infections by any means that produces in the organism the contact of the active agent with the site of action of the agents. They can be administered by any of the conventional methods available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutics. Preferably, the compounds of the present invention are administered as a pharmaceutical formulation comprising at least one compound of the present invention, as defined above, together with one or more pharmaceutically acceptable carriers. It can be co-administered in the form of a tablet or capsule, as an agglomerated powder or in liquid form or as a liposome. The compounds of the present invention can also be administered as liposomal delivery systems, for example, unilamellar vesicles and P1363 multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines. The (5-aryl-1,2,4-thiadiazole) -3-yl thiourea derivatives or the (5-aryl-1,2,4-thiadiazole) -3-ylurea derivatives of the present invention can also be combine with soluble polymers as drug carriers that can be selected as white. These polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be combined with a class of biodegradable polymers, useful for achieving controlled release of a medicament, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, polyepsiloncaprolactone, polyhydroxy butyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and block copolymers of amphipathic or crosslinked hydrogels. 1. Combination Therapy The compounds of the present invention can be further combined with other antiviral compounds to provide an operative combination. The intention is to P1363 include any chemically compatible combination of a compound of this group of the invention with other compounds of the group of the invention or other compounds outside the group of the invention, as long as the combination does not eliminate the antiviral activity of the compounds of the group of the invention. For example, one or more derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or (5-aryl-l, 2,4-thiadiazole) -3-ylurea derivatives can be combined with other enhancers or antiviral agents. Enhancers are materials that influence the body's response to the antiviral agent. In the case of HIV, a combination therapy with AZT, TC-3 or with protease inhibitors is effective. In the case of hepatitis, cyclovir, famciclovir or valaciclovir, ribavirin, interferon or combinations of ribavirin and interferon or beta-globulin, are administered as combination therapy. For herpes, a recombinant alpha interferon can be used as a combination therapy. In some embodiments of the invention, a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative of (5-aryl-l, 2,4-thiadiazole) -3- is used. ilo in combination with one or more therapeutic agents, for example, anti-inflammatory, antiviral, antifungal, amoebicidal, trichomonocidal, analgesic, antineoplastic, anti-hypertensive, antimicrobial agents and / or P1363 steroid drugs, to treat antiviral infections. In some preferred embodiments, the viral infections are treated with a combination of two or more derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or derivatives of (5-aryl-1,2,4). -thiadiazole) -3-yl urea with one or more beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, bramidine, bacitracin, sulfonamides, nitrofurasone, nalidixic acid, cortisone, hydrocortisone, betamethasone, dexamethasone, fluorcortolone, prednisolone, triamcinolone, indomethacin, sulindac, acyclovir, amantadine, rimantadine, recombinant soluble CD4 (rsCD4), antireceptor antibodies (for rhinoviruses), nevirapine, cidofovir, (Vistide ™), trisodium phosphonoformate (Foscarnet ™), famciclovir, penciclovir, valaciclovir, replication / nucleic acid inhibitors , interferon, zidovudine (AZT, Retrovir ™), didanosine (dideoxinosine, ddl, Videx ™), stavudine (d4T, Zerit ™), zalcitabine (dideoxycytosine, ddC, Hivid ™), neviparin (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, clatiromicin, erythropoietin, colony stimulating factors (G-CSF and GM-CSF), non-nucleoside reverse transcriptase inhibitors, nucleoside inhibitors, adriamycin, fluorouracil, methotrexate, asparaginase and combinations