SI9820003A - Cytokine related treatments of disease - Google Patents

Abstract

Nucleosides and other compounds to selectively modulate Th1 and Th2 responses relative to each other in the treatment of disease. In one aspect of the invention, administration of a nucleoside or other compound reduces the dosage at which a primary drug is administered. In another aspect of the invention, an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines. In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Th1 activity without significantly reducing Th2 activity. In yet another aspect of the invention, a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Th1 or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result.

Description

DISEASE TREATMENT RELATED TO CYTOKINS

This application refers to the advantage (1) of provisional application with serial no. 60/028586, filed April 23, 1997; (2) Provisional applications with serial no. 60/043974, filed April 23, 1997; (3) Provisional applications with serial no. No. 60/055487, filed Aug. 12, 1997, and (4) Provisional applications with serial no. 60/036094, filed January 14, 1997.

FIELD OF THE INVENTION

The present invention is in the field of nucleosides.

BACKGROUND OF THE INVENTION

The mammalian immune system contains two major classes of lymphocytes: B lymphocytes (B cells) derived from the bone marrow; T lymphocytes (T cells) derived from the adrenal gland. B cells are mainly responsible for the overall immune response (i.e.: antibody production), whereas T cells are mostly responsible for cell-mediated immunity.

T cells are generally divided into two subclasses: helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes including B cells, cytotoxic T cells and macrophages by releasing soluble signaling proteins called cytokines, which are involved in the cell-mediated immune response. In our case, lymphokines are a subset of cytokines.

Helper T cells are divided into two subclasses: Thl and Th2. Thl cells (also known as type 1 cells) synthesize interleukin 2 (IL-2), tumor necrosis factor (TNFα) and interferon gamma (IFNγ) and are primarily responsible for cell-mediated immune responses such as delayed hypersensitivity and immunity to viruses . In contrast, Th2 cells (also known as type 2 cells) synthesize the interleukins IL-4, IL-5, IL-6, IL-9, IL-10 and IL13 and are primarily involved in assisting the general immune response that occurs upon allergen response, for example: upon activation of IgE and IgG4 isotype antibodies (Mosmann, 1989, Annu Rev Immunol 7: 145-173).

The expression Thl and Th2 response used herein includes the full range of effects triggered by the induction of Thl and Th2 lymphocytes. Among other such responses include fluctuations in the synthesis of responsive cytokines via transcription, translation, secretion and other possible mechanisms, increased proliferation of responsive lymphocytes, and other effects associated with increased cytokine production, including the motility effect.

Previous applications, each referenced herein, relate to our recent findings involving the effects of different nucleosides (as defined herein, such that the definition includes natural nucleoside derivatives and analogs) on selectively regulating the response of lymphocytes relative to one another. Among other things, we have shown that either Thl and Th2 responses can be selectively inhibited while the other is induced or relatively unaffected, or one of Thl or Th2 responses is selectively induced while the response of the other is inhibited or relatively unchanged. We found that nucleosides act in selectively mediating Thl and Th2 responses relative to each other via two models. Among other things, nucleosides that tend to inhibit or induce both Thl and Th2 activities in relatively high doses have a selective effect on Thl and Th2 relative to each other in relatively small amounts.

The mechanisms by which nucleosides and other compounds selectively affect the Th1 and Th2 responses relative to one another are still unexplained. One possible explanation is that effective nucleosides affect the amount of guanosine triphosphate (GTP), which in turn affects the rate of cytokine synthesis. Theoretically, the concentration of Thl and Th2 cytokines may be affected by relatively large changes in the available GTP, while the relatively small changes in the concentration of available GTP may differently affect the concentration of Thl and Th2 cytokines.

The effect of 2-PD-ribofuranosylthiazole-4-carboxamide (Thiazofurin), a synthetic analogue of Cnucleoside, on the amount of GTP confirms the above explanation. Tumor cells are characterized by high inosine monophosphate dehydrogenase (IMP DH) activity. IMP DH is an enzyme that regulates the rate of GTP synthesis (Weber, G. 1991. IMP dehydrogenase and GTP as a target in human leukemia treatment. Adv Exp Med Biol 309B: 287-292). Thiazofurine selectively blocks IMP DH activity and inhibits guanidine synthesis, which in turn forces various tumors to fail (Weber, G. 1989, Critical issues in chemotherapy with Tiazofurin. Adv Enzyme Regul 29: 75-95). Typical starting amounts of Tiazofurin are about 4400 mg / m ² and combined with amounts of about 1100 to 3300 mg / m 2 ^? . With these amounts, the response of both Thl and Th2 is greatly reduced, causing the immune system to be silenced. One aspect of the present invention is the use of Tiazofurin in much smaller amounts, in the range of one tenth to one half of the amount presented above, which is sufficient to specifically inhibit the Th1 response or Th2 response without significantly affecting the response of the second class of cytokines.

The influence of LPD-ribofuranosyl-1,2,4-thiazole-3-carboxamide (Ribavirin) also supports the theory presented. Ribavirin is a potent broad-spectrum antiviral agent that also inhibits IMP DH (Yamada, Y. et al. 1988. Action of the active metabolites of Tiazofurin and Ribavirin on purified IMP dehydrogenase. Biochem 27: 2193-2196). Ribavirin inhibits IMP DH by a different mechanism than Thiazofurin by binding to another site of the enzyme molecule. Ribavirin is converted to the active metabolite, ribavirin monophosphate (RMP), which in turn inhibits the IMP DH enzyme at the ΙΜΡ-ΧΜΡ site. As with Tiazofurin, the affinity of the enzyme to the active form of Ribavirin is much greater than that of natural metabolites. At relatively high doses of about 2200 mg / m ² to about 1200 to 1500 mg / day in adults, Ribavirin lowers IMP DH activity to such an extent that the Thl and Th2 response is greatly reduced. At relatively low doses of about 600 to 1000 mg / day, Ribavirin increases the Th1 response and decreases the Th2 response.

Despite the unexplained mechanics, we have found a lot of useful in selectively modulating Thl and Th2 responses relative to one another. We concluded that specific modulation of Thl relative to Th2 may be useful in treating the vast majority of diseases such as: infections, inflammations, tumors, and increased susceptibility to autoimmune diseases.

