MXPA02006251A - Compositions and methods for lnucleosides, lnucleotides, and their analogs. - Google Patents

Abstract

Nucleoside and nucleotide compounds and their analogsprodrugs are provided. Particularly contemplated compounds include 1bgr;Lribofuranosyl1,2, 4triazole3carboxamide, which may be modified andor phosphorylated. Contemplated compounds may further be combined with other pharmacological compounds, especially including Ribavirin, antibodies, and cytokines. Preferred uses of contemplated compounds include use as an antiviral compound, antiinflammatory compound, antineoplastic compound, and as a compound to stimulate cellular growth.

Description

COMPOSITIONS AND METHODS FOR L-NUCLEOSIDES, L-NUCLEOTIDES AND THEIR ANALOGS Field of the Invention The field of the invention is the pharmaceutical compositions and the uses thereof.

BACKGROUND OF THE INVENTION There are numerous challenges to a person's health, many of which result from infection or accumulation of toxins in a vital organ, which can also result in an adverse reaction of the immune system to the infected organ. For example, an infection with the hepatitis C virus (HCV) often leads to a persistent inflammatory viral infection in which the inflammation of the organ can not be immediately attributed to the HCV virus, but rather to an imbalance induced by the infection in the immune response. The majority of known treatments for viral infections can generally be characterized as either a direct antiviral treatment or an indirect antiviral treatment. In direct antiviral treatment, the virus is targeted as an antiviral, direct, appropriate drug. For example, patients infected with the HIV virus typically receive a cocktail of drugs to block REF: 136736 the spread of the virus, and several classes are known in the art for direct antiviral treatment. For example, some direct antiviral drugs block reverse transcriptase. Inhibitors of reverse transcriptase (TI) are typically nucleoside analogs such as AZT, 3TC, or ddl. Alternatively, non-nucleoside analogue inhibitors, including quercetin, can be used. In vitro, inhibitors of IT are typically potent antiviral drugs. However, in vivo, and especially during a period of relatively high viral duplication rate, the generation of viral mutants resistant to inhibitors of IT is problematic. Other direct antiviral drugs block or interfere with the processing of viral proteins, and are commonly known as protease inhibitors. Typically, protease inhibitors are highly specific towards the proteolytic enzymes of the viruses. However, due to its mainly hydrophobic nature, administration at desired concentrations tends to be problematic. In addition, the development of cross-resistance and serious side effects often make up the difficulties that arise from the use of protease inhibitors. In order to reduce the development of viral strains resistant to multiple drugs, mixtures of inhibitors of IT and protease inhibitors. Although these mixtures are currently used with relative success, the relatively high occurrence of adverse side effects and the potential to generate viral strains resistant to multiple drugs persist. In indirect antiviral treatment, the immune response to a viral challenge can be modulated. For example, immunosuppressive drugs can be used to reduce the inflammatory condition associated with viral infection, and various immunosuppressive drugs are known in the art. Among other immunosuppressant drugs, cyclosporin A is known as a potent immunosuppressant and is frequently used to suppress tissue rejection after organ transplantation. However, the use of cyclosporin A tends to be problematic due to its general immunosuppressive effect, which makes the patient more prone to new infectious diseases. In addition, long-term administration of cyclosporin A is frequently associated with serious side effects, including hirsutism and gingival hyperplasia. In addition, the bioavailability of cyclosporin A is at least partly dependent on bile, which may present additional problems in an infection with hepatitis. To overcome at least some of the problems associated with cyclosporin A, Tacrolimus may be used (FK506) as an immunosuppressant drug. For example, Tacrolimus has found acceptance in the treatment of atopic, facial dermatitis. Topical administration of the immunosuppressant results in a significant improvement of 95% of all treated patients [Alaiti, S. et al., Tacrolimus (FK506) ointment for atopic dermatitis: A phase I study in adults and children. J Am Acad Dermatol 1998; 38 (1): 69-76]. In addition, it seems that Tacrolimus does not cross the skin barrier, thereby eliminating the problems associated with systemic administration. Although it is generally well tolerated, treatment with Tacrolimus, without generally compromising immunity, is limited to topical administration. When administered systemically for prolonged periods, Tacrolimus frequently leads to lymphoproliferative disorders and cardiomyopathy. Many known immunosuppressive drugs provide some relief for inflammatory conditions. However, the effects are not organ specific when administered systematically. Consequently, immunity to exogenous and endogenous challenges such as bacterial and viral infections, neoplastic or malignant cells, etc., is reduced systemically. In this way, the window of a usable concentration of immunosuppressant drugs isdefined by the maximum concentration that will not completely compromise a patient's immune system, and the minimum concentration that will provide at least some desirable effect. Although various compounds and methods are known in the art for the treatment of inflammatory diseases and infections, all or almost all of these have one or more disadvantages. Therefore, there is a need to provide improved methods and compositions for the treatment of those conditions.

Brief Description of the Invention The present invention is directed to methods and compositions in which a nucleoside and / or nucleotide drug or its analog is administered to a subject in an effective concentration or dosage to achieve a desired pharmacological or physiological effect. In one aspect of the inventive content, the contemplated compounds have a structure according to formula I, wherein R is H, a group P032 ~, (P03) 23- / or (P03) 34".

In addition, the contemplated compounds are optionally modified with a modifying group that is covalently coupled to the carbonyl atom and it is further contemplated that the compounds according to the inventive content are in a D or L configuration. In another aspect of the inventive content, the Contemplated compounds are used to treat a viral infection and can also be co-administered with a cytokine preferably IFN-alpha-2b, and an antibody, or Ribavirin (1- ß-D-ribofuranosyl-1,2,4-triazole-3 -carboxamide). In a further aspect of the inventive content, the selectivity of the contemplated compounds with respect to a pharmacological effect in a target cell is increased by modifying the compounds with a modifying group, wherein the modifying group is covalently bound to the drug by means of an atom of nitrogen, and wherein the modifying group is enzymatically removed from the drug in the target cell. Modifying groups in particular contemplated include = NH, and -N (Ri) (R2) or = NRi, wherein Ri and R2 are independently hydrogen, a linear alkyl, branched alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, or an aryl, and in where Ri and R2 may further independently comprise a nitrogen atom, an oxygen atom, a sulfur atom, or a halogen atom. In a still further aspect of the inventive content, a method for treating a disease characterized by inflammation of an organ in a patient has a stage in which the contemplated compounds are administered to a patient in a dosage that causes the systemic immunomodulation and not the Systemic immunosuppression of Type I and Type II responses. This causes the immunosuppression of the Type I and Type II responses in the patient's organ, due to the selective accumulation of the compounds contemplated in the organ. And still in yet another aspect of the inventive content, a method for stimulating neuronal growth has a stage in which it is recognized that the contemplated compounds are effective in stimulating the growth of neurons within a given concentration range. In a further step, the compounds are provided to the neurons within the given concentration range.

Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of the various embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C are exemplary compounds according to the inventive content. Figure 2 is an exemplary reaction scheme for the synthesis of β-β-L-ribofuranosyl-1,2,2-triazole-3-carboxamide. Figure 3 is an alternative, exemplary reaction scheme for the synthesis of β-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide. Figure 4 is another exemplary reaction scheme for the synthesis of β-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide. Figure 5 is a flowchart representing an exemplary method of immunosuppression directed to an organ according to the inventive content. Figure 6 is a flowchart representing an exemplary method for stimulating cell growth according to the inventive content.

Detailed description of the invention Compounds contemplated It is generally contemplated that all nucleotides, nucleosides and their corresponding analogs are suitable for use in conjunction with the teachings presented herein, wherein all of the contemplated compounds may be in their respective L configuration or D configuration. However, particularly preferred compounds include phosphorylated or unphosphorylated Levovirin ™ (β-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide, Structure 1), where R can be hydrogen or a phosphorus-containing group or sulfur. Where R is a group containing phosphorus, it is especially preferred that R is a monophosphate, diphosphate or a triphosphate as depicted in Figures 1A-1C.

Structure 1 Depending on the chemical environment (and especially depending on the pH), it should be appreciated that the phosphate groups can be in their corresponding mono-, di-, tri-, and tetra-protonated forms and it should also be appreciated that when the phosphate groups they are partially or completely deprotonated, salts can be formed with one or more mono- or multivalent cations.The cations especially contemplated are alkali metal ions or alkaline earth metal ions such as Mg2 +, Cs2 +, Na +, etc. _ In alternative aspects of the content inventive, R may also be a group P032 ~, (P03) 23 ~ or (P03) 34 ~, in which one or more of an oxygen is replaced with a sulfur atom, while the phosphate groups are generally preferred substituents for R, other chemical groups can also be used and the groups contemplated in particular include mono- or polyanionic groups, preferably with a tetragonal geometry. embedded especially include phosphorylated, modified or unmodified Levovirin ™. Furthermore, it should be appreciated that the contemplated compounds may also have a sugar portion in the D configuration, and a compound especially contemplated with sugar in the D configuration is Ribavirin ™ (β-β-D-ribofuranosyl-1,2,4-triazole). -3-carboxamide). Furthermore, it should be appreciated that at least some of the contemplated compounds exhibit a direct antiviral effect (ie, the contemplated compounds immediately inhibit viral propagation). Since most organisms possess phosphatases in various compartments, it is contemplated that the compounds according to the inventive content may be dephosphorylated gradually and one or more of a phosphate group may be removed at the same time. For example, a triphosphorylated compound can be converted into a diphosphorylated or monophosphorylated compound, or a diphosphorylated compound can be converted to Levovirin ™ in an individual reaction. With respect to the dephosphorylation of the phosphorylated Levovirin ™, it is particularly contemplated that the antiviral mode of action changes from a direct antiviral effect to an indirect antiviral effect. The change from a direct antiviral response to an indirect antiviral response is particularly advantageous, because although the contemplated compounds are metabolized, they retain the antiviral action for an extended period. Therefore, it should be appreciated that the mode of action of the contemplated compounds, and particularly the phosphorylated Levovirin 1"1, is actually at least bimodal - comprising a portion of direct antiviral effect and a portion of indirect antiviral effect. At the rate of dephosphorylation, it is contemplated that phosphorylated Levovirin is dephosphorylated at a considerably slower rate than the phosphorylated Ribavirin, an effect that is contemplated to be due to the L configuration of the ribose in Levovirin ™. With respect to the compartment or organ where dephosphorylation may occur, it is contemplated that dephosphorylation preferably takes place in the liver, however, other organs and compartments may also be contemplated, which include the kidney, neuronal cells, and the bloodstream. It should be especially appreciated that all known prodrug forms of the contemplated compounds are suitable for use in conjunction with the teachings presented herein, and particularly contemplated prodrug forms include covalent modifications that can be enzymatically removed (e.g. an aminohydrolase, an oxidoreductase, or a transferase) of the contemplated compounds. Suitable exemplary prodrug forms are described in U.S. Patent Application No. 09 / 594,410, filed 06/16/00, incorporated herein by reference and in "Prodrugs" by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), or "Design of Prodrugs" by Hans Bundgaar (ASIN: 044480675X), also incorporated by reference in this document.

