SK94099A3 - 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

Technical field

The present invention relates to nucleosides.

BACKGROUND OF THE INVENTION

The mammalian immune system consists of two large groups of lymphocytes: B lymphocytes (B cells) that are formed in thin bones; and T lymphocytes (T cells) that originate in the thymus. B cells are largely responsible for humoral immunity (i.e., antibody production), T cells are largely responsible for mediating cellular immunity.

T cells are known to be divided into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes including B cells and cytotoxic T cells and macrophages. This activation is carried out by soluble proteins, called cytokines, which also mediate cellular immunity. As disclosed in this application, lymphokines are a subset of cytokines.

helper T cells are also generally known to be divided into two subclasses Th1 and Th2. Th1 cells (known as type 1 cells) produce interleukin 2 (IL-2), a tumor necrosis factor (TNFα) and interferon gamma (IFNγ); they are primarily responsible for mediating cellular immunity in which hypersensitivity and antiviral immunity are delayed. In contrast, Th2 cells (known as type 2 cells) produce IL-4, IL-5, IL-6, IL-9, IL10, and IL-13 and are primarily involved in an assisting humoral immune response, such as those that are distinguished in response to allergens, for example, the status of changing IgE and IgG4 antibodies (Mosmann, 1989, Annu Rev Immunol, 7: 145-173).

As used herein, the term Th1 and Th2 responses include all responses that result from the induction effects of individual Th1 and Th2 lymphocytes. Together with other formalities, such as responses containing changes in the production of the corresponding cytokines during transcription, translation, custody, and possibly other mechanisms, incremental with the proliferation of the corresponding lymphocytes and other effects identifying with the relevant cytokine production, including moving effects.

Each preferred application of the present invention relates to aspects of our current knowledge that relate to the effect of the response of different nucleosides (as defined in this application, including nucleoside derivatives and analogs) on a selective lymphocyte. We have shown that both Th1 and Th2 responses can be selectively suppressed while others are induced or relatively remain unchanged and both Th1 and Th2 responses can be selectively induced while others also remain relatively unchanged. We have also surprisingly found that the efficacy of nucleosides in selectively altered Th1 and Th2 tend to produce a bimodal effect. Together with other properties, nucleosides that tend to generally suppress or induce Th1 and Th2 activity at a relatively higher dose tend to selectively change Th1 and Th2 at relatively lower doses.

The mechanisms that selectively alter Th1 and Th2 relative responses to nucleosides and other compounds are still unclear. Currently, the inventors are contemplating the possibility of current that nucleoside efficiency is altered by folding guanosine triphosphate (GTP), which affects the rates at which cytokines are produced. According to this theory, relatively large changes in the usefulness of GTP are sufficient to affect Th1 and Th2 cytokine concentrations, while the relatively less useful GTP affects the magnitude of Th1 and Th2 cytokine concentrations at different intervals.

This view is supported by the effect of 2-β-D-ribofuranosylthiazole-4-carboxamide (Thiazofurine), a synthetic analog of Cnucleoside on GTP levels. Tumor cells are characterized by a high level of inosine monophosphate dehydrogenase (IMP DH) activity and IMP DH is known to be an enzyme limiting the rate of GTP biosynthesis. Weber, G., IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment, Adv. Exp. Med. Biol. 309B: 287-292 (1991). Thiazofurin has been discovered to selectively block IMP DH activity and to consume guanine nucleoside, which is forced to destroy various tumors. Weber, G., Critical Issue in Chepotherapy with Tiazofurin, Adv. Enzyme Regul. 29: 75-95 (1989). The initial doses of thiazofurine are typically about 4,400 mg / m ² , after a dose consolidation of about 1,100 to 3,300 mg / m ² . At this level of synthesis of both Th1 and Th2, the response is greatly reduced, thus essentially shutting down the immune system. In one aspect of the present invention, it is contemplated that a much smaller dose of Thiazofurin in the range of 1/10 to 1/2 may be sufficient for a specially suppressed response or a Th2 response, without further limiting the other responses.