The discoveries are particularly important because the current treatment for many diseases has limited efficacy, side effects, or a combination of both. Treatment of an autoimmune disease, for example, is often associated with palliative criteria, the removal of toxic antibodies (as in: muscle weakness) and the prescription of dangerous drugs, including corticosteroids, chloroquine derivatives, antimetabolic or antitumor drugs, and drugs such as: cyclosporins the target is the immune system of the cells.

SUMMARY OF THE INVENTION

The application relates to the use of nucleosides in relatively low amounts to selectively modulate Thl and Th2 responses relative to one another in the treatment of the disease. According to the invention, the use of a nucleoside or other compound reduces the amount of the prescribed primary drug in a patient. From the aspect of the invention, abnormalities reflecting the increased response of one group of cytokines are treated with the prescribed nucleoside or another component that increases the response of another group of cytokines. The patient is preventively treated with the prescribed nucleoside or other compound that selectively reduces Th1 activity without a marked decrease in Th2 activity. A nucleoside or other component is administered to a patient in an amount that reduces the amount of GTP by indirectly selectively reducing the response of one of the Th1 or Th2 cytokines without noticeably lowering the other group of cytokines. The controlled release of the drug makes it much easier to achieve results.

Examples of nucleosides that are expected to be effective in said manner are D- and L-forms of: (a) bicyclic nucleosides corresponding to any of formulas 1,1-A to 1-F and (b) monocyclic nucleosides, corresponding to any of formulas 2 to 5.

Examples of primary compounds that are intended to be effective in the above-mentioned manner are: antiviral agents such as: Ribavirin, acyclovir (acyclovir) and AZT ™; fungicides such as: tolnaftate, Fungizone ™, Lotrimin ™, Mycelex ™, nystatin (Nystatin) and amphoteracin (Amphoteracin); parasite-acting compounds such as: Mintezol ™, Niclocide ™, Vermox ™ and Flagyl ™; agents for intestinal diseases such as: Immodium ™, Lomotil ™ and Phazyme ™; anticancer agents such as: Adriamycin ™, Cytoxan ™, Imuran ™, Methotrxate ™, Mithracin ™, Tiazofurin ™, Taxol ™; dermatological agents such as: Aclovate ™, Cyclocort ™, Denorex ™, Florone ™, Oxsoralen ™; coal tar and salicylic acid; migraine preparations such as: ergotamine compounds; steroids and immunosuppressants not listed above and including cyclosporine, Diprosone ™, hydrocortisone, Floron ™, Lidex ™, topicort (topicort) and valizone (Valisone) and a metabolic agent such as insulin.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following terms, which are used anywhere in this specification, are meant as indicated below:

The terms a and p represent the specific stereochemical configuration of the substituent on the asymmetric carbon atom in the chemical structure.

The term abnormal refers to conditions associated with a medical condition. The Th1 and / or Th2 response resulting from an autoimmune disease is considered herein as an abnormality of the responding cytokines, despite the fact that the cytokine response is a normal disease response.

The term aryl refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (for example: phenyl) or two fused rings (for example: naphthyl) and may be optionally substituted by a hydroxyl group, lower alkyl, chloro or cyano group.

The term effective amount refers to the amount of a compound of formula (I) that normalizes the immune response or enhances the immune response to reduce the effect of infection.

The term enantiomers refers to a pair of stereoisomers, which are mirror images of each other. A 1: 1 ratio enantiomeric mixture of steam is called a racemate.

The term heterocycle refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, which is: N, O or S and each site in the ring may be independently substituted by, for example: hydroxyl, oxo, amino, imino group, lower alkyl, bromo, chloro and / or cyano. Purine and pyrimidines are also included in this group of substituents. The term immune mediator or modulator refers to a natural or synthetic product that is capable of altering the normal or abnormal state of the immune system through stimulation or suppression.

The term isomers refers to various compounds having the same phonula. Stereoisomers are isomers that differ only in the orientation of the atoms in space.

The term L-configuration is used in the present application to interpret the chemical configuration of a ribofuranosyl residue that is bound to a nucleotide. The L-configurations of the sugar residues differ from the ribose residues of the D-configurations, which are found in natural nucleosides, such as: cytosine, adenosine, thymine, guanosine and uridine.

The term lower alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, I-butyl or nhexyl This term is further extended to cyclic, branched or straight chains containing from one to six carbon atoms.

The term monocyclic refers to a monovalent saturated carbocyclic radical having at least one pd carbon atoms replaced by O, N, S, Se or P in the ring, and each possible position can be optionally independently substituted by a sugar moiety or any group such as : bromo, chloro and / or cyano, so that the monocyclic ring may also be flavored (for example: thymidine, J- (2'-deoxy -? - erythro-pentofuranosyl) thymine).

The term nucleoside refers to a compound composed of any pentose or modified pentose moiety attached to a specific heterocycle site or to a neutral site of purine (site 9) or pyrimidine (site 1) or to an equivalent position in the analogue, including both D- and L-forms of nitrogen the two and mono heterocycles shown in Figures 1, 1-A to 1-F and 2 to 5, respectively.

The term C-nucleoside is used to interpret the type of linkage between the sugar moiety and the heterocyclic base. In C-nucleosides, the linkage originates from the C-l site of the ribose sugar moiety and binds to the carbon of the heterocyclic base. The C-type linkage in C-nucleosides is carbon-carbon.

The term D-nucleoside refers to a nucleoside compound containing D-ribose (for example: adenosine).

The term L-nucleoside refers to a nucleoside compound containing an L-ribose residue. The term N-nucleoside is used to interpret the type of linkage between the sugar moiety and the heterocyclic base. In N-nucleosides, the linkage originates from the C-l site of the ribose moiety and binds to the nitrogen of the heterocyclic base. The N-nucleoside bond is carbon-nitrogen.

The term nucleotide refers to a phosphate ester with a nucleoside at position 5 '.

The term pharmaceutically acceptable salt refers to salts, derivatives of inorganic and organic bases and acids.

The term group of protecting compounds refers to groups of chemicals which, in order to prevent the reaction of these atoms in the process of derivatization of other parts of the molecule, bind to an oxygen or nitrogen atom, many skilled in the art of organic synthesis are familiar with oxygen and nitrogen.

The term purine refers to the nitrogen bicyclic heterocycles presented in Figure 1,1-A through 1-F,

The term pyrimidine refers to the nitrogen monocyclic heterocycles presented in Figures 2 to 5.