In addition, especially contemplated examples of suitable prodrugs include prodrugs formed by the addition of a nitrogen-containing group to the carboxamide portion of Levovirin ™, which may be especially advantageous where the contemplated compounds are preferably directed to the liver. For example, the inventors have discovered that (unpublished results) the specificity of Levovirin with respect to its pharmacological effect on hepatocytes can be improved by modifying Levovirin ™ with a nitrogen-containing modifier group that is selectively removed in hepatocytes. Structure 2 below shows Levovirin ™, and Structure 3 shows modified Levovirin ™ in the carboxamide group to form a carboxamidine group.

Structure 2 Structure 3 It is particularly contemplated that a modification of the * · MR Levovirm with a modifier group (preferably containing nitrogen) that can be selectively removed in a target cell (eg, a hepatocyte) (1) will increase the selectivity of Levovirin ™ with respect to the target cell, whereby (2) the total dosage will be reduced to achieve a desired effective concentration and (3) will reduce the potential toxicity in non-target cells. In addition, it is contemplated that the modifying group is covalently linked to the carbonyl atom of the carboxamide group. In additional alternative aspects, the nitrogen-containing modifier group need not be limited to a group = NH, but may also include various primary and secondary amines. It is generally contemplated that suitable modifying groups have the structure -N (Ri) (R2) or = Ri, wherein Ri and R2 are independently hydrogen, linear or branched alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkynyl, aryl, all which may further comprise heteroatoms which include nitrogen, oxygen, sulfur or halogen. However, it is especially preferred that the alternative modifying groups be enzymatically removable from Levovirin, and that the enzymes particularly contemplated include aminohydrolases, such as liver deaminases (eg, adenosine or cytokine deaminase), liver deamidases (eg, aryl). deamidase) and transaminases of the liver (glutamate-pyruvate transaminase) Although without limiting the inventive concept presented in this document, it is contemplated that the modifier group can inactivate Levovirin ™, or prevent activation Subsequent once the modified Levovirin is present in a non-target cell. On the other hand, the nitrogen-containing modifier group can also prevent the metabolic activation of the modified Levovirin ™. With respect to the modification step of Levovirin ™, it is contemplated that the modification may comprise an organo-synthetic modification, an enzymatic modification or a de-novo synthesis to produce the modified Levovirin ™. With respect to the enzymatic removal of the modification group, it is contemplated that, depending on the type of target cell and the modifier group, the enzymatic removal may vary considerably. Enzymatic removal can include enzymes of various kinds, including hydrolases, transesrases, lyases and oxidoreductases and the particularly preferred subclasses are adenosine and cytosine deaminase, arginase, transaminase and arylamide. Furthermore, it should be appreciated that the enzymes contemplated for the enzymatic removal of the modification group can be expressed exclusively in the target cells, however, in alternative aspects of the inventive content, the appropriate enzymes can also be expressed in cells other than the target cells, as long as the enzyme is not expressed obiqually in all cells in a system that contains cells. In addition, it should be appreciated that the enzymes contemplated are expressed from preference natively (ie, are not recombinant) in the respective target cells under normal and / or pathological conditions. For example, glutamine-pyruvate transaminase is known to be essentially expressed with a relatively high selectivity in liver cells, and therefore, it may be a suitable enzyme for the removal of a modification group. Alternatively, it is known that cytosine deaminase is expressed in relatively high amounts in colon cancer cells, but not, or only in minor amounts, in normal colon cells.

Synthesis of the Contemplated Compounds It is generally contemplated that all known methods of synthesis for the D-nucleotides, D-nucleosides, and their respective analogs can be adapted for the synthesis of the compounds contemplated in the L-configuration (for example, by replacing the sugar portion in the configuration D with a portion of sugar in the corresponding L configuration). The exemplary reaction scheme for the synthesis of Levovirin ™ (β-β-L-ribofuranosyl-1,2,4-triazole-3-carboxamide) is depicted in Figure 2.

Synthesis of 2,2,3,5-Tetra-0-acet-l-fi-L-ribof'uranosa (1) To a stirred solution of L-ribose (50.0 g, 333.33 mol) in anhydrous methanol (500 ml) at room temperature was added methanol, dried, freshly prepared HC1 (40 ml, prepared by bubbling gas of dried HC1 in methanol to 0 ° C at a weight increase of 4 g) by means of an eringa for a period of 15 minutes under an argon atmosphere. After the addition of methanolic HC1, the reaction mixture was allowed to stir at room temperature for 3-4 hours. Dry pyridine (100 ml) was added and evaporated to dryness under high vacuum below 40 ° C. This process was repeated a second time with additional dry pyridine (100 ml). The residue was dissolved in dry pyridine (250 ml) and cooled in an ice bath at 0 ° C under an argon atmosphere. To this stirred, cold solution was added acetic anhydride (100 ml) by means of a dropping funnel over a period of 15 minutes. After the addition of acetic anhydride, the reaction was allowed to stir at room temperature under the exclusion of moisture for 24 hours. The reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (400 ml) and water (400 ml), and extracted into EtOAc. The aqueous layer was extracted again with EtOAc (100 mL). The combined EtOAc extract was washed with water (400 ml), saturated NaHCO 3 (2x300 ml), water (300 ml) and brine (200 ml) The organic extract was dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was co-evaporated with dried toluene (2x150 ml) under high vacuum. The oily residue, dried (92 g, 95%) was used as it was for the next reaction without further characterization. The syrup (92 g) from the above reaction was dissolved in glacial acetic acid (300 ml) and treated with acetic anhydride (75 ml) at room temperature. The solution was cooled to 0-5 ° C in an ice bath under an argon atmosphere. Concentrated H2SO4 (21 ml) was added slowly over a period of 15 minutes. After the addition of H2SO4, the reaction mixture was stirred at room temperature for 14 hours, poured into crushed ice (500 g), and stirred until the ice melted. Water (500 ml) was added and extracted with CHC13 (2x300 ml). The chloroform extract was washed with water (3x400 ml), saturated NaHCO 3 (2x300 ml), water (200 ml) and brine (200 ml). The washed organic extract was dried over anhydrous MgSO4, filtered and evaporated to dryness to give an oily residue (99 g). The residue was co-evaporated with dry toluene (200 ml) and dissolved in ethyl ether (200 ml), which upon cooling to 10 ° C for one day produced colorless crystals. The crystalline solid was filtered, washed with hexanes, ether (2: 1, 50 ml), and dried to give 60.5 g of the product.

Synthesis of Metxl-1- (2,3,5-tri-O-acetyl-fi-L-ribofuranosyl) -l, 2,4-triazole-3-carboxylate (3) and Methyl-1- (2,3, 5-tri-O-acetyl-fi-L-ribofuranosyl) -1, 2,4-triazol-5-carboxylate (4) A mixture of methyl-1,2,4-triazole-3-carboxylate (25.4 g, 200 mmol), 1, 2, 3, 5-tetra-0-acetyl-pL-ribofuranose (63.66 g, 200 mmol) and bis (p-nitrophenyl) phosphate (1 g) was placed in a RB flask. (500 mi). The flask was placed in a preheated oil bath at 165-175 ° C under a vacuum of water aspirator with stirring for 25 minutes. The displaced acetic acid was collected in an ice-cooled separator that was placed between the aspirator and the RB flask. The flask was removed from the oil bath and allowed to cool. When the temperature of the flask reached barely 60-70 ° C, EtOAc (300 mL) and saturated NaHCO3 (150 mL) were added and extracted into EtOAc. The aqueous layer was extracted again with EtOAc (200 ml). The combined EtOAc extract was washed with saturated NaHCO3 (300 mL), water (300 mL) and brine (200 mL). The organic extract was dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was dissolved in EtOH (100 mL) and diluted with MeOH (60 mL), which on cooling to 0 ° C for 12 hours produced colorless crystals. The solid was filtered, washed with cold EtOH, minimum (20 ml) and dried at high vacuum over solid NaOH to give 60 g (78%). The filtered product was evaporated to dried and purified on a silica column using ChCl3- > EtOAc (9: 1) as the eluent. Two products of the filtrate were isolated: the fast-moving product 8.5 g (11%) and the slow-moving product 5 g (6.5%). The product of slow movement was equated with the crystallized product. The fast-moving product was found to be (4) and obtained as a foam. The combined yield of (3) was 65 g (84%).