thereof. An "enhancer" can be any material that improves or increases the efficacy of the pharmaceutical composition or acts as an immunomodulator. This enhancer is triprolidine and its cis isomers which are used in combination with more derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or (5-aryl-1,2,4-thiadiazole) - 3-yl urea and optionally other therapeutic agents or antiviral agents. Triprolidine is described in US 5,114,951 (1992). Another enhancer is procodazole, lH-benzimidazole-2-propanoic acid; [β- (2-benzimidazole) propionic acid; 2- (2-carboxymethyl) benzimidazole; propazole]. Procodazole is a non-specific immunoprotective agent against viral and bacterial infections, which are used with the compositions claimed herein. Together with one or more derivatives of (5-aryl-l, 2,4-thiadiazole) -3-yl thiourea or (5-aryl-l, 2,4-thiadiazole) -3-yl urea it is effective to treat viral infections and can be combined with one or more other therapeutic agents. The combination therapy can be sequential, that is, the treatment is first with an agent and then with the second agent or it can be a treatment with the two agents at the same time. Sequential therapy may be in a reasonable time after the end of the P13S3 first therapy, before starting the second therapy. The treatment with the two 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. 2. Unit dose The compounds of the present invention can be administered in unit dose form and can be prepared by any of the methods well known in the art. These methods include combining the compounds of the present invention with a carrier or diluent consisting of one or more auxiliary ingredients. In general, the formulations are prepared by uniformly mixing the active ingredient with liquid carriers or finely divided solid carriers or both and then if necessary shaping the product. A pharmaceutical carrier is selected based on the chosen route of administration and standard pharmaceutical practices. Each vehicle must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the subject. This vehicle can be solid or liquid and is usually selected P1363 based on the type of administration used. Examples of suitable solid carriers include lactose, sucrose, gelatin, agar and bulking powders. Examples of suitable liquid carriers include pharmaceutically acceptable water, fats and oils, alcohols or other organic solvents, including, esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions and solution and / or reconstituted suspensions at from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. These liquid carriers may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners and melting agents. Preferred vehicles are edible oils, for example, corn or cañola oils. Polyethylene glycols, for example, PEG, are also good vehicles. The dosage forms (compositions suitable for administration) comprise between 1 milligram and 1000 milligrams of active ingredient per unit dose. Preferably, the dosage forms contain between about 10 mg and 500 mg. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of P13S3 approximately between 0.5 and 95% by weight, based on the total weight of the dosage unit. 3. Pharmaceutical Cases The present invention also includes useful pharmaceutical kits, for example, for the treatment of hepatitis infection, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a thienyl imidazole derivative [4, 5] pyridine. These kits may also include, if appropriate, one or more of the various components of conventional pharmaceutical kits, such as, for example, packages with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. technique. Printed instructions, either as booklets or labels, indicating the quantities of the components to be administered and / or instructions for mixing the components can also be included in the kits. In the present disclosure it will be understood that the materials and conditions specified are important to carry out the invention, but that the materials and conditions that are not specified are not excluded, provided that they do not prevent the benefits of the invention from occurring when the latter is produced. is carried out.