The term tumor refers to a wide range of independently abnormally growing tissues that can become malignant. The term includes all neoplasms and cancers.

The term cure and treat disease refers to the execution of instructions that may include the administration of one or more drugs to a patient in order to alleviate the signs or symptoms of the disease. Treatment or treatment does not require complete removal of signs or symptoms, does not require recovery and specifically includes instructions, which, however, have only a marginal effect on the patient.

Combinations and methods

The intended combinations of the present invention generally include the primary or first drug and the secondary or second drug, and the contemplated methods of the invention comprise the selection and combination of the first and second drug in combination therapy. It is desirable to provide for the treatment of a patient's disease identified by the abnormal production of at least one of the cytokines, such that the first drug is selected from components that have been shown to treat the disease in monotherapy doses and the second drug, which may be a double-acting nucleoside, as discussed herein and is selected from known components which are characterized by an increase in abnormalities when prescribed in a particular area. The first drug should be prescribed in lower doses than used in monotherapy and the secondary drug should be prescribed outside the range of abnormalities. Given that the secondary drug has a dual mode of action with respect to at least some cytokines, the combination of the drugs is still effective in treating the disease and the administration of the second drug allows the prescribed amounts of the first or primary drug to be reduced,

Examples of primary drugs that are expected to be effective in combination with a modulator selected from Figures 1, 1-A to 1-F and 2 to 5 are antiviral agents such as: interferons, including but not limited to interferon a and γ, Ribavirin , acyclovir (acyclovir) and AZT ™; fungicides such as: tolnaftate, Fungizone ™, Lotrimin ™, Mycelex ™, nystatin (Nystatin) and amphoteracin (Amphoteracin); parasite-acting compounds such as: Mintezol ™, Niclocide ™, Vermox ™ and Flagyl ™; agents for intestinal diseases such as: Immodium ™, Lomotil ™ and Phazyme ™; anti-tumor substances such as: interferon a and γ, Adriamycin ™, Cytoxan ™, Imuran ™, Methotrxate ™, Mithracin ™, Tiazofurin ™, Taxol ™; dermatological agents such as: Aclovate ™, Cyclocort ™, Denorex ™, Florone ™, Oxsoralen ™; coal tar and salicylic acid; migraine preparations such as: ergotamine compounds; steroids and immunosuppressants not listed above and including cyclosporine, Diprosone, hydrocortisone, Floron, Lidex, Topicort and Valisone, and a metabolic agent such as insulin and other drugs not included in the above categories including cytokines such as: IL2, IL4, IL6, IL8, IL10 and IL12. Particularly preferred primary drugs are: AZT, 3TC, 8-substituted guanosine analogue, 2 ': 3'-dideoxynucleosides, interleukin II, interferons such as: ΙαΒ-interferons, tucaresol (tucaresol), levamisole, isoprinosine and cyclolignans.

Examples of effective secondary drugs of the present invention are: D- and L-forms of (a) bicyclic nucleosides corresponding to the generic formulas 1, 1-A to 1-F and (b) monocyclic nucleosides corresponding to formulas 2 to 5. Other effective nucleosides and non-nucleoside effective compounds of the present invention can be identified in the process of searching for such components in vitro when acting on IL-2, TNF-a, IFN-γ, IL-4 and IL-5, as explained in PCT / US97 / 00600 .

The compound of formula 1 is a purine nucleoside with the structure:

wherein R 1, R ₂ , R ₃ , R 4, R ₅ , R ₂ 'and R ₃ ' are independently selected from the group: H, OH, NH ₂ , F, Cl, Br, I, N ₃ , -CN, -OR ', -NR' ₂ , -SR ', -NHNH ₂ , -NHOH, CHO, COOR', CONR ' ₂ , alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl wherein the substituent is selected from F, Cl, Br, I, N ₃ , -CN, -OR, NO ₂ , NR ₂ , -SR, -NHNH ₂ , -NHOH, CHO, COOR, CONR ₂ , and where R 'and RH, alkyl, alkenyl, alkynyl, aryl, aralkyl;

W is O, S, CH ₂ , Se;

Z 1, Z ₂ are independently selected from N, C, CH;

Z ₃ , Z 4, Z 5 are independently selected from the group consisting of: -CR-, -NR-, -O-, -S-, -Se-. C = O, -C = S, -S = O, -CR = CR-, -CR = N-, -N = N-, where R is selected from the group consisting of: H, F, Cl, Br , I, N ₃ , -CN, -OR ', -NR' ₂ , -SR ', -NHNH ₂ , -NHOH, -NO ₂ , CHO, COOR', -CONH ₂ , -C (O) -NH ₂ , -C (S) -NH ₂ , -C (NH) -NH ₂ , -C (NOH) -NH ₂ , = O, -NH, = NO, = NR, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, wherein the substituent is selected from H, OH, NH ₂ , F, Cl, Br, I, N ₃ , -CN, -COOR, -CONR ₂ , -OR , -NR ₂ , -SR, -NHNH ₂ , NHOH, -NO ₂ , and wherein R 'and RH are alkyl, alkenyl, alkynyl, aryl, aralkyl acetyl, acyl, sulfonyl. The chemical bond between Z ₃ and Z ₄ or Z ₄ and Z5 is selected from CC, C = C, CN, C = N, NN, N = N, CS, NS;

X and Y are independently selected from the group consisting of: H, OH, NH ₂ , F, Cl, Br, I, N ₃ , -SNH ₂ , -S (O) -NH ₂ , -S (O ₂ ) -NH ₂ , -CN, -COOR ', -CONR' ₂ , -OR ', -NR' ₂ , -SR ', -NHNH ₂ , NHOH, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl , substituted alkynyl, substituted aryl, substituted aralkyl, wherein the substituent is selected from F, Cl, Br, I, N ₃ , -CN, -OR, NO ₂ , -NR ₂ , -SR, -NHNH ₂ , -NHOH, and where R 'and RH are alkyl, alkenyl, alkynyl, aryl, aralkyl;

The compounds of formula 1-A are 8-substituted β-L- or D-guanosine analogues of the structure:

wherein X is selected from: H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR ₂ , -NHNH ₂ , -NHOH, CHO, -CONH2, -COOR, and -LA; wherein R is selected from alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl, L is a linker and is selected from alkyl, alkenyl, alkynyl, aralkyl, and A is selected from H, -OR ', -SR', - NR ' ₂ , -NHNR' ₂ , -CHO, -COOR ', -CONR' ₂ , wherein R 'is selected from H, Me, Et, allyl, acetyl, -COCF ₃ ;

Υ is selected from H, R, F, Cl, Br, I, N3, CN, OR, SR, NR ₂ , wherein R is selected from H, alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl;

ZjeNaliCH; and

R 1, R ₂ and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O ₂ ) OH.