Synthesis of β-β-Ribofuranosyl-l, 2,4-triazole-3-carboxamide (5) Methyl-1- (2, 3, 5-tri-0-acetyl-pL-ribofuranosyl) -1,2,4-triazole-3-carboxylate (62 g, 161 mmol) was placed in a steel pump and treated with freshly prepared methanolic ammonia (350 ml, prepared by passing dry HC1 gas in dry methanol at 0 ° C until saturation) at 0 ° C. The steel pump was closed and stirred at room temperature for 18 hours. The steel pump was then cooled to 0 ° C, opened and the contents evaporated to dryness. The residue was treated with dry ethanol (100 ml) and evaporated to dryness. The residue obtained was triturated with acetone to give a solid, which was filtered and washed with acetone. The solid was dried overnight at room temperature and dissolved in a hot mixture of EtOH (600 ml) and water (10 ml). The volume of the EtOH solution was reduced to 150 ml when heating and when stirring on a hot plate. The hot EtOH solution on cooling provided colorless crystals, which were filtered, washed with acetone and dried under vacuum. The additional concentration of the filtrate gave an additional material. The total yield was 35 g (89%). In an alternative aspect of the inventive content, it is contemplated that the synthesis of Levovirin ™ may also employ one or more enzymatic conversions. For example, acetylation of L-ribose can be performed with a suitable acetyltransferase (e.g., EC 2.3.1.xx). In another example, formation of the carboxamide group from the corresponding methyl ester can be facilitated by a single or double enzyme system involving an esterase (eg, EC 3.1.1.xx) and / or aminotransferase (eg, EC 2.6.1.xx). In yet another example, Levovirin ™ can be converted enzymatically into the corresponding mono-, di-, triphosphate (for example, EC 3.1.3.xx or EC 3.1.4.xx). It is further contemplated that various catalysts other than bis (p-itrophenyl) phosphate may be used in amounts other than 1 g. The change in the amount (ie mole fraction) of the catalyst can advantageously increase the selectivity of the reaction towards a higher yield of the Ni isomer. desired (L-ribose coupled to the Ni atom of the triazole ring) on the N2 isomer. For example, the appropriate amounts of bis (p-nitrophenyl) phosphate include amounts between 3-30 mol, and more. Alternatively, where appropriate, amounts of less than 3 mmoles (0.3 mmol - 2.99 mmoles) may be included. In further alternative aspects of the inventive content, it is not necessary that the catalyst be limited to bis (p-nitrophenyl) phosphate, and alternative catalysts include p-toluenesulfonic acid, trichloroacetic acid and p-nitrobenzoic acid. With respect to the reaction temperature, it is particularly contemplated that lower temperatures may further increase the selectivity of the reaction towards a higher yield of the desired Ni isomer over the N2 isomer. Therefore, it is contemplated that the temperatures appropriate for the coupling reaction between the triazole portion and the ribose portion include temperatures between about 155-165 ° C. more preferably between 145-165 ° C, and most preferably between 130-165 ° C. In further alternative aspects of the inventive content, it is contemplated that the selectivity of the reaction towards a higher yield of the desired Ni isomer over the N 2 isomer may also be favorably influenced by a chemical modification of the methyl-1,2,4-triazole -3- carboxylate. Chemical modifications include the formation of a complex structure that involves the N2 atom a steric hindrance, and direct chemical modifications of the N2 atom. For example, the pair of free electrons in the N2 atom of the triazole portion and an electron donor in a modified carboxylate group can be used to create complexes of a metal ion, thereby reducing the availability of the N2 atom for the coupling with the ribose portion. In another example, a carboxylate group in methyl-1,2,4-triazole-3-carboxylate can be modified with a relatively bulky group that preferentially and sterically blocks or reduces the reactions that occur in the N2 atom. Alternatively, the N2 atom can be directly modified by a protecting group, and suitable protecting groups include t-Boc, and benzyl. Still further, it is contemplated that a higher yield of the desired Ni isomer on the N2 isomer may also be achieved using enzymatic synthesis in which the portion of ribose (or an L-ribonucleotide) and a methyl-1, 2, Modified or unmodified 4-triazole-3-carboxylate serve as a substrate for a ribosyltransferase (e.g., EC 2.4.2.5 or EC 2.4.2.6). Alternatively, Levovirin ™ can be synthesized by coupling an L-ribose protected to a 1,2,4-triazole-3-nitrile, with the subsequent conversion of the nitrile group to the carboxamide as shown in Figure 3. In an even further alternative synthesis, the coupling of the triazole portion with the of ribose can also be achieved in a reaction in which a ribose. { for example, protected with benzyl) has a -NHNH2 group coupled to the Ci atom, which is reacted with the triazole carboxylate i atom, wherein the triazole carboxylate is subsequently converted to the carboxamidine as depicted in the Figure. With respect to the synthesis of prodrug forms of the L-nucleotides, L-nucleosides contemplated and their respective analogues, it should be appreciated that a particular reaction scheme will generally depend on the structure of the particular compound. However, all forms of synthesis are considered adequate and the reaction schemes contemplated include in vitro synthesis, enzymatic synthesis, in vivo conversions, and any chemically reasonable combination thereof. Exemplary reaction schemes for the formation of the contemplated prodrugs are described in U.S. Patent Application No. 09 / 594,410 [supra]. Where the L-nucleotides, L-nucleosides contemplated and their respective analogs are phosphorylated, it is contemplated that all the ways to incorporate a group are adequate. phosphate in a nucleotide, nucleoside or their respective analogues. The conversion of the contemplated nucleosides to their corresponding phosphorylated forms can be achieved synthetically (Hughes BG et al., (1983); 2 ', 5'-oligoadenylated and related 2', 5'-oligonucleotide analogues 1. Substrate specificity of the interferon -induced murine 2 ', 5' -oligoadenylate synthetase and enzymatic synthesis of oligomers, Biochemistry, 22: 2116-2126). However, various alternative methods are also contemplated and include enzymatic phosphorylation (see for example, Van Rompay, AR, et al. (2000): Phosphorylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases; Pharmacol. Ther. 3): 189-198), and enzymatic phosphorylation in aqueous media (Schwartz, A. and Ponnamperuma, C (1968); Phosphorylation of adenosine with linear polyphosphate salts in aqueous solution (Nature 218, 443).

Uses of the Contemplated Compounds It should generally be recognized that the contemplated compounds can be employed in any treatment or therapy of a system that responds positively to the administration of the contemplated compounds. However, it is particularly preferred that the compounds contemplated they can be used in antiviral treatments (as a direct antiviral compound and / or as an indirect antiviral compound), in treatments to modulate the immune system, and in treatments to stimulate cell growth. In addition, the uses particularly contemplated include the administration of the compounds contemplated in anti-neoplastic treatments.

Antiviral Treatments It is generally contemplated that the compounds according to the inventive content can be employed as a direct and / or indirect antiviral agent in a viral infection. Particularly, it is contemplated that a method of treating a viral infection in a patient comprises a step in which the composition is administered to the patient in an effective dosage to inhibit viral spread (i.e., a process involving a host cell in which one or more of the viruses causes the host cell to produce one or more copies of the virus, wherein the term "to produce" refers to nucleotide synthesis, protein processing and protein assembly), wherein the composition comprises at least one of the contemplated compounds, and preferably at least one of a compound according to Structures 1 and 3. The dosages Preferred are in the range of between 5-2500 mg / day, and more preferably between 50-500 mg / day. However, dosages, routes, programs and alternative formulations are also contemplated, and suitable alternative administrations are described below. While the use of the contemplated compounds is not restricted to a particular virus in a particular viral infection, viral infections especially contemplated are an infection with HIV, an infection with HCV, an infection with HBV, an infection with RSV, an infection with influenza virus and an infection with parainfluenza virus. Peripheral blood mononuclear cells (PBMCs) are currently used to study several different infections, such as Hepatitis C, HIV, Hepatitis B and Herpes virus varieties. (Antivir, Chem. Chemother, July 2000, 11 (4): 291-301, J. Infect, October 1998, 178 (4): 1189-92, March 2000, 268 (1): 12 -60). The CMSPs are infected with the desired virus, and the cell lines are then studied for relevant information on how the particular drugs interact with the CMSPs and how the infected PBMCs act over time and under different environmental conditions. Based on the studies conducted with infected CMSPs, models can be generated that show the effects of pharmaceutical products, environments and / or particular conditions on CMSP cells infected with viruses. The present inventors have discovered (unpublished results) that Ribavirin shows a positive response against CMSP cells infected with HIV. Surprisingly, Levovirin ^ also shows a similar immunomodulatory profile against CMSP cells infected with HIV despite the lack of enzymes needed by the body to phosphorylate the Levovirin ™ present in the patient. Based on the above observations, along with other information and related evidence, it is contemplated that Levovirin ™, phosphorylated Levovirin ™ and modified Levovirin ™ according to Structure 3 can be used in the treatment of HIV and related viruses.

Immunomodulation In Figure 5, a method of immunosuppression directed to an organ 500 has a first step of 510 in which a drug is provided that reduces both a Type 1 response and a Type 2 response when administered above an immunosuppressive concentration. , and increases the Type 1 response in relation to the Type 2 response when administered below the immunosuppressive concentration, where the drug accumulates preferably in an objective organ. In a subsequent step 520, the drug is administered to a patient in an effective dosage to accumulate the drug in the target organ at the immunosuppressive concentration. Consequently, it is contemplated that a method of treating a disease characterized by inflammation of the liver in a patient may comprise a step in which a compound is provided, wherein the compound comprises Levovirin ™, phosphorylated Levovirin ™, phosphorylated and modified Levovirin ™ or modified Ribavirin (supra). ). In a further step, the compound is administered to the patient in a dosage that (a) causes the systemic immunomodulation and not the systemic immunosuppression of the Type I and Type II responses, and (b) causes the immunosuppression of the Type I responses. and Type II in the patient's liver. The term "immunosuppression" refers to a case in which the clones of T and / or B cells of lymphocytes are reduced in size and suppressed in their reactivity, expansion or differentiation. Immunosuppression may give rise to the activation of T-specific or non-specific T suppressor lymphocytes of either T or B clones, or by drugs that have generalized effects on most or all T or B lymphocytes. For example, Ciclosporin A and FK506 act in a relatively specific manner on the cells, whereas alkylating agents such as cliclofosfamida are less specific in their action. As used herein, the term "cytokine" refers to a group of soluble proteins and peptides which act as humoral regulators at nano- to picomolar concentrations and which, under either normal or pathological conditions, modulate functional activities of individual cells and tissues. Cytokines also mediate the interactions between cells directly and regulate the processes that take place in the extracellular environment. As further used herein, the term "lymphokines" refers to a subset of cytokines produced by T helper cells and is generally considered to lie within two subclasses, Type 1 and Type 2. Type 1 cells produce interleukin 2 (IL-2), tumor necrosis factor (TNFa) and interferon gamma (IF and), and are mainly responsible for cell-mediated immunity such as delayed-type hypersensitivity and antiviral immunity. In contrast, Type 2 cells produce interleukins, IL4, IL-5, IL-6, IL-9, IL-10, and IL-13 and are primarily involved in aiding immune, humoral responses such as those observed in response to allergens (eg, switching isotypes of IgE and IgG4 antibodies).

Therefore, the terms "responses" of Type 1 and Type 2 mean that they include the full range of effects resulting from the induction of Type 1 and Type 2 lymphocytes, respectively. Among other things, these responses include the increased production of the corresponding cytokines, the increased proliferation of the corresponding lymphocytes and other effects associated with the increased production of cytokines, which include motility effects. A Type 1 response is generally characterized by an increase in IL-2, TNF-cx, and IFN-α, while a Type 2 response is typically characterized by an increase in IL4, IL-5, IL-6, and IL-10. As still further used herein, the term the drug "preferentially accumulates" in a target organ refers to a selective mechanism of an objective organ that results in an increased, enhanced uptake or retention of the drug in the target organ with relationship to other tissue or organs. The mechanism can include with that an active import by means of transporters, receptors, vesicles, etc., but it can also be based on physicochemical principles, which include the drug loading depending on the pH, different solubility of the drug in environments with altered ionic potential , chemical or enzymatic modification within the target organ or target cell, and so on.