P1363 Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate the oral dosage forms of the present inventionare described in U.S. Patent No. 3,903,297 to Robert, issued September 2, 1975. The following describes techniques and compositions for making dosage forms used in the present invention. Oral formulations suitable for use in the practice of the present invention include capsules, gels, pills, tablets, powders or tablets, effervescent or non-effervescent powders or granules; as a solution or suspension in aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion. The compounds of the present invention may also be present as boluses, electuary or paste. Formulations for oral administration may comprise an inert, non-toxic, pharmaceutically acceptable carrier, for example, lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, cyclodextrin and derivatives thereof. cyclodextrin and the like. Capsules or tablets can easily beP1363 formulate and make them easy to swallow or chew. The tablets may contain binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents and suitable melting agents. A tablet can be formed by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing the active ingredient that is in a free-flowing form (eg, powder or granules) optionally mixed with a binder (eg, gelatin, hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate, crosslinked carboxymethylcellulose), a surfactant agent or a dispersant. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets P1363 molded can be formed by molding in a suitable equipment a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated in such a way as to provide slow or controlled release of the active ingredient. The tablets may also be provided with an enteric layer to allow the release in some parts of the intestines other than the stomach. Formulations suitable for topical administration in the mouth, in which the active ingredient is dissolved or suspended in a suitable vehicle, include pellets which may comprise the active ingredient in a flavored vehicle, usually sucrose and acacia or tragacanth; gelatin, glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid vehicle. Topical applications for administration according to the method of the present invention include ointments, cream, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosol or oil. Alternatively, a formulation may comprise a transdermal patch or bandages, for example, a bandage impregnated with an active ingredient and as an option one or more carriers or diluents. When administered as a P13S3 transdermal delivery system, of course the administration of the dose will be rather continuous than intermittent, throughout the dosing regimen. Topical formulations may conveniently include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of these dermal penetration enhancers include dimethyl sulfoxide and related analogues. The oily phase of the emulsions of the composition used in the present invention for the treatment of the subjects can be constituted from known ingredients and in a known manner. This phase may comprise one or more emulsifiers. For example, the oil phase comprises at least one emulsifier with a fat or an oil or both and an oil or a hydrophilic emulsifier is included together with a lipophilic emulsifier which functions as a stabilizer. Together, the emulsifier (s) with or without stabilizer (s) form an emulsifying wax and the wax together with the oil and / or fat form the emulsifying base of the ointment, which forms the dispersed oil phase of the cream formulations. The emulsifiers and emulsion stabilizers suitable for use in the formulation, P13S3 include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate, paraffin, straight or branched chain mono or dibasic alkyl esters and mineral oil. The choice of suitable oils or greases for the formulation is based on achieving the desired cosmetic properties, the required properties and the compatibility with the active ingredient. The compounds can also be administered vaginally, for example, as pessaries, tampons, creams, gels, pastes, foams or spray formulations that also contain the active ingredient. These vehicles are known in the art. The formulations for rectal application can be presented as suppositories, with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration can be administered in liquid form, for example, nasal spray, nasal drops or by aerosol administration by a nebulizer, which includes aqueous or oily solutions of the active ingredient. Formulations for nasal administration, in which the carrier is a solid, include a coarse powder having a particle size, eg, less than about 100 microns, preferably less than P1363 approximately 50 microns, which is administered in the form in which snuff is aspirated, that is, by rapid inhalation through the nostrils from a container with the powder, which is held close to the nose. Formulations suitable for parenteral administration include aqueous and non-aqueous solutions, isotonic with the blood of the recipient to which they are intended; and aqueous and non-aqueous sterile suspens which may include suspen systems which are designed to direct the compound to the blood components or to one or more organs. The formulations can be presented in sealed unit dose or multiple dose containers, for example, ampoules and vials. Extemporaneous injectable solutions and suspens can be prepared from sterile powders, granules and tablets of the type already described. In general, water, a suitable oil, a saline solution, aqueous dextrose (glucose) and solutions of related sugars and glycols, for example, propylene glycol or polyethylene glycols, are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a salt of the water-soluble active ingredient, suitable stabilizing agents and, where appropriate, buffering substances. Antioxidant agents such as bisulfite P1363 sodium, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and the sodium salt of EDTA are also used. In addition, parenteral solutions may contain preservatives, for example, benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a common reference text in this field. Intravenously, the doses that are most preferred may vary between about 1 and 10 mg / kg / minute during an infusion at constant speed. The derivatives of (5-aryl-1,2,4-thiadiazole) -3-yl or the derivatives of (5-aryl-l, 2,4-thiadiazole) -3-ylurea may be administered in a single daily dose or the total daily dose can be administered in divided doses of two, three or four times a day. Derivatives of (5-aryl-l, 2,4-thiadiazole) -3-yl- or the derivatives of (5-aryl-l, 2,4-thiadiazole) -3-ylurea may be administered in one or more daily or one to three times a week. The present invention further includes administering compounds of the formula described herein, for use in the form of veterinary formulations, which can be prepared, for example, by methods that are conventional in the art.