The compounds of formula 1-B are 7-substituted-8-oxo-- or β-L-guanosine analogs of the structure:

The compounds of formula 1-C are 7-deaza-7,8-mono- or disubstituted or β-L- or D-analogs of guanosine having the structure:

wherein X ₁ and X _{2 are} independently selected from the group H, R, F, Cl, Br, I, N 3, -CN, -OR, -SR, -NR ₂ , -NHNH ₂ , -NHOH, -CHO, -CONH ₂ , -COOR and -LA; wherein R is selected from alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl, L is a linker and is selected from alkyl, alkenyl, alkynyl, aralkyl, and A is selected from H, -OR ', -SR', - NR ' ₂ , -NHNR' ₂ , -CHO, -COOR ', CONR' ₂ , wherein R 'is selected from H, Me, Et, allyl, acetyl, -COCF3;

Υ is selected from H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl;

Z is N or CH; and

R 1, R ₂ and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O ₂ ) OH.

The compounds of formula 1-D are 7-deaza-8-aza-7-substituted- or β-L- or D-analogs of guanosine with the structure:

Formula 1-D wherein X is selected from the group H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR ₂ , -NHNH ₂ , -NHOH, -CHO, - CONH ₂ , -COOR and -LA; wherein R is selected from alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl, L is a linker and is selected from alkyl, alkenyl, alkynyl, aralkyl, and A is selected from H, -OR ', -SR', - NR ' ₂ , -NHNR' ₂ , -CHO, -COOR ', -CONR' ₂ , wherein R 'is selected from H, Me, Et, allyl, acetyl, -COCF ₃ ;

Y is selected from H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR ₂ , where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl , sulfonyl;

Z is NaliCH; and

R 1, R ₂ and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O ₂ ) OH.

The compounds of formula 1-E are thiazolo [4,5-d] pyrimidine - or β-L- or D-nucleosides with the structure:

Formula 1-E

X 1 is O, S, = NH, = NNH 2, = NHOH, = NR, wherein R is selected from alkyl, alkenyl, alkynyl and aralkyl, acyl;

X ₂ is S, O or Se;

Y is selected from the group: H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR ₂ , where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl;

Z is N or CH;

R 1, R ₂ and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O ₂ ) OH.

The compounds of formula 1-F are β-L- or D-purine nucleosides of the structure:

X is selected from H, R, -SNH ₂ , -S (O) NH ₂ , -SO ₂ NH ₂ , F, Cl, Br, I, N ₃ , -CN, -OR, -SR, NR ₂ , where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl, acyl, sulfonyl;

Υ is selected from the group H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR ₂ , where R is selected from H, alkyl, alkenyl, alkynyl and aralkyl, acetyl , acyl, sulfonyl;

Z 1, Z ₂ and Z ₃ are independently selected from N, C, CH;

R 1, R ₂ and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O ₂ ) OH.

The compounds of formula 2 have the structure:

D,

Formula 2

A is independently selected from N or C;

B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR ¹ , CCONH2, CCH3, CR ² or P; R ¹ is independently H, lower alkyl, lower alkylamine, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryl. R ² is independently H, OH, halogen, CN, N ₃ , NH ₂ , C (= O) NH ₂ , C (= S) NH ₂ , C (= NH) NH ₂ .HC1, C (= NOH) NH _2j C (= NH) OMe, lower alkyl, lower alkylamine, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryl or substituted heterocycle;

D is independently selected from CH, CO, N, S, Se, O, NR ¹ , CCONH2, CCH3, CR ² , P or zero, where R ^{1 is} independently H, O, lower alkyl, lower alkylamine, COCH3, lower alkyl alkenyl, lower alkyl vinyl and lower alkyl aryl; R ^{2 is} independently H, OH, halogen, CN, N ₃ , NH ₂ , lower alkyl, lower alkylamine, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryl or substituted heterocycle;

X is independently O, S, CH ₂ or NR, where R is COCH ₃ ;

R 1 and R 4 are independently selected from H, CN, N ₃ , CH ₂ OH, lower alkyl and lower alkylamine;

R ₂ , R ₃ , R ₅ , R ₆ , R 7 and Rg are independently selected from: H, OH, CN, N ₃ , halogen, CH ₂ OH, NH ₂ , OCH 1, NHCH 3, ONHCH ₃ , SCH ₃ , SPh, alkenyl , lower alkyl, lower alkylamine or substituted heterocycle; and

R 1, R ₂ , R ₃ , R 4, R 5, R 1, R 7 and Re are not all substituted simultaneously, such that when R ₂ = R 3 ^: = H represents R ₇ and R 8 is hydrogen or zero;

when R 1, R 4 or R 5 are substituted, R ₇ = Rg = H and R ₂ = R 3 = OH;

when R ₂ or R 3 are substituted, R ₇ and R 8 are H or OH;

when R ₇ or R 8 are substituted, R ₂ and R 3 are H or OH;

when R ₇ and R 8 are hydroxyl groups, these are not R ₂ and R ₃ ;

when A = N; B = CO, C = N or NH, D = CO or C-NH ₂ ; E is CH or C substituted; F-CH, X = O, S or CH ₂ , R ₂ will not be H, OH, CH ₃ , halogen, N ₃ , CN, SH, SPh, CH ₂ OH, CH ₂ OCH ₃ , CH ₂ SH, CH ₂ F, CH ₂ N 3, aryl, aryloxy or heterocycle;

when A = N; B = CO, C = N or NH, D = CO or C-NH ₂ ; E is CH, C-CH3 or halogen, F = CH; X = N-COCH ₃ , R ₂ will not be H or OH;

when A = N; B = CH, C = CH or CH ₃ , D = CH or C-CH ₃ ; E is CH, C-CH ₃ or C-CONH ₂ ; F = CH; X = O or CH ₂ , R ₂ is not H or OH;

when A = N; B = N, CO or CH, C = CH, C-Cl or C-OCH3, D = CH or C-Ph; E is CH, C-Cl or C-Ph; F = N or CO; X = O, R ₂ is not H or OH;

when A = N; B = CO or CS, C = N or NH, D = CO or C-NH ₂ ; E is CH or N; F = N or CH, X = O, then R ₂ is not H or OH;

when A = C; B = CH; C = NH; D = CO, CS or C-NH ₂ , E is N or NH; F is CO, CH; X = O, then R ₂ is not hydrogen or hydroxyl.