In a preferred aspect, the drug is Ribavirin, which is provided to a patient with an infection with HCV (Hepatitis C Virus), and Ribavirin is administered orally to the patient in an individual dosage of 600 mg / day for a period of time. 180 days An individual dosage of 600 mg / day is generally below a systemic immunosuppressive concentration, however it is effective to accumulate preferentially in the liver. In this way, the concentration of Ribavirin in the target organ (in this case: the liver) will increase significantly and reach an immunosuppressive concentration in the liver. It is known that Ribavirin increases a Type 1 response in relation to a Type 2 response, and reduces the Type 1 and Type 2 responses in relatively high concentrations. The examples are set forth in International Patent Application Number PCT / US98 / 00634 filed January 13, 1998, incorporated herein by reference. In alternative aspects of the inventive content, it is not necessary that the drug be limited to Ribavirin, and alternative drugs include the compounds contemplated (supra), particularly modified or unmodified Levovirin ™ and phosphorylated Levovirin ™. Additional, alternative drugs include the compounds contemplated as long as the alternative compounds reduce both the Type 1 response and the Type 2 response in an immunosuppressive concentration and increase the Type 1 response in relation to the Type 2 response below the immunosuppressive concentration. With respect to the patient, various viral infections other than HCV infection, including infections with arboviruses, can also be contemplated. Consequently, the target organ is not restricted to the liver, but may also include other organs such as the brain, lung, vessels, thymus, kidneys, and so on. In general, it is contemplated that the disease that can be treated with the method according to the content presented herein, will depend on the specific accumulation pattern of the drug (ie, on the organ that preferentially accumulates the drug). For example, Ribavirin and Levovirin® both preferentially accumulate in the liver, and reduce both the Type 1 and Type 2 responses above an immunosuppressant concentration. Therefore, diseases in which deletion in an immune response in the liver is desired are especially contemplated, and include hepatitis C, autoimmune / lupoid hepatitis, liver transplant recipients, and the like. It should be especially appreciated that the method according to the inventive content is not designed to provide a direct antiviral treatment, but rather is designed to suppress at least partially an immune response in an organ that is infected with a virus. Organ-directed immunosuppression is seen to be especially advantageous in hepatitis C, where damage to the organ is not immediately attributable to the HCV virus, but rather to an imbalance induced by infection between a Type 1 response and a response of Type 2. Therefore, a method for treatment with a drug that specifically reduces both the type 1 and type 2 responses in the liver of a patient infected with HCV is considered to prevent hepatic damage prophylactically as well as in a therapeutic approach. Since Ribavirin and Levovirin® both have excellent tolerability in humans, long-term prophylaxis and long-term treatment are particularly advantageous. With respect to the administration (route, dosage, schedule, term, etc.) of the Ribavirin or the contemplated, alternative compounds, the same considerations described below apply. It is further contemplated that Ribavirin or the contemplated, alternative compounds may be employed in a general sanitary environment, as opposed to a therapeutic, clinical environment. Consequently, it is contemplated that Robavirin or the contemplated, alternative compounds can also be used to improve digestion. For example, one or more of The compounds can be taken by an individual suffering from poor digestion - if poor digestion is due to liver conditions such as infections with Hepatitis B or C, or in fact any other condition characterized by inflammation of the liver. In such cases, the person's digestion may be improved by taking Ribavirin or a compound similar to Ribavirin below an amount that normally produces systemic immunosuppression, but in an amount that accumulates in the liver at a concentration that produces immunosuppression in the liver of the person. Another example of a non-therapeutic, non-clinical use is for a person taking Ribavirin or the contemplated, alternative compounds as a means to improve skin color. It is particularly contemplated that the skin color of the person can be improved by taking Ribavirin or the contemplated, alternative compounds below an amount that normally produces systemic immunosuppression, but in an amount that accumulates in the liver at a concentration that produces Immunosuppression in the liver of the person. In all these methods, it is particularly contemplated to use Ribavirin (1- (5-Deoxy-pD-ribofuranosyl) -1,2,4-triazole-3-carboxamide), or Levovirin ™ (1- (5-Deoxy-3-L- ribofuranosyl) -1,2,4-triazole-3-carboxamide), or any of its mono-, di-, or tri-phosphorylated forms. The amount taken or administered is preferably sufficient to produce a systemic immunomodulation of Type I or Type II responses, and a deletion in the liver of both Type I and Type II responses. Especially preferred amounts are between about 300 mg / day and about 800 mg / day, although in some individuals the range may be as low as about 50-100 mg / day to as high as 2000-2400 mg / day. Effects on other organs are also contemplated, including the brain or other organs in which it is known that Ribavirin accumulates significantly.

Stimulation of neuronal growth As used in this document, the term "neuronal growth stimulation" refers to any process in which cell growth and / or division is either initiated from a resting cell, or accelerated into a growing cell and / or division, where "neuronal" refers to to all cells that are directly or indirectly involved in the propagation of cognitive, sensory or motor signals. For example, neurons are contemplated that are directly involved in the propagation of signals, while the cells of the myelin layer or glial cells are involved indirectly by virtue of their insulating function or structural / metabolic support to a neuron. Similarly, receptors are also considered neuronal cells within the scope of this definition. In contrast, the cells that form the inner and outer layers of the dura are not considered neuronal cells, since they are not directly or indirectly involved with the propagation of cognitive, sensory or motor signals. The inventors surprisingly discovered that Ribavirin is effective in stimulating neuronal growth, and the inventors further contemplate that. The various phosphorylated analogs of Ribavirin may also be effective in stimulating this growth. Still further, it is contemplated that Levovirin ™ and its phosphorylated analogs may be effective in a similar manner. In a particular experiment, it has been recognized that Levovirin ™ is effective in stimulating the growth of unipolar neuronal cells in vitro within a concentration range of 0.5 μm. at 500 μ ?. Consequently, the addition of Levovirin ™ to a culture medium at a concentration of approximately 5.0 μ? It can be used to stimulate the growth of unipolar neuronal cells. In addition, it should be appreciated that methods to stimulate neuronal growth do not need to be limited to unipolar neuronal cells, but may include various alternative cells, including bipolar or multipolar neuronal cells. In addition, it is contemplated that in the alternative aspects of the methods for stimulating neuronal growth, the individual cell types can be targeted as a population of various neuronal cells. For example, unipolar, bipolar and multipolar neuronal cells can be targeted as complex neuronal structures such as the brain, spinal cord or eye. Therefore, neurons can be part of a neuronal tissue that includes at least four of the following cell types: an astrocyte, a dendrocyte, a myelin layer cell, a glial cell, a unipolar neuronal cell, a cell bipolar neuronal, a multipolar neuronal cell and a receptor cell. Consequently, the methods contemplated do not necessarily have to be limited to the stimulation of neuronal growth in a cell culture. In further alternative aspects of the inventive content, it is contemplated that the cells may be stimulated in a tissue culture, and it is particularly contemplated that the neuronal cells may be stimulated in vivo. In vivo stimulation of neuronal growth can be used advantageously as a treatment prophylactic, or as a therapeutic treatment. For example, the methods contemplated according to the inventive content can be used for the prevention of demyelination disorders or neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, or as a preventive treatment prior to the operative procedures in a patient. The therapeutic treatments contemplated include the reversion or attenuation of attacks of asphyxia, traumatic, toxic, infectious, degenerative, metabolic, ischemic or hypoxic. Accordingly, as depicted in Figure 6, a method 600 for improving coordination in a patient has a first step 610 in which it is recognized that Ribavirin or phosphorylated or non-phosphorylated Levovirin ™ is effective in stimulating the growth of neurons in vivo within of a given concentration interval. In a subsequent step 620, the patient takes an amount of phosphorylated or unphosphorylated Ribavirin or Levovirin ™ that is effective to stimulate the growth of at least some neurons of the person. The improvement of eye-hand coordination is especially contemplated. In a preferred method for improving coordination in a person, it is recognized that Ribavirin is effective in stimulating the growth of neuronal cells in vivo within a concentration range of 0.5 μ? at 500 uM, and the Ribavirin is administered orally to a patient suffering from traumatic damage to the nervus ischiadicus in a dosage of 1200 mg / day. With respect to the patient, various conditions other than traumatic injury to the Ischiadicus nervus are also contemplated, including mechanical and chemical damage to a plurality of nerve cells, infection of neuronal cells with bacteria and / or viruses, and degenerative diseases. Regardless of the nature of the patient's condition, it is contemplated that the method according to the inventive content may stimulate a wide range of neuronal cells, and it is especially contemplated that the stimulated neurons communicate between the person's brain and the voluntary muscles, or between the person's brain and the skin sensors. Another class of contemplated methods includes the improvement of tactile or other sensitive sensitivity in a patient. Even another class of contemplated methods includes the improvement of general and fine motor control. While not wishing to be bound by a particular theory, it is contemplated that the administration of Ribavirin, Levovirin ^ 1 or mono-, di- and triphosphorylated forms of Levovirin or Ribavirin may effect a change in Type 1 or Type A responses. 2 in a patient, which can lead concomitantly to a neuroprotective state, or a stimulation of neuronal growth. Therefore, it is contemplated that compounds according to the inventive content may be administered as part of a disease treatment in a patient in an effective dosage range to increase a Type 1 response and decrease a Type 2 response in the patient. With respect to the in vivo administration (route, dosage, schedule, term, etc.) of Ribavirin or the alternative contemplated compounds, the same considerations described below apply.

Anti-neoplastic treatment It is further contemplated that the compounds according to the inventive content may be employed as an anti-neoplastic agent in the treatment of a solid or lymphatic tumor, and the neoplasms contemplated include various carcinomas, sarcomas and lymphomas, and particularly include acute myeloid leukemia and chronic myeloid leukemia in blasts crisis. Furthermore, it should be appreciated that the administration of the compounds contemplated in the antiviral treatments will generally follow a route, dosage, program and term such as those used with the D-nucleotides, D-nucleosides, known and their respective analogs in anti-neoplastic treatments.