P13S3 The dosage dosage forms that are used for the administration of the compounds of this invention are illustrated below: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules, each with 100 milligrams of active ingredient powder, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate.

Soft gelatin capsules A mixture of active ingredient is prepared in an edible oil such as soybean, cotton or olive oil and injected into the gelatin by means of a positive displacement pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the unit dose is 100 mg of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings can be applied to increase palatability or delay absorption.

Injectables 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 For oral administration, an aqueous suspension is prepared, such that each 5 ml contains 10 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution U.S.P. and 0.025 ml of vanillin.

G. TREATMENT METHOD The method of treatment can be any suitable method that is effective in the treatment of the particular virus or the viral infection being treated. The treatment includes administering to a subject in need of treatment, a therapeutically effective amount of the compounds of the present invention in the manner set forth herein.

P1363 described earlier. As described above, the composition can be administered orally, rectally, topically, vaginally, nasally, parenterally, intravenously and the like. The method of applying an effective amount varies depending on the viral infection being treated and the desired blood level. Parenteral treatment by intravenous, subcutaneous or intramuscular application of 5-aryl-l, 2,4-thiadiazole) -3-yl thiourea derivatives or derivatives of (5-aryl-l, 2,4-thiadiazole) is considered. ) -3-yl urea, formulated with an appropriate vehicle, compound or additional viral inhibitory compounds or diluent to facilitate application, will be the preferred method for administering the compounds in mammals or warm-blooded animals.

H. TEST METHODS Protease inhibition assay Protease inhibition is evaluated by a fluorometric method. Enzyme (Bachem) is diluted at 116 μg / ml in 50 mM NaOAC, 5 mM DTT, 2 mM EDTA, 10% glycerol (pH 5.0) and stored as 10 μl samples at -20 ° C, the HIV protease substrate I (Molecular Probes) is diluted to a test concentration of 0.32 nmol / μl. Enzyme (20 μl) and medication (20 μl) are added to each well of an appropriate microtiter plate. The controls P13S3 positive and negative are evaluated in parallel. The fluorescence is quantified in a Labsystems Fluroskan II equipment that uses 355 nm / 460 nm at 37 ° C, at time zero and at intervals of 30 minutes for 2 hours. In cases where autofluorescence prevents the use of the HIV-1 protease fluorometric assay or confirmation of a result is required, a protease analysis with HPLC can be used.

Integrase Inhibition Assay It is a biochemical integrase assay described by Craigie et al. (HIV, vol.2: A practical Approach) Biochemistry, Molecular Biology and Drug Discovery, Ed. J. Karn 1995) to select agents based on their ability to inhibit integrase HIV-1. In this system, an oligonucleotide with a kinase functions as a target for 3 'processing and the subsequent strand transfer reaction. The 3 'processing reaction involves the removal of 2 nucleotides from the 3' terminals of the substrate and this is followed by the transfer reaction in which the 3 'terminals bind to the exposed 5' terminals. The 20 μl reaction mixture contains 25 mM MOPS (pH 7.2), 100 g / ml BSA, 10 mM β-mercaptoethanol, 10% glycerol, 7.5 mM MnCl 2, substrate (Oligo's Etc., Wilsonville, OR) 25 nM ( 7 ng) e P1363 integrase 200 nM (128 ng) (NIAID AIDS Research and Reference Reagent Program, Bethesda, MD). The reaction proceeds at 37 ° C for 1 to 2 hours and is terminated by the addition of 20 μl of solution to interrupt the sequencing (USB Amersham, Arlington Heights, IL). The reaction products are visualized by autoradiography after polyacrylamide 6M Urea 15% polyacrylamide gel electrophoresis. The substrate moves as a 30 mer, the processing product 3 'moves as an N-2 band and the web transfer products move more slowly in various sizes larger than the substrate.