The effects of 1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamides (Ribavirin) also support the present theory. Ribavirin is a potent, broad-spectrum antiviral agent that also aims to suppress IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Thiazofurin and Ribavirin on Purified IMP Dehydrogenase, Biochem. 27: 2193-2196 (1988). Ribavirin acts by a different mechanism than Thiazofurin in inhibition of IMP DH, but interferes at a different site of the enzyme molecule. Ribavirin is converted to its active metabolite, ribavirin monophosphate (RMP), which prevents the enzyme

IMP DH at IMP-XMP site. As with Thiazofurin, the affinity of the active form of Ribavirin for the enzyme is greater than that of the neutral metabolites. At relatively large doses, an average of 2,200 mg / m ² , or about 1,200 - 1,500 mg / day for an adult, Ribavirin IMP DH reduces activity to such an extent that both Th1 and Th2 responses are inhibited. At relatively smaller doses of about 600 to 1000 mg / day, Ribavirin supports the Th1 response and suppresses the Th2 response.

Although some mechanisms are not defined, it has been found that a large dose potential can be obtained from a selective change in the relative responses of Th1 and Th2 to one another. It has been found that some change in Th1 relative to Th2 can be successful in the treatment of many conditions and diseases, ranging from infections, infestations, tumors and hypersensitivity to autoimmune diseases.

These findings are very important because a modern treatment strategy for the above diseases has either limited effect, important side effects, or both. For example, the treatment of autoimmune diseases is commonly limited by the amount of quenching effects, the removal of toxic antibodies (as in myasthenia gravis) and the administration of dangerous drugs including corticosteroids, chloroquine derivatives and antimetabolic or anticancer drugs and drugs such as cyclosporins that attack the immune system.

SUMMARY OF THE INVENTION

This application relates to the use of nucleosides in a relatively small dose range for selectively altered Th1 and Th2 responses in the treatment of disease. In one aspect, administration of a nucleoside or other compound reduces the dose at which the main drug is administered. In another aspect, an unusual manifestation in an increasing response is treated by administering nucleosides or another compound that enhances the response in another group of cytokines. In another aspect, a patient is treated preventively with nucleosides or another compound that selectively limits Th1 activity without significantly limiting Th2 activity. In yet another aspect, a nucleoside or other compound is administered to a patient at a dose that limits the patient's GTP supply to such an extent that it selectively limits either the Th1 or Th2 response. Partial control of dose administration is required to achieve the result.

Examples of primary drugs of contemplated efficacy in this sense are the D- and L-forms:

(a) bicyclic nucleosides of formulas 1, 1-A to 1-F; and (b) monocyclic nucleosides corresponding to any of formulas 2 to 5.

Examples of major drugs of effectiveness considered in this sense are antiviral agents such as Ribavirin, acyclovir and AZT ™; antifungal agents such as Fungizone ™, Lotrimin ™, Mycelex ™, Nystatin and Amphoteracin; antiparasitic agents such as Mintezol ™, Niclocide ™, Vermox ™ and Flagyl ™; intestinal agents such as Immodium ™, Lomotil ™ and Phazyme ™; antitumor agents such as Adriamycin ™, Cytoxan ™, Imuran ™, Methotrexate, Mithracin ™, Tiazofurin ™, Taxol ™; dermatological agents such as Aclovate ™, Cyclocort ™, Denorex ™, Florone ™, Oxsoralen ™, coal tar and salicylic acids; a migraine preparation such as ergotamine compounds; steroids and immune suppressants not listed above including cyclosporins, Diprosone ™, hydrocortisone; Floron ™, Lidex ™, Topicort, and Valison; and metabolic agents such as insulin.

definitions

The terms used in this application are defined below.

The terms a and β mean specific stereochemical «

the configuration of the substituent on the asymmetric carbon atom in the drawn chemical structure.

The term abnormality refers to conditions associated with the disease. Therefore, Th1 and / or Th2 responses leading to an autoimmune disease are considered in this application as abnormalities corresponding to the cytokine (s), although the cytokine response may normally be caused by the disease.