Administration of the Contemplated Compounds With respect to the administration of the contemplated compounds, it should be appreciated that the compounds can be administered under any appropriate protocol in any appropriate pharmaceutical formulation. It is generally preferred that the contemplated compounds be administered orally. In alternative aspects of the inventive content, it should be appreciated that various alternative administrations are also suitable and it should further be recognized that a particular administration will generally depend on the chemical stability, bioavailability, dosage, formulation and / or desired pharmacokinetic / pharmacodynamic properties of the compounds contemplated. In this manner, appropriate administrations will include topical delivery (eg, ointment, spray, cream, etc.), parenteral systemic delivery (eg, inhalation) and direct or indirect delivery to the bloodstream (eg, iv or im injection). , etc). Consequently, the formulation of the contemplated compounds can vary considerably. For example, where the drug or drug composition exhibits sufficient stability to pass through the gastrointestinal system without undesired chemical or enzymatic modification, oral formulations may include syrup, tablets, gel capsules, powder, etcetera. On the other hand, where the absorption or passage of the compounds contemplated through the gastrointestinal tract into the bloodstream is problematic, suitable formulations especially include injectable solutions or suspensions (eg, saline, physiological, buffered to a pH of about 7.2 to 7.5). With respect to the dosage of the contemplated compounds, it should be appreciated that various dosages are suitable and it should be contemplated that the dosages contemplated are typically in the range of 1 mg to several 100 mg, and a further. For example, where the contemplated compounds are excreted or metabolized at a relatively low rate, or where long-term treatment is desired, the dosages will typically be in the range of 5 mg-200 mg per day. On the other hand, where the bioavailability of the contemplated drugs is relatively low, or where the metabolic conversion (eg, dephosphorylation) is relatively rapid, the dosages will typically be between the range of 100 mg-2500 mg per day. With respect to the dosage of L-nucleosides, and especially Levovirin, it should be further appreciated that Levovirin ™ appears not to be phosphorylated in vivo, at least not in hepatocytes not in erythrocytes, and that the antiviral effect of Ribavirin appears to be dependent on phosphorylation, a person of ordinary skill in the art would not expect Levovirin ™ to have a direct antiviral effect. In fact, the experiments (not reported) do not show a direct antiviral effect. The antiviral effect of Levovirin ™ appears to be surprisingly at a dosage no greater than 200 mg per day, preferably in the range of 10 to 200 mg, more preferably in the range of 50 to 200 mg, and even more preferably in the range of 50 to 200 mg. 100 mg. This is supported by experimental evidence demonstrating that a given dose of Levovirin ™ results in a level in serum five times that of an equivalent dose of Ribavirin. Experiments show that Ribavirin is removed from the serum by becoming phosphorylated in red blood cells (see, for example, Homma, M. et al., High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes; Antimicrob. Agents Chemother . (1999), 43 (11): 2716-9). Once phosphorylated, Ribavirin can not leave the cells. Consequently, the red blood cells act as a collector of Ribavirin, and higher doses of Ribavirin are necessary to achieve a given level in the serum. Levovirin ™ is not phosphorylated, and therefore tends not to accumulate in red blood cells. As a result, red blood cells do not act as a Levoviri collector, and lower doses of Levovirin ™ are sufficient to achieve a desired level in the serum. The schedule of administration may vary considerably, and the programs contemplated include an individual dose during the entire course of treatment, multiple individual doses per day during the entire course of treatment, multiple daily doses, and permanent dosing (eg, permanent infusion, pump osmotic implant, etc.) during at least part of the course of treatment. While it is generally preferred that adequate programs sustain a constant supply of the contemplated compounds, an explosion supply (ie, at least one administration in a first dose followed by at least one administration in a lower dose than that in the second dose) is also appropriate. first dose). With respect to the term (ie, duration) of the treatment, it is contemplated that the appropriate durations may vary between an individual administration and several days, several weeks, several years and even more. For example, where the contemplated compounds are employed in a cell culture, an individual administration, or a relatively short administration, may be sufficient. On the other hand, where the compounds contemplated to treat a watery liver disease are administered, the appropriate duration of the Treatment can be in the interval between several days and several weeks. Similarly, where chronic liver diseases are treated by administration of the contemplated compounds, extended administration for one or more years may be suitable. In still further alternative aspects of the inventive content, the contemplated compounds can be combined with additional pharmaceutically active substances to aid in the treatment of various diseases, and particularly viral infections. The additional pharmaceutically active substances can be administered separately or together, and when administered separately, the administration can occur simultaneously or separately in any order. Additional pharmaceutically active substances, especially contemplated include antiviral agents and immunodulatory substances. For example, antiviral agents include protease inhibitors, nucleotide and / or nucleoside analogues (and especially Ribavirin), and immunomodulatory substances may include cytokines [e.g., interferon a, IL2, IL4, IL6, IL8, IL10, and IL12). In addition, the pharmacologically active agents contemplated include anti-fungal agents such as tolnaftate, Fungizone ™, Lotrimin "*, Mycelex ™, Nistatin and Amfoteracin; anti-parasitic agents such as Mintezole, Niclocide 1 ^, VermoxMR, and FlagylMR, agents for the gut such as Immodium ^, Lomotil ™, and Phazyme ™, anti-tumor agents such as interferon and α, Adriamycin ™, Cytoxan ™, Imuran ™, Methotrexate, Mithracin ™, Tiazofurin ™, Taxol ™; dermatological agents such as Aclovate ™, Cyclocort ™, Denorex ™, Florone ™, Oxsoralen ™, mineral tar and salicylic acid; migraine preparations such as ergotamine compounds, steroids and immunosuppressants not listed above, which include cliclosporins, Diprosone ™, hydrocortisone; Florón ^, LidexMR, TopicortMR, and ValisoneMR; and metabolic agents such as insulin and other drugs which may not correspond to the previous categories.

Preferred combinations of the contemplated compounds with an interferon In a particularly preferred aspect of the inventive content, a synergistic combination of Levovirin ™ and at least one interferon, preferably IFN-oc-2b, is contemplated. Levovirin ™ is typically not phosphorylated, or only to a lesser degree than Ribavirin, in erythrocytes while still exhibiting antiviral and immunomodulatory activity. Consequently, it considers that the pharmacological action of interferon and especially in the treatment of liver diseases can be increased by the co-administration of Levovirin in significantly lower dosages compared to Ribavirin. For example, it is contemplated that the effective synergistic doses of Levovirin ™ in combination with the interferon necessary to treat HCV infection are expected to be in the range of 1-600 mg, more preferably in the range of 10-400 mg, further preferably in the range of 50-300 mg, and most preferably in the range of 100-300 mg. The equivalent synergistic doses of Ribavirin are considered to be 600-800 mg. In another aspect of the inventive content, it is contemplated that the synergistic combination of Levovirin ™ and interferon will result in reduced toxicity relative to the combination of Ribavirin and interferon in equivalent effective dosages, predominantly due to the lack of significant phosphorylation in erythrocytes. . Looking from another perspective, it is contemplated that the synergistic combination of Levovirin ™ and interferon specifically allows targeting the liver due to the lack of phosphorylation of Levovirn ™ in different compartments of the liver, especially erythrocytes.

With respect to co-administration of Levovirin and interferon, it is contemplated that all suitable routes and protocols are appropriate, and it is especially preferred that Levovirin "1 * and interferon be administered in a protocol similar to known administration protocols. Ribavirin- and interferon For example, Levovirin® can be administered orally while interferon can be injected subcutaneously.In general, it is contemplated that the co-administration of Levovirin ™ and interferon can use programs and routes independent of each other provided that Both drugs are in the bloodstream at measurable concentrations at the same time.It is further contemplated that effective dosages of Levovirin ™ can be projected from the effective concentrations of Ribavirin in the liver where Ribavirin was administered, while Levovirin ™ is particularly contemplated, as well modifications are appropriate Examples include prodrug forms such as modified Levovirin ™ (1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine), mono-, di- and triphosphorylated Levovirin ™ and stereochemical variants (eg, antimicrobials, isomers, etc.). Examples for suitable chemical modifications and prodrug forms are described in U.S. Patent Application No. 09/594410, [supra]. HE further contemplates that suitable prodrugs may also include drugs other than Levovirin ™ and its variants, and alternative drugs particularly contemplated include liver-specific prodrugs with an amine or amide group that can be deaminated / deamidated enzymatically in the liver. With respect to interferon, it is contemplated that coadministration of Levovirin ™ does not have to be limited to IFN-2b, and co-administration may also include natural and synthetic fragments, isoforms and consensual forms of interferon-alpha. In addition, interferons other than interferon-alpha are also suitable, including interferon-beta and its natural and synthetic fragments, isoforms and consensual forms. While interferon is particularly contemplated, other cytokines other than interferon and chemokines, including IL-2, IL-12 and TNF are also suitable. It is especially contemplated that the pegylated forms of the contemplated interferons (ie, the contemplated interferons associated with polyethylene glycol) are also suitable for use in conjunction with the teachings presented herein.

Combination of the contemplated compounds with a second compound that binds to a viral protein or a cytokine Where the combination of the contemplated compounds is employed with other pharmacologically active agents in an antiviral therapy, it is particularly contemplated that these combinations may comprise the contemplated compounds with a direct antiviral effect and an indirect antiviral effect, and a second compound that increases the antiviral defect. total (the total antiviral effect includes the direct antiviral effect and the indirect antiviral effect), wherein the second compound binds specifically to a viral protein or a cytokine. With respect to the compounds contemplated in the combination, nucleoside analogs are preferred, and it is even more preferred that the nucleoside analog is Ribavirin (1- (5-Deoxy-D-ribofuranosyl) -1,2,4-triazole-3. -carboxamide). It is known that Ribavirin has a direct antiviral effect by inhibiting viral duplication of RNA and DNA [Huffman et al., Antimicrob. Agents Chemother (1973), 3: 235; Sidwell et al., Science (1972), 177: 705] and an indirect antiviral effect by suppressing T cell responses mediated by Type 2 and promoting T cell responses mediated by Type 1 as described in the application US Patent No. 09 / 156,646, which is incorporated in this document by reference. However, several compounds other than Ribavirin are also contemplated, and particularly include L-nucleoside analogs, provided that these alternative compounds have a direct antiviral effect and an indirect antiviral effect. For example, where especially high concentrations of a nucleoside analogue are desirable, Levovirin ™ may be employed. Furthermore, it should be appreciated that depending on the chemical nature of the first compound, the first compound may have a more pronounced direct antiviral effect or a more pronounced indirect antiviral effect. The direct antiviral effects contemplated include the inhibition of viral duplication, for example, an inhibition of a reverse transcriptase, while the indirect antiviral effects contemplated include a change in the balance from Type 1 / Type 2 to a response of Type 1 or Type 2 as described in the US patent application Number. 09 / 156,646. It should also be appreciated that an indirect antiviral effect may comprise a suppression of a Type 1 and Type 2 response, which is described in greater detail in U.S. Provisional Patent Application Number 60 / 172,097 (supra). The change of a Type 1 / Type 2 balance to a Type 1 or Type 2 response or the suppression of the Type 1 / Type 2 response can be advantageously controlled by the same first compound, where the Dosage of the first compound determines the change or deletion in a Type 1 or Type 2 response. With respect to the second compound, it is preferred that the second compound comprises an antibody (e.g., a monoclonal or polyclonal antibody). However, it should be appreciated that in alternative aspects of the inventive content, the antibody need not be restricted to a naturally-occurring form of an antibody, but may also include a synthetic form of an antibody (e.g., mini-antibodies obtained by the antibody). phagocyte tray culture, or other molecular evolution technology), or antibody fragments. Antibody fragments are especially desirable, where these fragments are produced by a recombinant cell or where the molecular weight of the second compound should be relatively low (ie, below 75kDa). Antibody fragments contemplated include Fab, F (ab) 2, and scFab. In addition, it is contemplated that appropriate antibodies can be modified to introduce various additional features, including a reporter group, a second affinity moiety (eg, a bispecific antibody), or a pharmacologically active molecule. For example, a reporter group may include a radioisotope, or a metal that is detectable with in vivo scanning devices (e.g., resonance imaging). magnetic). The pharmacologically active molecules contemplated may include reverse transcriptase inhibitors, protease inhibitors, or cytotoxic agents. The production of recombinant or non-recombinant antibodies is well known in the art (for example, see Current Protocols in Immunology; John Wiley &Sons (1999); Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober), and it is contemplated that all methods known for their production are suitable for use in conjunction with the teachings presented in this document. Antibodies are typically administered by injection (e.g., an i.v injection), and the actual dosage will typically be between 0.01 mg and several 10 mg, however, where appropriate, lower doses are also contemplated. It should be further appreciated that the binding of the second compound to a viral protein or a cytokine is particularly advantageous where the binding leads to an inactivation of a viral protein and / or a cytokine, and it is contemplated that inactivation may occur by means of various mechanisms . For example, inactivation of a virus can be achieved by antibody-mediated precipitation (e.g., the formation of a molecular structure between antibodies and viruses). Alternatively, the binding of the second compound can inactivate a virus by blocking or otherwise obstructing proteins or other viral surface structures that are essential for the infectivity or spread of the virus. Furthermore, the binding of the second compound can occur with the non-structural viral proteins, which include the polymerases and viral proteases. For example, the contemplated binding targets [i.e., hafteños) include proteins such as gp120 / 41 of an HIV virus, but also proteins such as the reverse transcriptase of the HIV virus. Additional, contemplated viral proteins include proteins from an HIV virus, a hepatitis virus, an influenza virus and a RSV virus. With respect to cytokines, it is contemplated that inactivation can be achieved by sequestering the cytokine from the accumulation of cytokines. For example, where the hafteño for the second contemplated compounds is a Type 1 cytokine, particularly contemplated cytokines include interlucin-2, interferon-gamma, and tumor necrosis factor-beta, whereas in cases where haftene for the second compound is a Type 2 cytokine, cytokines particularly contemplated include interlucin-4, interlucin-5, and interlucin-10. It is generally contemplated that the inactivation of a virus or a cytokine by the second compound can have a plurality of desirable effects, which can or they can not exhibit an additive or synergistic effect in combination with the first compound. For example, it is contemplated that in cases where the first compound has a direct antiviral effect (resulting from a significant reduction of the viral titer), a second compound can further reduce the titer of the virus by precipitation of the remaining viruses. Alternatively, the second compound can reduce the number of infectious viral particles by binding to the viral components that are essential for infectivity. It is further contemplated that where the second compound binds to a cytosine, the second compound may change in Type 1 / Type 2 balance to a Type 1 response by sequestering one or more Type 2 cytokines from the accumulation of cytokines, and with that help to restore cellular immunity while the virus load is already significantly reduced. In another example, it is contemplated that where the first compound has an indirect antiviral effect (also resulting from a significant reduction of the virus titer), a second compound can further reduce the virus titer by precipitating the remaining viruses. Alternatively, one or more Type 1 / Type 2 cytokines can be sequestered by a second compound or a mixture of second compounds whereby a Type 1 / Type 2 response is "precisely adjusted" (ie, modulated). induced by the first compound.