Toxicity values The quantification of toxicity involves the evaluation based on XTT. Trials were designed to characterize the long-term effects of the compounds on virus production and to characterize the short-term effects of the compounds on virus production from cells chronically infected with HIV. CEM-SS cells chronically infected with an HIV isolate, eg SKI (CEM-SKI) were cultured in RPMI1640 tissue culture medium supplemented with 10% fetal bovine serum and antibiotics. The selection is made by culturing the cells in the presence of the compound P1363 to be tested in T25 flasks. CEM-SKI cells or other infected cells without addition of the drug are used as control cells. The cells were cultured to a density of about 1 x 10 6 cells / ml and then subcultured at a 1:10 dilution. After a period of time, usually one week intervals of treatment with the drug, the cells were evaluated to determine if the inhibitory activity of the compound had been affected by treating the cells with any of the compounds. The concentration of the drug in the flask then increased twice and the cells were conserved according to the above. The cell population contained integrated copies of the HIV genome and constitutively produced HIV at relatively high levels or an infected latency and only produced viruses after stimulation with phorbol esters, tumor necrosis factor or IL6 (Ul and ACH2). The reduction in virus products was observed by quantifying the activity of reverse transcriptase in the supernatant.

Reverse Transcriptase Inhibition Assay A purified HIV-1 reverse transcriptase enzyme (RT) of the recombinant type provided by the P13S3 Dr. Steven Hughes (ABL, NCI-FCRDC) was the one employed. The characterization of the RT inhibitory properties for the selected test compounds was carried out using an RT assay described by Boyer et al (1993) with minor modifications. Recombinant RT enzymes were evaluated shortly thereafter in microtiter plates in a 100 ml reaction mixture containing 25 mM Tris-HCl, pH 8.0, 75 mM KCL, 8 mM MgCl 2, 2 mM DTT, 10 mMdGTP, template 0.01 U rC: dG (Pharmacia), 10 mCi [P32] -a-dGTP (800 Ci / mmol) and the test compounds in indicated concentrations. The concentration of the RT enzyme used in these assays varied from 0.4-0.9 mgm / ml for the different recombinant proteins; all reactions of the RT enzymes proceed for 30 minutes at 37 ° C before terminating the enzymatic reaction by the addition of 10% TCA; 100 mg of the salmon sperm DNA sonified, denatured with heat are added to help the precipitation of AD? and his recovery. When finishing the enzymatic reaction, the AD? Precipitated with TCA is collected on glass fiber filters (GF / C), washed twice with 10% TCA in ice water and subjected to scintillation counting in liguids. To increase the performance of the sample and decrease the handling of the sample from this test, a 96-well fiberglass filter plate and a distributor of P13S3 vacuum (Millpore) to collect and wash the DNA. Subsequently labeled DNA samples are counted directly in the multi-well plate by the addition of 20 ml scintillation fluid (OptiPhase Super Mix, Wallac) to each well and using a 96-well scintillation counter MicroBeta (Wallac).

EXAMPLE 1 Mechanism The mechanism of action of the derivatives of (5- aryl-1,2,4-thiadiazole) -3-yl thiourea or derivatives of (5-aryl-1,2,4-thiadizole) -3-ylurea It is known. (5-Phenyl-1,2,4-thiadiazole) -3-yl thiourea showed no activity as the protease inhibitor method or as an integrase inhibitor. The compound was classified using a fluorometric assay (protease inhibition assay) and autoradiography (integrase inhibition assay). The results are summarized in the following tables.

Inhibition of protease by 654021F - a known protease inhibitor P1363 Inhibition of protease by (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea The EC50 value is > 100 μg / ml for (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea and 0.699 μM / ml for 654021. The results of the test using the compounds of the present invention are summarized as follows: Inhibition of HIV-1 integrase by (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea Inhibition of HIV-1 integrase by TPX - a known integrase inhibitor The EC50 value is 0.648 μM for TPX and > 100 μg / ml for (5-phenyl-1,2,4-thiadiazol) -3-yl thiourea. These tests show that the mechanism for P1363 effective activity against HIV does not correspond to that of a protease inhibitor or that of an integrase inhibitor. The following examples are illustrative and are not intended to limit the invention.