The compounds of formula 3 have the structure:

X is independently O, S, CH ₂ or NR, where R is COCH 3;

R 'and R are independently selected from H, CN, C (= O) NH ₂ , NH ₂ , C (= S) NH ₂ , C (= NH) NH ₂ .HC1, C (= NOH) NH ₂ , C (= NH) OMe, heterocycles, halogens, lower alkyl or lower alkyl aryls;

R 1 and R 4 are independently selected from H, CN, N ₃ , CH ₂ OH, lower alkyl and lower alkylamine; and R ₂ , R _3j Rs, Rs, R7 and Rs are independently selected from: H, OH, CN, N ₃ , halogen, CH ₂ OH, NH ₂ , OCH ₃ , NHCH ₃ , ONHCH3, SCH ₃ , SPh, alkenyl , lower alkyl, lower alkylamine or substituted heterocycle; such that when Rr = R ₃ = H represents R 7 and R 1 is hydrogen or zero.

In compounds of formula 3, preferably R 'is carboxamide or CN and R is hydrogen or halide; R 1 = R 4 = R 5 = R 7 = R 8 = H and R ₂ = R ₃ = OH, preferably X is oxygen.

The compounds of formula 4 have the structure:

A is independently selected from N or C;

B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR ¹ , CCONH2, CCH3, CR ² or P; R ¹ is independently H, lower alkyl, lower alkylamine, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryl. R ² is independently H, OH, halogen, CN, N ₃ , NH ₂ , C (= O) NH ₂ , C (= S) NH ₂ , C (= NH) NH ₂ .HC1, C (= NOH) NH ₂ , C (= NH) OMe, lower alkyl, lower alkylamine, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryl or substituted heterocycle;

X is independently O, S, CH ₂ or NR, where R is COCH ₃ ;

R 1 and R 4 are independently selected from H, CN, N ₃ , CH ₂ OH, lower alkyl and lower alkylamine;

R ₂ , R ₃ , R 5, R 6, R 7 and R 5 are independently selected from: H, OH, CN, N ₃ , halogen, NH ₂ , CH ₂ OH, OCH ₃ , NHCH ₃ , ONHCH ₃ , SCH ₃ , SPh, alkenyl, allyl, lower alkyl, lower alkylamine or substituted heterocycle; such that when R ₂ = R ₃ = H, R 7 and R 8 are hydrogen or zero;

when A is carbon; B = E = N; C is N-Ph, F is not CH;

when A = N; C is CH; B = E = C-CH ₃ , F is not nitrogen; and when A is carbon; B = N; C = C-CONH ₂ ; E-CH; F = S, X is not CH ₂ .

In the compounds of formula 4, R ^{1 is} preferably H, lower alkyl or allyl; R ² is preferably H, OH, halogen, CN, N3, NH2, C (= O) NH2, C (= S) NH2, C (= NH) NH2.HC1, C (= NOH) NH2 or C (= NH) ) OMe; and when R 1 = R 4 = R 5 ⁼ R 7 = R 8 ⁼ H are preferably R 2 = R ₃ = OH and X are oxygen.

The compounds of formula 5 have the structure:

A is independently selected from N or C;

B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR ¹ , CCONH2, CCH3, CR ² or P; R ¹ is independently H, lower alkyl, lower alkylamine, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryl. R ² is independently H, OH, halogen, CN, N ₃ , NH ₂ , C (= O) NH ₂ , C (= S) NH ₂ , C (= NH) NH ₂ .HC1, C (= NOH) NH ₂ , C (= NH) OMe, lower alkyl, lower alkylamine, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryl or substituted heterocycle;

D is independently selected from CH, CO, N, S, Se, O, NR ¹ , CCONH2, CCH3, CR ² , P or zero, where R ^{1 is} independently H, O, lower alkyl, lower alkylamine, COCH3, lower alkyl alkenyl, lower alkyl vinyl and lower alkyl aryl; R ² is independently H, OH, halogen, CN, N ₃ , NH ₂ , lower alkyl, lower alkylamine, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryl or substituted heterocycle;

X is independently O, S, CH ₂ or NR, where R is COCH ₃ ;

R 1 and R 4 are independently selected from H, CN, N ₃ , CH ₂ OH, lower alkyl and lower alkylamine;

R ₂ , R ₃ , R 5, Rg, R ₇ and Rg are independently selected from: H, OH, CN, N ₃ , halogen, CH ₂ OH, NH ₂ , OCH ₃ , NHCH _3j ONHCH ₃ , SCH ₃ , SPh, alkenyl, lower alkyl, lower alkylamine or substituted heterocycle; such that when R ₂ = R ₃ ^: = H, then R 7 and R 8 are hydrogen or zero;

when A = N; B = CO, C = N or NH, D = CO or C-NH ₂ ; E is CH or C substituted; F = CH, X = O, S or CH ₂ , R ₂ will not be H, OH, CH ₃ , halogen, N ₃ , CN, SH, SPh, CH ₂ OH, CH ₂ OCH ₃ , CH ₂ SH, CH ₂ F, CH ₂ N ₃ , aryl, aryloxy or heterocycle;

when A = N; B = CO, C = N or NH, D = CO or C-NH ₂ ; E is CH, C-CH ₃ or halogen, F = CH; X = N-COCH ₃ , R ₂ will not be H or OH;

when A = N; B = CH, C = CH or CH ₃ , D = CH or C-CH ₃ ; E is CH, C-CH ₃ or C-CONH ₂ ; F = CH; X = O or CH ₂ , R ₂ is not H or OH;

when A = N; B = N, CO or CH, C = CH, C-Cl or C-OCH ₃ , D = CI I or C-Ph; E is CH, C-Cl or C-Ph; F = N or CO; X = O, R ₂ is not H or OH;

when A = N; B = CO or CS, C = N or NH, D = CO or C-NH ₂ ; E is CH or N; F = N or CH, X = O, then R ₂ is not H or OH;

when A = C; B = CH; C = NH; D = CO; CS or C-NH ₂ ; is EN or NH; F = CO or CH; X = O, then R ₂ is not H or OH;

The abnormality represented by the increased response of one of the cytokine groups is treated according to the invention by prescribing a nucleoside or other compound that enhances the response of another group of cytokines. Thus, for example, the usual rapid onset of an allergy leads to an abnormal increase in Th2 response. The phenomenon was treated with Ribavirin between 600 mg / day and 1000 mg / day (for the average adult), which induces a Thl response at such doses. The treatment is effective because Thl and Th2 have in this case an inversely proportional relationship, resulting in a reduced Th2 response.