It should be appreciated that a combination of a first compound having a direct and indirect antiviral effect with a second compound that binds specifically to a virus and / or a cytokine will reduce a viral titer not only by mechanical action (i.e. enzymes), but also through a systemic action (ie, stimulation / modulation of immunity). It is especially contemplated that preferred antiviral drug compositions include a first and a second compound having a synergistic effect, which will advantageously assist in reducing the effective dosage of the first and second compounds. It is further contemplated that appropriate antiviral drug compositions may also be employed in a prophylactic treatment.

Combination of the compounds contemplated with Ribavirin It is particularly contemplated that co-administration of Levovirin ™ with Ribavirin will reduce adverse side effects and improve the tolerability of Ribavirin and / or Levovirin ™. With respect to the ratio of Ribavirin to Levovirin ™ in co-administration, it is preferred that Levovirin ™ be present in at least an equimolar amount of Ribavirin. However, it should be appreciated that various alternative relationships are also appropriate, and the The particular relationship will predominantly depend on the desired effect and the dosage / route of administration. For example, where hemolytic anemia is of particular interest, Levo-ririn ™ may be present in the co-administration of a range of about 51 mol% to about 80 mol% or more. On the other hand, where the tolerability of Levovirin ™ is limited, Levovirin ™ may be present in the co-administration in a range of about 49 mol% to about 20 mol% or less. Furthermore, it should be appreciated that the co-administration of Ribavirin and Levovirin ™ does not necessarily have to use the same route of administration. The term "co-administration" used herein refers to any form of administration of Ribavirin and Levovirin ™ such that Ribavirin and Levovirin ™ are present in a measurable concentration in the system at the same time. Therefore, co-administrations contemplated include protocols in which Ribavirin is administered in one route and Levovirin ™ is administered in another route, where co-administration can be performed simultaneously or at two different time points. For example, Ribavirin can be administered orally while Levovirin ™ can be injected intravenously. In another example, Ribavirin can be orally administered BID, and Levovirin can be administered orally QID. It is particularly contemplated that by varying the molar fractions of Ribavirin and Levovirin "" in a co-administration protocol, the particularly desirable biological effects may be accommodated to the specific needs of a patient, including modulation of the balance of the Type 1 / Type 2 cytokines, the direct antiviral effect, the reduction in hematotoxic properties, and so on. In another aspect of the inventive content, it is contemplated that the administration or co-administration of Ribavirin or Levovirin ™ will include a continuous release and / or a reduced dosage at more frequent intervals. It is particularly contemplated that sustained release and / or reduced dosage at frequent intervals will reduce undesirable side effects and may increase the direct and / or indirect antiviral effect. While it is generally contemplated that the compounds according to the inventive content may be administered to any system, it is preferred that the contemplated compounds be administered to a mammal, preferably a human, or to a cell or tissue culture.

Metabolites of the Contemplated Compounds It is generally contemplated that Levovirin is metabolically inert when administered to a system, however, the inventors also contemplate that Levovirin ™ may have metabolites, which are shown in Structures 4-8.

Structure 4 Structure 5 Structure 6 Structure 7 Structure 8 Structure 4 is a triazole carboxamide, Structure 5 is a trizol carboxylic acid, Structure 6 is a triazole carboxamide of L-ribofurasonyl, Structure 7 is a triazole carboxamide of 5'-acetyl-L-ribofurasonyl and Structure 8 is a triazole carboxamide of 5'-acetyl-ct-L-ribofurasonil. While it is generally contemplated that the metabolic products of Levovirin ™ are formed as a product of an enzymatic reaction, it must also be recognized that under suitable intra- or extracellular conditions in a cellular system, the metabolites can be formed without an enzymatic reaction. In this way, the formation of metabolites from Levovirin ™ may include redox reactions (particularly oxidation), enzymatically catalyzed reactions (eg, hydrolysis), and photochemical reactions. The contemplated reaction products are typically degradation products of Levovirin ™, however, it should be recognized that the metabolites may also include products formed by the addition of chemical groups eg, glycosylation, or acetylation), and that these modified compounds may be subject to to subsequent degradation in the same or different behavior. While it is generally contemplated that metabolites have a significantly reduced pharmacological effect compared to Levovirin ™, it should be appreciated that metabolites may have a pharmacological effect similar to Levovirin ™. For example, the portion of triazole or ribose can serve as an effector (for example, allosteric inhibitor). It is further contemplated that of a particular dose of Levovirin ™ administered to a system, between about 20% and 50%, preferably between 51% and 75%, more preferably between 76% and 99%, and much more preferably 100% are excreted in a non-metabolized form.

And emplos Liver immunosuppression targeting a target using Ribavirin Three controlled studies with placebos of Ribavirin in the treatment of chronic hepatitis C were conducted. These studies included 134 patients treated with Ribavirin and 97 patients who received a placebo. There were also two uncontrolled Phase II studies that included a total of 23 patients treated with Ribavirin. The primary response parameter was the normalization or reduction of ALT (transaminase) levels in the serum. The response was also assessed in terms of elimination or reduction of HCV RNA levels in the serum and improvement in liver histology assessed by changes in the Knodell records or indices.

In all controlled and uncontrolled studies, using the response definitions specified in the protocols and in the analysis plans, Ribavirin was significantly statistically superior to placebo in normalizing and reducing ALT levels during the treatment. In integrated analyzes based on all patients in the controlled studies, using a uniform definition of response that includes normalization of ALT at the end of treatment or a clinically significant level of partial response, 46% of patients treated with Ribavirin were responders compared to 4% of patients treated with placebo (p < 0.001). The patients responded generally after two or three months of treatment and the response remained as long as the treatment continued. There was no evidence of loss of response to ALT with the increase in treatment duration. After removing Ribavirin at the end of the active treatment phase, 11.5% of the responders had a sustained response through the complementary period. With respect to improvement in liver histology, in each of the controlled studies there was a non-significant bias in favor of Ribavirin in the changes in the total Knodell records and many of the component records. The analysis of the data Combined by analyzing the covariance using Knodell's baseline record as the covariant resulted in statistically significant differences in favor of Ribavirin for the total record and each of the component records. Thus, in the controlled studies, compared to all patients treated with Ribavirin with patients treated with placebo, Ribavirin had a modest but real effect on the improvement of liver histology. Within the Ribavirin group, the comparison of responders to ALT and non-responders revealed that responders to ALT experienced a significantly greater improvement in liver histology compared to non-responders to ALT. The significant decrease in the total Knodell registry was approximately two points for the responders to ALT compared with one point for all patients treated with Ribavirin. It is generally considered by hepatologists that a decrease in the total Knodell score of two points is clinically significant. Thus, there was a statistically significant positive correlation between the response to ALT and a clinically significant degree of improvement in liver histology. In all the studies, the primary endpoint was defined as a reduction in the level of ALT. In all the studies, a complete response to ALT was defined as the Normalization of the ALT level at the end of the treatment. A partial response to ALT was defined as a reduction of either 50% or greater at the end of the treatment of the baseline value of the patients, or a reduction of 50% or greater to a level no greater than 1.5 times the upper limit of normal. In studies 92-001 and 91-DK-178, the treatment groups were compared with respect to the effect of the study drug on symptoms relevant to hepatitis. This could not be done in study CT00 / 002 because the form of the case report did not allow the systematic collection of symptom data. In study 92-001, there was a statistically significant difference in favor of Ribavirin due to decreased fatigue. At the end of the treatment and at the end of the supplemental period, a higher proportion of the patients treated with Ribavirin showed some improvement of the baseline in fatigue compared with patients treated with placebo (p = 0.04 by the end of treatment and p = 0.006 for the end of the complementary period). In this study, there were no significant differences between the treatment groups for any of the other symptoms. In study 91-DK-I78, there were significant, isolated differences between treatment groups in individual symptoms in individual visits, some they favored the group treated with placebo and some of the group treated with Ribavirin, but there were no overall trends in favor of any treatment group. Table 1 shows the response ratios in terms of improvement in liver histology. There were no statistically significant differences between the treatment groups in the changes in the Knodell records in any of the studies, although there were numerical trends in favor of Ribavirin. In study CT00 / 002 there was a difference in favor of Ribavirin in one of the secondary parameters (aggregates of lifoids, p = 0.05).

Protocol Definition of the Protocol for the Definition of the Analysis Plan Result Response Response Comparison of the groups of the same No significant difference treatment with respect to the between groups of changes of the pre-treatment after-treatment in each of the Knodell records of the patient Long-term response: Comparison of the groups of No significant difference Improvement in the histopathology treatment with respect to the between-groups of the liver by changing the pre- to post-treatment treatment "classification in anonymity of each of the records of all Knodell liver biopsies from the patient for the degree of liver damage current using the Wilcoxon test for independent samples "CT00 / 002 Improvement in the degree of comparison of the groups of No significant difference inflammatory activity of the pre-treatment with respect to those between the post-treatment groups assessed pre-treatment changes post-treatment treatment using the nodell records in each of the patient's Knodell records Changes in pre-treatment after treatment in other parameters Reduction in histological samples that are thought to be lymphoid aggregates in the hepatitis C-relevant group treated with Ribavirin Table 1-Comparison of Results of Controlled Studies -Histology of the liver Additional analyzes were performed with respect to different studies. However, in order to make the results of these analyzes more significant, the data from the control studies were combined to make the dimensions of the samples larger.

Results of the Integrated Analysis Analysis of Response to Ribavirin in Accordance with Relevant Effectiveness Criteria-Response to ALT During Ribavirin Therapy For the purposes of integrated effectiveness analyzes, the following definitions of the response to ALT were used: Complete Response: Return to within the normal range at the end of treatment.

Partial Respect: Reduction of 50% or greater of the level of the baseline of the patient to within 1.5 times the upper limit of the normal at the end of the treatment.