Example 2 BVDV Test In vitro (5-phenyl-1,2,4-thiadiazol) -3-yl thiourea against BVDV was tested at a dose range of 316 μg / ml at O.Ollμg / ml and compared with Ribavirin at 0.032 μM / ml up to 10 μM / ml. The solvent was DMSO (dimethylsulfoxide) and a control test of DMSO was classified at a dose range of 1% to 0.00316%. The antiviral index (AI) which is the TC5o / lC5o ratio is greater than 4000. A second classification test using (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea had an AI of 1000.4. The AI for Ribavirin at 50% is 2.25. DMSO had no effect, as expected. BVDV is a bovine diarrhea virus and is a well-known subrogated virus for hepatitis C that can not be cultured in vi tro. This test demonstrates the efficacy of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea in the treatment of type C hepatitis viruses.

P1363 Example 3 Herpes simplex test The (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea was tested against HSV-2MS, a herpes simplex virus in 2 vero cells and compared with Acyclovir. The IC50 for Acyclovir is 0.81 and 0.85 in a duplicate study. The TC50 is > 1 and the IT or therapeutic index is > 1.2. For (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea, the IC50 is 159.6, the TC50 is > 200, the IT or therapeutic index is > 1.3. The test demonstrates that phenyl thiadiazolyl thiourea derivatives are effective in the treatment of herpes simplex.

Example 4 Kaposi's sarcoma (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea was tested against Kaposi's sarcoma, a herpes virus, in vi tro, using the HHV8 cell line, the BCBL- 1 induced by TPA. The DNA copy number and the toxicity value were measured and compared with Cidofovir.

Data for Cidofovir Copy number of AD? (for 3μl) P1363 Toxicity values ICso μ = 1.1 TC50 μM = 21.1 TI = 19.2 Data for (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea DNA copy number (per 3μl) P13G3 Toxicity values IC50 μM = 56.8 TC5Q μM = 100.3 TI = 1.8 This classification test demonstrates the effectiveness of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against Kaposi's sarcoma, a herpes virus.

Example 5 Hepatitis In a production test of hepatitis B virus in vi tro, HEPG2 2.2.15, the following results were obtained with (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea.

Copy number of AD? (for 3μl) P13 (.3 Toxicity values The IC 50 is 0.94 μg / ml; the TC50 is > 200 μg / ml and the therapeutic index or TI is 212.8. In a duplicate experiment, the IC 50 is 0.76 μg / ml; the TC50 is > 200 μg / ml and the TI is 263.2. By comparison, 3TC was tested and the following data were obtained: DNA copy number (per 3μl) P1363 Toxicity values The IC 50 is 0.089 μg / ml; the TC50 is > 1 μg / ml and the TI is 14.6. In a duplicate experiment, the IC 50 is 0.021 μg / ml; the TC50 is > 1 μg / ml and the TI is > 47.6. (5-Phenyl-1,2,4-thiadiazole) -3-yl thiourea can be used to treat hepatitis B.

Example 6 CEMRF A long-term in vitro study of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-1 cell line, CEMRF was carried out at three different levels. The results of the CEMRF cells are reported at weekly intervals. The data is summarized below.

P1363 CEMRF cell line CEMRF is a viral strain of the CEMSS cell line. This test demonstrates the effectiveness of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea in treating HIV-1.

Example 7 CEMIIIB A long-term in vi tro study was carried out (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-1 cell line, CEMIIIB, and was carried out at three different levels. The results of CEMIIIB cells are reported at weekly intervals. The data is summarized below.

CEMIIIB P1363 The CEMIIIB cell line is a viral strain of the CEMSS cell line.

Example 8 CEMROD A long-term in vi tro study of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-2 cell line, CEMROD, was carried out at three different levels. The results with the CEMROD cells were reported at weekly intervals. The data is summarized below.

CEMROD The CEMROD cell line is a viral strain of the CEMSS cell line.

P1363 Example 9 U937IIIB A long-term in vi tro study of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-1, U937IIIB cell line was performed at three different levels. The results with U937IIIB cells were reported at weekly intervals. The data is summarized below.