The invention also relates to the preventive treatment of a patient by prescribing a nucleoside or other compound that selectively reduces Th1 activity without noticeable effect on Th2 activity. Prevention can prepare the patient for an organ or tissue transplant or for allergen contact.

A nucleoside or other compound is prescribed to a patient in. an amount that reduces the amount of patient GTP to a concentration that allows one of Thl or Th2 responses to be selectively reduced without noticeably affecting the other. Keeping the amount of serum components at the desired concentrations should make it easier to achieve said result. This can be achieved by the controlled release of the named compounds. In the case of Ribavirin, for example, serum levels between about 2 μΜ and about 5 μΜ should be maintained. Compounds in controlled release formulations are expected to have an in vitro decay rate modified by the USP Paddle method at 100 rpm and 900 ml of aqueous buffer (pH 1.6 to 7.2) between about 15% and about 40% (w / w) compounds after one hour, between about 30% and about 50% (w / w) of the compound after two hours, about 50% and 70% (w / w) of the compound after four hours, between about 60% and about 80% (w / w) m) compounds after six hours.

Use

It is contemplated that the required combinations are intended to be used to treat most diseases, in fact all forms of diseases that respond positively to the administration of one or more of these compound combinations. In particular, it is contemplated that said combinations may be used to treat infections, inflammations, tumors, hyper-sensitivity or autoimmune diseases.

Infections to be treated with the compounds of the present invention are: syncytial respiratory virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, genital herpes, corneal herpes, herpes inflammation of the brain, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantan virus (hemorrhagic fever), human papillomavirus (HPV), measles and fungi. The combinations named here are expected to be useful in the treatment of chronic viral and bacterial infections, including HIV, tuberculosis, leprosy and more.

The compounds of the invention are intended to treat inflammations such as: intracellular inflammations with protozoa, disease states caused by parasites and other parasitic inflammations. The combination required is expected to be useful in the treatment of chronic inflammation.

Tumors to be treated include those caused by viruses. The compounds can inhibit the transformation of virus-infected cells into a neoplastic state, inhibit the spread of the virus from transformed cells to other normal cells, and / or inhibit the growth of virus-transformed cells.

Increased sensitivity, treatable hypersensitivity, includes all types of allergies, including IgE and IgG allergies, hyper IgE syndrome. Skin changes such as atopic dermatitis could be treated. It is expected that these compounds can be used to treat transplant rejection and prevent the body's negative response to implants.

Autoimmune diseases can be classified as non-organ specific or organ specific. The following non-organ-specific diseases include: rheumatoid arthritis, painful inflammatory arthritis of the joints, systemic lupus erythema (SLE), Sjorgen syndrome, sclerodemia (hard tissue), polymyositis and dermomyositis, ankylosing spondylitis and rheumatic fever. Organ-specific autoimmune diseases include, but are not limited to: insulin-dependent diabetes, thyroid disease (diseases characterized by increased thyroid and consequently increased underlying thyroid metabolism), Addison's disease, certain kidney and lung diseases including allergies and asthma, multiple sclerosis, disease muscle weakness, uveitis, flushing, forms of hepatitis and cirrhosis, digestive disorders such as gluten (celiac), bowel inflammation and certain types of male and female infertility. The autoimmune process can be stimulated by a viral infection including HIV, may lead to transplant rejection and may occur in some tumors. It can be caused by certain chemicals.

It is expected that abnormalities conditioned by the increased response of one group of cytokines may be treated by administration of a nucleoside that increases the response in the other group of cytokines. Thus, for example, because common IgE allergy is associated with a Th2 response, the allergy may be treated with Ribavirin, which increases the Thl response at low doses from about 500 mg / day to about 1000 mg / day.

Preventive treatment of a patient can be accomplished by administering a compound of the invention that selectively reduces Th1 activity without a marked decrease in Th2 activity. Preventive treatment may be aimed at reducing the expected side effect of an organ or tissue transplant, or to alleviate the symptoms of an expected attack on the lungs, such as with an increase in pollen in the spring (hay fever).

Synthesis

The synthesis of the compounds of formulas 1 and 1-A to 1-F is explained in PCT Patent Application PCT / US97 / 18389, which is incorporated herein in its entirety. The synthesis of the compounds of formulas 2 to 5 is presented in PCT application PCT / US97 / 00600.

Administration

The compounds of the invention are expected to be prescribed in suitable pharmaceutical formulations and by any suitable protocol. In the case of the use of the primary or first drug as discussed above, the recommended amount of monotherapy treatment and the protocol for the use of the drug are described in the PDR or at least available from the manufacturer or seller. The recommended amount and protocol for the use of another secondary drug, such as the bi-modal nucleosides explained here, is best identified through a patient test. The test does not need to be extensive and it is expected that a secondary drug containing the nucleosides of the invention should be prescribed between about 100 mg / day and about 5000 mg / day.

One of ordinary skill in the art will recognize that the therapeutically effective amount fluctuates with the type of infection or conditions to be treated, the sensitivity, the mode of treatment, the pharmacological kinetics of the drug used, as well as the patient (s). Thus, the effective dose may be between about 1 mg / kg body weight or less, up to 25 mg / kg body weight or more. In general, a therapeutically effective amount of a secondary drug is expected to be slightly less than about 1 mg / kg to about 25 mg / kg of body weight of the patient, depending on the compound used, the conditions of treatment and the type of infection, as well as the mode of treatment. The effective concentration of the active substance in the blood is generally in the range from about 0.04 to about 100 mg / cm ^{3 of the} patient's blood. The prescribing and dosing regimen should be patient specific. The amounts of medicines should initially be smaller and increase over time until the desired effects are achieved or until side effects occur. The method of administration of the invention may be: oral, parenteral (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technique), spray inhalation, rectal, surface and other and in unit dosage formulations containing conventional non-toxic pharmaceutical pharmaceuticals mounts, accessories and gears.