Responder: Meets the previous definitions of either the complete or partial response. The definition of "responder" was determined by applying in a diagram the values of ALT over time for the groups of patients that fit with several definitions of response used within each study. (The data was adjusted with a flexible cubic rule that facilitates the Reinsch 1967 function). Three definitions of the answer were used: to. Complete response = ALT in a normal range at the end of the treatment. b. Partial response (A) = reduction of 50% or greater from the baseline level of the patient to within 1.5 times the upper limit of normal at the end of treatment. c. Partial response (B) = reduction of 50% or greater of the level of the baseline of the patient at the end of the treatment.

All other patients were considered non-responders. Diagrams were also constructed for non-responders treated with Ribavirin - within each study and for all placebo-treated patients (responders and non-responders) within each study. The three curves for the "full response" showed that this response was achieved after approximately one third of the treatment period and remained thereafter. The three curves for the "partial response (A)" showed a similar response pattern. The three curves for the "partial response (B)" clearly showed more variability of the ALT levels during the treatment periods. The diagrams for the non-responders treated with Ribavirin and the diagrams for patients treated with placebo demonstrated, as expected, a dispersion of data points that did not change in any recognizable pattern through treatment and complementary periods. It was decided that the definition "partial response (B)" was inappropriate for the purpose of the integrated effectiveness analyzes. Due to the consistent pattern of response demonstrated by the definitions "complete response" and "partial response (A)", and the fact that these definitions are clinically significant, it was decided that for the purpose of integrated analyzes of effectiveness a "response" would be defined as either "full response" or "partial response (A)". Table 2 shows the results for each study and for the combined database, using the previous definition of the response to ALT. The proportions of the responders in the two treatment groups were compared using either a Chi-square or Fisher's Exact test.

Study Ribavirin n / N (%) Placebo n / N (%) Value p 92-001 15/28 (53.6) 1/30 (3.3) < 0.001 91-DK-178 11/29 (37.9) 1/29 (3.4) < 0.001 CT00 / 002 32/70 (45.7) 2/36 (5.6) < 0.001 Combined database 58/127 (45.7) 4/95 (4.2) < 0.001 n = Number of patients with a response to ALT (integrated definition), N = All patients treated (population proposed for treatment) minus those without valid observations not missing. Table 2: Percentage of ALT Response Proportions.

To identify the ALT value corresponding to the end of the treatment, the last valid observation not missing, returning to a maximum of two visits, was carried out for those patients who lacked this true value. This same policy was used in two of the three controlled studies (91-DK-178 and CT00 / 002). Nine patients in the group treated with Ribavirin and two patients treated with placebo did not have available a valid observation not missing. The proportions of response to ALT were consistent across the three controlled studies and ranged from 37.9 to 53.6%. When the data were combined, the response rate to ALT was 45.7%. In all cases, the proportions of response to ALT for patients treated with Ribavirin were significantly statistically superior to the proportions in patients treated with placebo. In the group treated with placebo, the proportions of response to ALT were consistently low, and ranged from 3.3 to 5.6% and 4.2% when data were combined.

Response to ALT in the Complementary Period Table 3 summarizes the proportions of the sustained response in studies 92-001 and 91-DK-178 and in these two studies combined. The individual study, definitions of the plan of analysis of the sustained response were used. A sustained responder is essentially a patient with either normalization of ALT or a partial response at the end of treatment, who still meets any of these criteria during the entire complementary period. It was not possible to provide this same analysis for study CT00 / 002 because very few patients had complete ALT data during the entire complementary period.

Study Ribavirin n / N (%) Placebo n / N (%) 92-001 1/15 (6.7) 0/1 (0.0) 91-DK-178 2/11 (18.2) 0/1 (0.0) Database combined 3 / '26 (11.5) 0/2 (0.0) n = Number of patients with a sustained response to ALT, N = Number of patients with complete or partial response at the end of treatment (definitions of the study analysis plan) Table 3: Percentage of Sustained Response Proportions to the ALT - Definitions of the Protocol.

In the two studies analyzed, the proportions of sustained response to ALT were 6.7 to 18.2% for patients treated with Ribavirin compared to 0% for patients who received placebo. Due to the low sample size and the very low number of placebo responders, no statistical analysis was performed.

Improvement in Knodell Records Within each of the three controlled studies, there was a consistent numerical trend in favor of Ribavirin in changes in total records and in many of the component records. This same trend was apparent in this way when the data from the three studies were combined. The trend applies not only to improved records but also to worsening, which indicates that even if none of the patients in any treatment group improves, then fewer patients in the Ribavirin-treated group get worse. This is an important observation that considers that one goal of treatment is to prevent the deterioration of a chronic and progressive condition. The analysis of the data combined by the chi-square CMH test does not reveal any statistically significant difference. Analyzes of the combined data by the analysis of variance (used in the 92-001 and 91-DK-178 studies) revealed a statistically significant difference in favor of Ribavirin for the total Knodell record but not for any of the records of the components. Liver histology data were further examined by covariance analysis, using the Knodell registry of the baseline as a covariant. The regression analysis of Knodell's baseline records against the end of treatment records for all patients treated with Ribavirin and combined placebo treated resulted in a slope of less than 1.0 but greater than 0. This indicated that Knodell's baseline record influenced the expectation of treatment outcome, regardless of any difference between Ribavirin and placebo. Where the regression slope differs markedly from 1.0, the analysis of the covariance is a more appropriate test than the analysis of variance (Fisher 1951). The result of the analysis of the covariance is shown in Table 4. The average changes in the records of the patients treated with Ribavirin were only small, but due to the small variances, the differences of the placebo are statistically significant.

It is interesting to note that only the nodell sub-registry that does not improve is fibrosis and that there is less deterioration in the Ribavirin group than in the placebo group.

Average Change in the Baseline Region at the end of the Treatment Component of Knodel l Ribavirin N = 107 Placebo N = 78 Value p Activity Peri portal -0.40 -0.01 0.0004 and necrosi s Infl ation portal -0.30 -0.10 0.0206 Necrosi s Lobul ar -0.33 -0.13 0.0019 Fibrosi s +0.07 +0.25 0.0071 Total Record -1.11 -0.05 0.0091 Table 4: Comparison of Ribavirin and Placebo in Terms of Changes in the Knodell Records of the Baseline at the End of the Treatment - Analysis of Covariance Using the Registry of Base Line Knodell as Covariate of All Combined Phase III Studies.

Review of the Correlation between ALT Response and Improvement in Knodell Records In each of the three controlled studies, Ribavirin was significantly more effective than placebo in normalizing and reducing ALT levels (an elevated level of ALT in the serum is a biochemical indicator of liver inflammation). There was also a correlation between the response to therapy with Ribavirin in terms of normalization or reduction of the level of ALT within individual patients, and by an improvement in liver histology determined by the Knodell records. It was found that there was actually a consistent trend towards a positive relationship between the responses to ALT and the improvement in the Knodell registries when both parameters were treated in a categorical way. In the combined database, this trend was statistically significant for the total Knodell registry (p = 0.008), fibrosis (p = 0.014), and Portal Inflammation (p = 0.022) using the Cochran-Mantel-Haenszel (CMH) test chi-square (Table 5-7) Respondent Nonresponder Protocol Response n% n% value P1 92-001 Improved 7 46.7 4 33.3 0.099 No change 7 46.7 3 25.0 Worsened 1 6.7 5 41.7 91-DK-178 Improved 10 90.9 7 38.9 0.021 No change 1 9.1 5 27.8 Worsened 0 0.00 6 33.3 CT00 / 002 Improved 11 42.3 12 48.0 0.171 No change 11 42.3 5 20.0 Worsened 4 15.4 8 32.0 Integrated Improved 28 53.8 23 41.8 0.008 Unchanged 19 36.5 13 23.6 Worsened 5 9.6 19 34.5 N = Number of patients in the study, n = Number of patients in the response category,% = (n / N) * 100 1 CMH statistics, * P < 0.05 Table 5: Knodell's Response Status by the Studies Controlled - Total by Response a. the the .

Responder Non-responder Protocol Response n% n% value P1 92-001 Improved 7 13.3 1 0.00 0.434 No change 12 80.0 11 91.7 Worsened 1 6.7 1 8.3 91-DK-178 Improved 5 45.5 2 11.1 0.119 No change 4 36.4 11 61.1 Worse 2 18.2 5 27.8 CT00 / 002 Improved 6 23.1 1 4.0 0.120 No change 18 69.2 20 80.0 Worse 2 7.7 4 16.0 Integrated Improved 13 25.0 3 5.5 0.014 Without change 34 65.4 42 76.4 Impaired 5 9.6 10 18.2 N = Number of patients in the study, n = Number of patients in the response category,% = (n / N) * 100, 1 CMH statistics, * P < 0.05 Table 6: Knodell's Response to Controlled Studies Fibrosis by the Response to ALT Respondent Non-responder Protocol Response n% n% value P1 92-001 Improved 5 33.3 3 25.0 0.220 Unchanged 9 60.0 5 41.7 Worsened 1 6.7 4 33.0 91-DK-178 Improved 5 45.5 4 22.2 0.227 Unchanged 6 54.5 11 61.1 Worsened 0 0.00 3 16.7 CTOO / 002 Improved 5 19.2 6 24.0 0.159 No change 21 80.8 16 64.0 Worsened 0 0.00 3 12.0 Integrated Improved 15 28.8 13 23.6 No change 36 69.2 32 58.2 Worsened 1 1.9 10 18.2 N = Number of patients in the study, n = Number of patients in the response category,% = (n / N) * 100, CMH statistics * P < 0.05 Table 7: Knodell Response Status by Controlled Studies - Portal Inflammation by Response to ALT.

The relationship between the response to ALT and improvement in liver histology was further studied in order to quantify the improvement in liver histology in patients who respond to Ribavirin, and to determine if there was a subgroup of patients who obtained a more substantial clinical benefit from treatment with Ribavirin. In each of these three controlled studies, the ALT responders treated with Ribavirin and the non-responders were compared in terms of the average changes in the total Knodell records during the course of treatment. This analysis, shown in Table 8, in this way quantifies the directional changes exhibited in Table 5. It can be seen that in each study there was a correlation between the response to ALT and improvement in liver histology, in which the response to ALT was associated with greater improvement in the histology of the liver compared with non-responders to ALT. This effect was particularly evident in the 91-DK-178 study, where there was a reduction of the average Knodell score of 4.09 in the ALT responders compared to 0.17 in the non-responders to ALT. A regression model was used to examine the relationship between the response to ALT and changes in the Knodell records. This revealed that in all three studies the response to ALT was a significant predictor of improvement in liver histology. Thus, the normalization or reduction of ALT correlates with the improvement in liver histology in patients with hepatitis C treated with Ribavirin, and in patients who achieve a response to ALT are likely to obtain a substantial clinical benefit. In patients treated with Ribavirin who do not achieve a response to ALT, there seems to be no clinical benefit compared to patients who received the placebo.