The term aryl means an unsaturated aromatic cyclic hydrocarbon radical with one ring (e.g. phenyl) or with two fused rings (e.g. naphthyl), which may be optionally substituted by hydroxyl, short alkyl, chlorine and / or cyano.

The term "effective amount" means that amount of a compound of formula (I) that will restore immune function to a normal level or increase immune function above a normal level or eliminate infection.

The term enantiomers means such a pair of stereoisomers. which are nonprintable mirror images of each other. A 1: 1 mixture of enantiomers is a racemic mixture.

The term heterocyclo ”means a saturated or unsaturated cyclic hydrocarbon radical with at least one heteroatom such as N, O or S within the ring, each available position may be optionally substituted with an independent hydroxy, oxo, amino, imino, bromo, chloro and / or cyano group and alkyl. This class of substituents includes purines and pyrimidines.

The term immunomodulators means natural or synthetic products capable of altering the normal or abnormal immune system upon stimulation or suppression.

The term "isomers" refers to different compounds of the same general formula.

Stereoisomers are isomers that differ in the spatial arrangement of the atoms in the molecule.

The term L-configuration is used throughout the present application to describe the chemical configuration of a portion of a ribofuranosyl compound such that it is linked to a nucleobase. The L-configuration of a portion of the sugar compound of the present invention is remarkably different from the ribose configuration, which is found in naturally occurring nucleosides, such as cytidine, adenosine, thymidine, guanosine and uridine.

The term short alkyl means methyl, ethyl, n-propyl. Isopropyl, n-butyl, t-butyl, i-butyl or n-hexyl. The term is also extended to include cyclic, branched or linear chains composed of one to six carbon atoms.

The term monocyclic means a monovalent cyclic hydrocarbon radical with at least one heteroatom such as O, N, S Se or P within the ring. Each available position may be optionally substituted with an independent sugar moiety or other group such as bromo, chloro and / or cyano such that the monocyclic ring system is optionally aromatized (e.g., Thymidine; 1- (2'-deoxy-β-D-erythro-pentafuranosyl) ) thymine).

The term nucleoside means a compound consisting of a pentose or an altered portion of pentose that is located at a specific position of the heterocycle or at a natural position of purine (9th position) or pyrimidine (1st position) or an equivalent position in the analogue, including both special forms D- and L- and the monocyclic heterocycles shown in formulas 1, 1-A to 1-F, and 2 to 5, which are disclosed in this application.

The term C-nucleosides is used throughout the application to describe a binding type formed between a portion of a ribose and a heterocyclic base. In C-nucleosides, a bond is formed from the C-1 position of a portion of the ribose to the attached carbon from the heterocyclic base. The bond that is formed in the C-nucleoside is a carbon-carbon bond.

The term D-nucleosides refers to those nucleoside compounds having a portion of D-ribose (e.g., adenosine).

The term L-nucleosides refers to those nucleoside compounds having L-ribose moieties.

The term N-nucleosides is used throughout the specification to describe a binding type that is between the ribose moiety and the heterocyclic base. In N-nucleosides, a bond is formed from the C-1 position of a portion of the ribose to the attached nitrogen from the heterocyclic base. The bond that is formed in the N-nucleoside is a carbon-nitrogen bond.

The term nucleotide means a phosphate ester substituted at the 5 'position of the nucleoside.

The term pharmaceutically acceptable salts refers to salts of inorganic and organic acids or bases.

The term protecting group means a chemical group that is attached to an oxygen or nitrogen atom to inhibit its further reaction during derivation of other moieties in the molecule in which oxygen and nitrogen are present. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in organic synthesis.

The term purine means the nitrogen bicyclic heterocycle shown in formulas 1, 1-A to 1-F in this application.

The term pyrimidine means the nitrogen monocyclic heterocycle shown in formulas 2-5.

The term tumor means almost all methods of abnormal tissue growth, which may or may not become malignant, including all methods of neoplasm and cancer.

The term treating or treating a disease means performing such a procedure, which may include administering one or more drugs to a patient, to alleviate the manifestation of the disease. Therefore, treatment or treatment is not required to cease alleviation of symptoms or symptoms, no cure or special procedures that have minimal effect on the patient are required.