It is expected that the compounds of the invention may be formulated in admixture with pharmaceutically acceptable carriers. For oral administration, the compounds of the invention may, for example, be in the form of pharmacologically acceptable salts. The compounds of the invention, which are mostly water soluble, may be prescribed intravenously in saline solution (for example, a buffer solution with a pH of about 7.2 to 7.5). For this purpose, conventional buffers such as phosphates, bicarbonates or citrates can be used. To the extent permitted, one skilled in the art may modify the formulations in order to provide various formulations for a particular mode of use without altering the composition of the invention, destabilizing or reducing therapeutic activities. Modification of the present compounds to increase their solubility in water or other solvent may be accomplished by minor modifications (salt composition, esterification) to those well known in the art. It is also well known in the art to modify the mode of administration and the dosage of a particular component in order to increase the pharmacological efficacy of the formulated compounds in a patient.

In some forms of pharmaceutical compositions, the compounds are desired in the form of pro-drugs and are preferably acylated (acetylated or otherwise) derivatives, pyridine esters, and various salt forms of the compounds presented. Methods of modifying compounds to pro-drug form are known to those skilled in the art, and the modified form can accelerate the transfer of the active compound to a target site in the host organism or patient. By accelerating the transfer of the present compound to a target site in the host organism or patient, the desired pro-drug effect is enhanced by improved pharmacological kinetics.

The compounds included in the combinations of the invention may be prescribed separately or in a group. In the case of taking compounds separately, this can be done in any order. The amount of active ingredients and pharmaceutically active agents and the relative dosing time of the dosage should be selected in such a way as to achieve the desired overall therapeutic effect.

The route of administration of the compounds of the invention may be continuous (intravenous) or up to several oral applications per day (Q.I.D.). Administration may be: oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetrating accelerating agent), buccal, and suppository.

The therapeutically effective amount of the compound is mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical techniques for the production of mixtures. The carriers may take various forms depending on the desired preparation and administration, for example: oral or parenteral.

In a composition of a pharmaceutical composition for oral use, any of the conventional pharmaceutical media may be used. For liquid oral preparation such as: suspension, elixir or solution, suitable carriers may be used, such as: water, glycols, oils, alcohols, flavoring agents, preservatives, colorants. For use in solid form, such as: tablets, capsules and solid compositions such as: suppositories, suitable carriers and additives may be used: starch, sugars: dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, breakdown agents, and the like. If desired, tablets or capsules may be coated for complete release or coated to allow for sustained release by standard techniques.

For the parenteral formulation, the carriers are said to be sterile water or aqueous sodium chloride solution, but the mixture may also contain other additives including those that aid dispersion. Where sterile water is to be used and the sterile condition is also maintained, the composition and supports must also be sterilized. Injectable suspensions may be prepared with suitable liquid carriers, suspending agents and may be used as such.

In general, it is desirable to use those compounds of the invention that are relatively less toxic to the host cells, especially those cells that are not treated and that have an active effect on the treated cells. To this end, it could be that L-nucleosides can improve stability over D-nucleosides, which may lead to improved pharmacological kinetics. This may be because L-nucleosides are not recognized by the enzymes and therefore have a longer breakdown time.

The therapies we have described include nucleosides and other components that selectively affect the Th1 and Th2 responses relative to one another in the treatment of the disease. Although specific uses have been described, the essence of the invention is not limited except through the interpretation of the claims.

Claims (74)