The U937IIIB cell line is a viral strain of the U937 cell line.

Example 10 U937RF A long-term in vi tro study was carried out (5-phenyl-l, 2,4-thiadiazol) -3-yl thiourea against U937RF, a protease resistant strain, at three different levels.

The results with U937RF cells were reported at weekly intervals. The data is summarized below.

P13S3 Example 11 Protease-resistant HIV strains A long-term in vi tro study was carried out. (5-phenyl-1, 2,4-thiadiazole) -3-yl thiourea against U937JE225R, a protease resistant strain, at three different levels.

The results with U937JE225R cells were reported at weekly intervals. The data is summarized below.

Similar results are obtained with U937KN1272, a strain resistant to protease, and reported below.

P1363 Example 12 HIV-2 A classification test in vi tro of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-2 virus, CEMROD, was carried out. The results of the test are shown below.

Reverse transcriptase activity Toxicity values P13 (Í3 Example 13 HIV-1 A long-term study was conducted in vi tro (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea against an HIV-1 cell line, CEMSKI, at three different levels. The results with CEMSKI cells were reported at weekly intervals. The data is summarized below.

Cell line CEMSKI The test was repaired and similar results were obtained: P1363 Cell line CEMSKI The CEMSKI cell line is a viral strain of the CEMSS cell line.

Example 14 Antifungal Activity The (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea was tested in vi tro against various fungi. Presented activity against cryptococcus neoformans and curvularai lunata. The biocidal activity for C. neoformans is high enough to show that it is biostatic against this yeast. The test was performed using a method that is based on the M-27A reference method of the National Standards Committee of Clinical Laboratory (NCCLS) published in 1997. For the tests the solvent, the medium and the culture controls were defined. Once these were read to validate the performance of the test, fungi QC were read to ensure that they gave the expected results. These P1363 steps validated the test system. DMSO was used as the chemical solvent for the drug. These tests were read after incubation at 35 ° C when the QC organisms (Candida spp.) Showed good development. The MIC values were the concentrations at which the growth was inhibited or reduced by at least 90% compared to the growth of the control. The 90% cut is necessary for azoles, which are biostatic and non-biocidal. The FMC or biocidal level was determined by subculturing a sample for each tube that showed no growth. The curvularai lunata causes fungal keratitis, infections of the breast and internal organs. It is opportunistic in immunocompromised patients. Cryptococcus neoformans is an opportunistic pathogen that involves the central nervous system in patients with AIDS and is a yeast that has a polysaccharide protective capsule, that is, a basidiomycete. The abbreviations used for the compounds analyzed are. AmB is amphotericin B Thia is thiabendazole «Methyl is methyl 1,2-benzimidazole carbamate or benomyl Itra is itraconazole Phth is (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea P1363 MIC data (μg / ml) Curvularia lunata MIC data (μg / ml) Cryptococcus neoformans MFC data (μg / ml) Cryptococcus neoformans MFC data (μg / ml) Curvularia lunata (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea is effective against these two fungi that is commonly found P1363 in patients with AIDS. These phenyl thiadiazolyl derivatives can be used to treat HIV and prevent the development of secondary fungal infections.

P1363

Claims (16)