Study CT00 / 002 92-001 91-DK-178 Combined Database Duration of Treatment 24 36 48 (week) Change of Knodell Average -1.23 -1.47 -4.09 -1.90 (Interval) in (-7.4) (-8.2) ( -9.0) (-9 4) Responders to the ALT n = 26 n = 15 n = 11 n = 52 Change of Knodell Average -0.96 +0.58 -0.17 -0.36 (Interval) in (-9.4) (-3.6) (-6.7) (-9.7) no Responders n = 25 n = 12 n = 18 n = 55 Value P ** 0.004 0.0001 0.002 0.0001 Change of Knodell Average -1.10 -0.56 -1.65 -1.11 (Interval) in all Patients (-9.4) (-8.6) (-9.7 ) (-9.7) Treatments with Ribavirin n = 51 n = 27 n = 29 n = 107 Change of Knodell Average -0.09 - + 0.44 -0.52 -0.51 (Interval) in all Patients (-4.4) (-3.5) (- 8.4) (-8.5) Treatments with Placebo n = 23 n = 27 n = 27 n = 77 Value P NS NS NS 0.01 * Response to ALT was defined as normalization at the end of treatment or reduction of 50% or greater from the baseline to within 1.5 times the upper limit of normal at the end of the treatment. "Regression analysis: Table 8 Thus, in summary, the phase III program on Ribavirin in chronic hepatitis C consisted of three randomized, double-blind, placebo-controlled, parallel-group studies with a total of 134 patients were randomized to receive Ribavirin and 97 to receive the placebo.The response to treatment was assessed, using three parameters: 1. Reduction or normalization of ALT level (ALT elevation is a biochemical marker of liver inflammation). 2. Improvement in liver histology as evidenced by a reduction in the Knodell registry (the Knodell registry system quantifies the degree of damage to the liver by assigning records to various microscopic, relevant characteristics and adding these sub-registers to give the record total). 3. Elimination of hepatitis C virus from the blood, or a reduction in the amount of the virus present.

Of the 134 patients in the phase III studies, there were 101 patients with complete data on ALT levels, Knodell records and virus levels. Among these 101 patients, 24 patients met the criteria for an optimal clinical response to therapy with Ribavirin. The criteria are the normalization or clinically significant reduction of the ALT level and the reduction in the total Knodell record of two or more points. For these 24 patients, the clinical response was obtained without an accompanying reduction in the level of virus in the blood. Table 9 below summarizes the data on ALT levels and Knodell records for the 24 patients who responded compared with the remaining 77 patients who demonstrated lower response grades.

Responders N = 24 No Responders N = 77 ALT baseline 142.5 (52-269) 176.9 (35-629) average (interval) in U / L ALT average at the end of 36.8 (21 -62) 91.7 (13-286) treatment (interval) * U / L Reduction in the record of 4.1 (2-9) 0.15 (-7 to +9) Average Knodell (interval) * the upper or normal limit is 40 U / L Table 9 In this way, the modalities and specific applications of nucleosides, nucleotides and their analogs have been described. However, it should be apparent to those skilled in the art that many modifications are possible in addition to those already described without departing from the inventive concepts in this document. Therefore, the inventive content should not be restricted except in the spirit of the appended claims. In addition, in interpreting both the specification and the claims, all terms must be interpreted as broadly as possible consistent with the context. In particular, the terms "comprises" and "comprising" are they must interpret as referring to elements, components or stages in a non-exclusive manner, which indicate that the elements, components or stages referred to may be present, or used, or combined with other elements, components or stages that are not expressly referred to.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (54)

1. Claims Having described the invention as above, the content of the following claims is claimed as property: 1. A compound, characterized in that it has the structure: R where R is P032", (P03) 23 ~, or (P03) 3 ~ 2. A compound, characterized because it has the structure: 3. A compound, characterized because it has structure: wherein W is -N (RX) (R2) or = NRi, wherein Ri and R2 are independently hydrogen, linear alky, branched alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl or aryl. 4. The compound according to claim 3, characterized in that Ri or R2 further independently comprise a nitrogen atom, an oxygen atom, a sulfur atom and a halogen atom. 5. The use of a compound according to claim 1, claim 2, claim 3 or claim 4 in the preparation of a medicament for treating a viral infection in a patient comprising administering the medicament in an effective dosage to inhibit viral propagation . 6. The use according to claim 5, wherein the dosage is between 50-500 mg / day. 7. The use according to claim 5, wherein the dosage is between 500-2500 mg / day. The use according to claim 5, wherein the viral infection is selected from the group consisting of an infection with HIV, an infection with HCV, an infection with HBV, an infection with RSV, an infection with influenza virus, and an infection with parainfluenza virus. 9. The use according to claim 5, wherein it further comprises co-administering to the patient a cytokine. 10. The use according to claim 9, wherein the cytokine is an interferon. 11. The use according to claim 10, wherein the interferon is interferon alfa-2b. 12. The use according to claim 5, wherein it further comprises administering Ribavirin. 13. The compound according to claim 1, characterized in that R is P032_. The use of a compound according to claim 13 in the preparation of a medicament for treating a viral infection in a patient comprising administering the medicament in an effective dosage to inhibit viral propagation. 15. The compound according to claim 1, characterized in that R is (PC> 3) 23 ~. The use of a compound according to claim 15 in the preparation of a medicament for treating a viral infection in a patient comprising administering the medicament in an effective dosage to inhibit viral propagation. 17. The compound according to claim 1, characterized in that R is (P03) 34 ~. 18. The use of a compound according to claim 17 in the preparation of a medicament for treating a viral infection in a patient comprising administering the medicament in an effective dosage to inhibit viral propagation. 19. A method for increasing the selectivity of a pharmacologically active molecule with respect to a pharmacological effect in a target cell, characterized in that it comprises: providing a drug, wherein the drug is 1-β-L-ribofuranosyl-1, 2, 4 -triazole-3-carboxamide; modifying the drug with a modifying group, wherein the modifying group is covalently bound to the drug by means of a nitrogen atom; and wherein the modifying group is enzymatically removed from the drug in the target cell. The method according to claim 19, characterized in that the modifying group is = NH, and wherein the modifying group is covalently bound to a carbonyl atom in the drug. The method according to claim 19, characterized in that the modifier group is -N (Ri) (R2) or = NRi, where Ri and R2 are independently hydrogen, linear alkyl, branched alkyl, alkenyl, alkynyl, aralkyl , aralkenyl, aralkynyl or aryl. 22. The method according to claim 21, characterized in that Rx or R2 further independently comprise a nitrogen atom, an oxygen atom, a sulfur atom or a halogen atom. The use of a compound according to claim 1, claim 2 or claim 3 in the preparation of a medicament for treating a disease characterized by the inflammation of an organ in a patient, comprising: - administering the medicament to the patient in a dosage that (a) causes systemic immunomodulation and not systemic immunosuppression of Type I and Type II responses, and (b) causes immunosuppression of Type I and Type II responses in the patient's organ. 24. The use according to claim 23, wherein the compound is a compound according to claim 1. 25. The use according to claim 23, wherein the compound is a compound according to claim 2. 26. The use according to claim 23, wherein - the compound is a compound according to claim 3. 27. The use according to claim 23, wherein the organ is a liver, and wherein the liver is infected with a virus. 28. The use according to claim 27, wherein the virus is a HCV virus. 29. A method for stimulating neuronal growth, characterized in that it comprises: recognizing that a compound having structure I is effective in stimulating the growth of neurons within a given concentration range; wherein Y is a? -β-L-ribofuranosyl, a? -β-L-ribofuranosyl-5-phosphate, a? -β-L-ribofuranosyl-5-diphosphate, a? -β-L-ribofuranosyl-5- triphosphate, a? -β-D-ribofuranosyl, a? -β-D-ribofuranosyl-5-phosphate, a? -β-D-ribofuranosyl-5-diphosphate, or a? -β-D-ribofuranosyl-5-triphosphate; and provide the neurons with the compound within the given concentration range. 30. The method according to claim 29, characterized in that the compound is Ribavirin. 31. The method according to claim 29, characterized in that the compound is a phosphorylated Ribavirin. 32. The method according to claim 29, characterized in that the compound is Levovirin ™. 33. The method according to claim 29, characterized in that the compound is Levovirin ™, phosphorylated R. 34. The method according to claim 29, characterized in that the compound is administered as part of a treatment of a disease in a patient, in an effective dosing range to increase a Type I response and decrease a Type II response. in the patient. 35. The method of compliance with the claim 29, characterized in that it also comprises targeting unipolar neuronal cells in the neurons. 36. The method according to claim 29, characterized in that it also comprises targeting the bipolar neuronal cells in the neurons. 37. The method according to claim 29, characterized in that the neurons are part of a neuronal tissue that includes at least four of. the following cell types, an astrocyte, a dendrocyte, a myelin-coated cell, a glial cell, a neuronal cell unipolar, a bipolar neuronal cell, a multipolar neuronal cell, and a receptor cell. 38. An antiviral drug composition, characterized in that it comprises: a first compound having a direct antiviral effect and an indirect antiviral effect; and a second compound that increases a total antiviral effect, wherein the total antiviral effect includes the direct antiviral effect and the indirect antiviral effect, and wherein the second compound specifically binds to a haftene selected from the group consisting of a viral protein and a cytokine. 39. The antiviral drug composition according to claim 38, characterized in that the first compound comprises a nucleoside analogue. 40. The antiviral drug composition according to claim 38, characterized in that the nucleoside analogue is Ribavirin. 41. The antiviral drug composition according to claim 38, characterized in that the nucleoside analogue is Levovirin ™. 42. The antiviral drug composition according to claim 38 or claim 39, characterized in that the nucleoside analogue is in the form of a prodrug. 43. The antiviral drug composition according to claim 38, characterized in that the direct antiviral effect comprises an inhibition of a viral replication. 44. The antiviral drug composition according to claim 38, characterized in that the indirect antiviral effect comprises a change from a balance of Type 1 / Type 2 to a response of Type 1. 45. The antiviral drug composition of -conformity with claim 38, characterized in that the indirect antiviral effect comprises a suppression of a Type 1 and a Type 2 response. 46. The antiviral drug composition according to claim 38, characterized in that the second compound comprises an antibody. 47. The antiviral drug composition according to claim 46, characterized in that the antibody is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a synthetic antibody and an antibody fragment. 48. The antiviral drug composition according to claim 38, characterized in that the viral protein is a protein of a virus selected from the group consisting of an HIV virus, hepatitis virus, influenza virus, parainfluenza virus and RSV virus. 49. The antiviral drug composition according to claim 38, characterized in that the viral protein is a reverse transcriptase. 50. The antiviral drug composition according to claim 38, characterized in that the cytokine is a Type 1 cytokine. 51. The antiviral drug composition according to claim 38, characterized in that the first compound and the second compound have a sine effect gistico. 52. The antiviral drug composition according to claim 38, characterized in that at least one of the first compound and the second compound selectively accumulates in an organ. 53. The antiviral drug composition according to claim 52, characterized in that the organ is selected from the group consisting of a liver and a brain. 54. The antiviral drug composition according to claim 38, characterized in that the first compound is Ribayirin and the second compound is an antibody that binds specifically to a cytokine of type