Use of a compound selected from the group consisting of nucleosides, D-nucleosides, L-nucleosides, Ribavirin and interferon for the preparation of a pharmaceutical composition for oral administration useful in the method of reducing the prescribed amounts of primary drug to a patient for the treatment of diseases characterized by the abnormal condition of at least one cytokine in a patient, the method comprising: - identification of the monotherapy amount of the first drug to effectively cure the disease; - identifying a secondary drug from that group that increases the abnormality in case it is prescribed monotherapy in the dosage range; and - administration of combination therapy containing the first drug in smaller quantities than is necessary for monotherapy and the second drug outside the dosage range. Use of a compound according to claim 1, characterized in that the diseases are chronic diseases. Use of a compound according to claim 1, characterized in that the diseases include chronic viral diseases. Use of a compound according to claim 1, characterized in that it comprises insulin dependent diabetes. Use of a compound according to claim 1, characterized in that the diseases are allergies. Use of a compound according to claim 1, characterized in that atopic dermatitis is classified as a disease. Use of a compound according to claim 1, characterized in that intracellular protozoal infections are classified as diseases. Use of a compound according to claim 1, characterized in that hyper IgE syndrome is classified as a disease. Use of a compound according to claim 1, characterized in that it is classified as HIV. Use of a compound according to claim 1, characterized in that the diseases include transplant rejection diseases. Use of a compound according to claim 1, characterized in that the systemic lupus erythema is classified as a disease. Use of a compound according to claim 1, characterized in that it is classified as a tumor. Use of a compound according to any one of claims 1 to 12, characterized in that the abnormalities contain an increase in Th1 activity. Use of a compound according to any one of claims 1 to 12, characterized in that the abnormalities contain a decrease in Th1 activity. Use of a compound according to any one of claims 1 to 12, characterized in that the abnormalities contain an increase in Th2 activity. Use of a compound according to any one of claims 1 to 12, characterized in that the abnormalities contain a decrease in Th2 activity. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a pharmaceutically acceptable nucleoside form. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a pharmaceutically acceptable form of D-nucleoside. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a pharmaceutically acceptable form of L-nucleoside. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a pharmaceutically acceptable form of Ribavirin. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a pharmaceutically acceptable form of interferon. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1- F. Use of a compound according to any one of claims 1 to 12, characterized in that the secondary drug is a nucleoside according to at least one of formulas 2, 3, 4 or 5. Use of a compound selected from the group consisting of nucleosides, D-nucleosides, L-nucleosides, Ribavirin and interferon for the preparation of a pharmaceutical composition for oral administration useful in a method of reducing the prescribed amounts of a primary drug to a patient for the treatment of diseases characterized by an abnormal condition of at least one cytokine in a patient, the method comprising: - finding that the disease is associated with an increase in activity of the first type of lymphokines; - determining that a particular pharmaceutical compound is capable of an amount-dependent increase and decrease in the second lymphokine phenotype; and - the administration of pharmaceutical compounds for the treatment of diseases that affect at least partially the activity of another lymphokine phenotype. Use of a compound according to claim 24, characterized in that the diseases are chronic diseases. Use of a compound according to claim 24, characterized in that the diseases include chronic viral diseases. Use of a compound according to claim 24, characterized in that it comprises insulin dependent diabetes. Use of a compound according to claim 24, characterized in that the diseases are allergies. Use of a compound according to claim 24, characterized in that atopic dermatitis is classified as a disease. Use of a compound according to claim 24, characterized in that the diseases include intracellular protozoal infections. Use of a compound according to claim 24, characterized in that hyper IgE syndrome is classified as a disease. Use of a compound according to claim 24, characterized in that it is classified as HIV. Use of a compound according to claim 24, characterized in that the diseases include transplant rejection diseases. Use of a compound according to claim 24, characterized in that the systemic lupus erythema is classified as a disease. Use of a compound according to claim 24, characterized in that it is classified as a tumor. Use of a compound according to any one of claims 24 to 34, characterized in that the first phenotype is Th2 and the second phenotype is Th1. Use of a compound according to claim 36, wherein the medicament comprises a pharmaceutically acceptable form of Ribavirin. Use of a compound according to claim 36, wherein the medicament comprises a pharmaceutically acceptable form of interferon. Use of a compound according to any one of claims 24-35, characterized in that it comprises prescribing the drug in combination therapy with a therapeutic agent. Use of a compound according to claim 39, characterized in that the therapeutic agent is selected from a list containing antiviral compounds, fungicides, anti-intestinal compounds, antitumor compounds, dermatological compounds, migraine preparations, steroids, immunosuppressants and metabolic compounds. Use of a compound according to claim 39, characterized in that the medicament contains a pharmaceutically acceptable form of Ribavirin or interferon. Use of a compound according to claim 39, characterized in that the first phenotype is Th2 and the second phenotype is Th1. Use of a compound according to any one of claims 24-35, characterized in that the secondary drug comprises a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1 -F. Use of a compound according to any one of claims 24-35, characterized in that the secondary drug comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. Use of a compound according to claim 39, characterized in that the secondary drug comprises a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1-F. Use of a compound according to claim 39, characterized in that the secondary drug comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. 47. Use of a compound selected from the group consisting of nucleosides, D-nucleosides, L-nucleosides, Ribavirin and interferon for the preparation of a pharmaceutical composition for oral administration useful in the method of reducing the prescribed amounts of primary drug to a patient for the treatment of diseases characterized by the abnormal condition of at least one cytokine in a patient, the method comprising: providing a drug that inhibits Thl activity in a patient when prescribed above the prescribed dosage level; and - administering the drug to the patient in quantities below the prescribed dosage level. Use of a compound according to claim 47, wherein the prevention comprises preparing the patient for an organ transplant. Use of a compound according to claim 47, characterized in that the prevention comprises preparing the patient for a tissue transplant. Use of a compound according to claim 47, wherein the prevention comprises preparing the patient for intended contact with the allergen. Use of a compound according to any one of claims 47 to 49, further comprising providing the drug in an amount that increases Th2 activity. Use of a compound according to any one of claims 47 to 49, characterized in that the medicament contains a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1- F. Use of a compound according to any one of claims 47 to 49, characterized in that the medicament contains a nucleoside according to at least one of formulas 2, 3, 4 or 5. 54. Use of a compound selected from the group consisting of nucleosides, D-nucleosides, L-nucleosides, Ribavirin and interferon for the preparation of a pharmaceutical composition for oral administration useful in the method of reducing the prescribed amounts of a primary drug to a patient for the treatment of diseases characterized by an abnormal condition of at least one cytokine in a patient, the method comprising: identifying a compound and dosage range for a compound that has an effective effect in inhibiting a patient's amount of GTP and thereby selectively downregulates one of Th 1 or Th 2 responses without noticeably lowering the other response; and - administration of the nucleoside in the dosing range. Use of a compound according to claim 54, characterized in that it comprises chronic diseases. Use of a compound according to claim 54, characterized in that the diseases include chronic viral diseases. Use of a compound according to claim 54, characterized in that it comprises insulin dependent diabetes. Use of a compound according to claim 54, wherein the diseases are allergies. Use of a compound according to claim 54, characterized in that atopic dermatitis is classified as a disease. Use of a compound according to claim 54, characterized in that intracellular protozoal infections are classified as diseases. Use of a compound according to claim 54, characterized in that hyper IgE syndrome is classified as a disease. Use of a compound according to claim 54, characterized in that it is classified as HIV. Use of a compound according to claim 54, characterized in that the diseases include transplant rejection diseases. Use of a compound according to claim 54, characterized in that the systemic lupus erythema is classified as a disease. Use of a compound according to claim 54, characterized in that it is classified as a tumor. Use of a compound according to any one of claims 54 to 65, characterized in that the compound contains a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1-F . Use of a compound according to any one of claims 54 to 65, characterized in that the compound contains a nucleoside according to at least one of formulas 2, 3, 4 and 5. 68. A controlled release preparation for oral administration comprising a compound that selectively modulates Thl and Th2 responses against each other in the dosage range, an aspect of the controlled release preparation helps maintain serum levels below that which would lower the response of both Thl and Th2 . 69. A controlled release preparation according to claim 68, characterized in that the composition comprises a nucleoside according to at least one of formulas 1, 1-A, 1-B, 1-C, 1-D, 1-E or 1-F. A controlled release preparation according to claim 68, characterized in that the composition comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. 71. The controlled release preparation of claim 68, wherein the composition comprises Ribavirin. 72. The controlled release preparation of claim 68, wherein the composition comprises interferon. A controlled release preparation according to any one of claims 68 to 73, characterized in that the patient maintains a serum level between about 2 μ okoli and about 5 μΜ of the compound. 74. A controlled release preparation according to any one of claims 68 to 73, characterized in that the composition has an in vitro dissolution rate when bordered by the USP Paddle method at 100 rpm in 900 ml of aqueous buffer (pH between 1.6 and 7.2 ), between about 15% and about 40% (w / w) of the compound after one hour, between about 30% and about 50% (w / w) of the compound after two hours, about 50% and 70% (w / w) of the compound after four hours, between about 60% and about 80% (w / w) of the compound after six hours.