1. CLAIMS: 1. Use of a pharmaceutical composition for treating a viral infection, wherein the composition comprises a therapeutically effective amount of a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative thereof. (5-aryl-1,2,4-thiadiazole) -3-yl urea having the formula: wherein X is oxygen or sulfur; R is hydrogen or alkyl having 1 to 3 carbon atoms; n is 0 to 4; and R is independently selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine, fluoro, oxychlor and alkoxy having the formula -0 (CH2) and CH3, wherein y is 1 to 6; or a pharmaceutical addition salt or a prodrug thereof.
2. 2. A use according to claim 1, wherein the viral infection being treated is selected from the group consisting of HIV, herpes simplex, hepatitis, retrovirus and Kaposi's sarcoma.
3. 3. A use according to claim 2, wherein the viral infection is hepatitis C, hepatitis B or HIV.
4. 4. A use according to claim 1, 2 or 3, in P13S3 wherein the pharmaceutical addition salt is selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and mixtures thereof.
5. A use according to claim 1, 2, 3 or 4 ~, wherein the composition provides a dose of between about 1 mg / kg of body weight to about 10,000 mg / kg of body weight of said (5-aryl) derivative -1,2,4-thiadiazole) -3-yl thiourea or derivative of (5-aryl-l, 2,4-thiadiazol) -3-yl urea.
6. 6. A use according to claim 1, 2, 3, 4 or 5, further comprising the use of an antiviral agent in a combination therapy with the derivative of (5-aryl-1,2,4-thiadiazole) -3 -yl thiourea or the derivative of (5-aryl-1,2,4-thiadiazol) -3-yl urea.
7. 7. A use according to claim 6, wherein the viral infection is by HIV and wherein the antiviral agent is selected from the group consisting of AZT, TC-3, protease inhibitors, cyclovir, famciclovir, valaciclovir, Ribavirin, interferon, combinations of Ribavirin and interferon, beta globulin and a recombinant alpha interferon.
8. 8. A use according to claims 1, 2, 3, 4, 5, 6 or 7, wherein the composition comprises an amount Therapeutically effective P1363 of (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea or a prodrug or pharmaceutical addition salt thereof.
9. 9. A use of a pharmaceutical composition for treating a fungal infection wherein the composition comprises a therapeutically effective amount of a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative of (5) -aril-l, 2,4-thiadiazol) -3-yl urea having the formula: wherein X is oxygen or sulfur; R is hydrogen or alkyl having 1 to 3 carbon atoms; n is 0 to 4; and Ri is independently selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine, fluoro, oxychlor and alkoxy having the formula -0 (CH2) and CH3, wherein y is 1 to 6; or a pharmaceutical addition salt or a prodrug thereof.
10. 10. A use according to claim 9, wherein the pharmaceutical composition comprises (5-phenyl-1,2,4-thiadiazole) -3-yl thiourea or a pharmaceutical addition salt thereof.
11. 11. A pharmaceutical composition comprising P13S3 a pharmaceutically acceptable carrier and a therapeutically effective amount of a derivative of (5-aryl-1,2,4-thiadiazole) -3-yl thiourea or a derivative of (5-aryl-l, 2, -thiadiazole) -3 -il urea that has the formula: wherein X is oxygen or sulfur; R is hydrogen or alkyl having 1 to 3 carbon atoms; n is 0 to 4; and Ri is independently selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine, fluoro, oxychlor and alkoxy having the formula -0 (CH2) and CH3, wherein y is 1 to 6; or a pharmaceutical addition salt or a prodrug thereof.
12. 12. A pharmaceutical composition according to claim 11, wherein the pharmaceutical addition salt is selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formats, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and mixtures thereof.
13. 13. A pharmaceutical composition according to claims 11 or 12, comprising from 150 mg to 5000 mg of said (5-aryl-l, 2, -thiadiazol) -3-yl thiourea derivative or a derivative of (5-aryl- 1,2,4-thiadiazole) -3-yl urea. P1363
14. 14. A pharmaceutical composition according to claims 11, 12 or 13, which is a solid form and wherein the pharmaceutically acceptable carrier is selected from the group consisting of lactose, sucrose, gelatin and sugar.
15. 15. A pharmaceutical composition according to claims 11, 12 or 13, which is a liquid form and wherein the pharmaceutically acceptable carrier is selected from the group consisting of an aqueous solution, an alcohol solution, an emulsion, a suspension solution, a liposome, a reconstituted suspension from effervescent and non-effervescent preparations and a suspension in pharmaceutically acceptable oils or fats.
16. 16. A pharmaceutical composition according to claims 11, 12, 13, 14 or 15, comprising (5-phenyl-1,2-thiadiazole) -3-yl thiourea or a pharmaceutical addition salt thereof.