DETAILED DESCRIPTION OF THE INVENTION

Combinations of one aspect of the present invention generally comprise a primary or first drug and another or second drug. The methods relate to selecting and combining the first and second medicines in combination with the method of treatment. Preferably, a disease is identified which is known to be abnormal in the production of at least one cytokine in a patient, the first drug being obtained from all compounds that treat the disease at a monotherapeutic dose and the second drug that may be a bimodal nucleoside modulator as described in the application from known compounds to reveal a major abnormality produced by the disease when administered over a dose range. The first drug is administered at a lower than the therapeutic dose and the second drug is administered at a higher dose than the normal dose that exacerbates the abnormality. Since the second drug has bimodal activity relative to at least one of the cytokines, the combination is still suitable for the treatment of the disease and the administration of the second drug allows dose reduction of the primary or first drug.

Examples of primary drugs of contemplated efficacy in combination with the modulator obtained from Formula 1, 1-A to 1-F and 2-5 are antiviral agents such as interferon including unrestricted interferon α and γ, Ribavirin, acyclovir and AZT ™; antifungal agents such as tolnaphthate, Fungizone ™, Lotrimin ™, Mycelex ™, Nystatin and Amphoteracin; anti-parasitic agents such as Mintezol ™, Niclocide ™, Vermox ™ and Flagyl ™; intestinal agents such as Immodium ™, Lomotil ™ and Phazyme ™; antitumor agents such as interferon α and γ, Adriamycin ™, Cytoxan ™, Imuran ™, Methotrexate, Mithracin ™, Tiazofurin ™, Taxol ™; dermatological agents such as Aclovate ™, Cyclocort ™, Denorex ™, Florone ™, Oxsoralen ™, coal tar and salicylic acids; a migraine preparation such as ergotamine compounds; stereoids and immune suppressants not mentioned above, including cyclosporins, Diprosone ™, hydrocortisone; Floron ™, Lidex ™, Topicort, and Valison; and metabolic agents such as insulin and other drugs that are not conveniently located in the above categories, including cytokines such as IL2, IL4, IL6, IL8, IL10 and IL12. Particularly suitable primary drugs are AZT, 3TC, 8-substituted guanosine analogs, 2 ', 3'-dideoxynucleosides, interleukin II, interferons such as IaB-interferons, tucaresol, levamisole, isoprinosine and cyclolignans.

Examples of secondary drugs of contemplated efficacy in the application are the D- and L-forms of (a) bicyclic nucleosides corresponding to formulas 1, 1-A to 1-F; and (b) monocyclic nucleosides corresponding to any of formulas 2 to 5. Other nucleosides and non-nucleoside active compounds of the present invention are readily discernible in screening compounds in vitro for their effect on IL-2, TNF-α, IFN-γ, IL- 4, IL-5 as described in PCT / US97 / 00600.

Example I

Compounds of the structure:

are purine nucleosides

Of formula (I)

(I) wherein R _; , groups containing H, OH,

R ₃ 'are obtained independently from

NH _; , F, Cl, Br, I, N ₃ , -CN,

-OR ', -NR'_; , -SR ', _-NHNH:, -NHOH, CHO, COOR ", _CONR', alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, and wherein R is derived from F, Cl, Br, I, _N3, -CN, -OR, NO _{2, NR;} , SR, -NHNH _; .

-NHOH, COOR, CONR; and wherein R 1 and R 2 are H, allyl, alkenyl, alkynyl, aryl aralkyl;

W = 0, S, _CH2, Se;

Z1, Z _: are obtained independently from N, C, CH;

Z ₃ , Z ₄ , Z ₅ are obtained independently from the groups consisting of -CR-, -NR-, -O-, -S-, -Se-, -C = O, -C = S, -S = O, - CR = CR-, -CR = N-, -N = N- and wherein R is selected from the group consisting of F, Cl, Br, I, N ₃ , -CN, -OR ', -NR' ₂ , -SR ' , -NHNH ,, -NHOH, N0 _2, CHO, COOR ', _C0NH: -C (0) _-NH2, -C (S) NH _2, -C (NH) _-NH2, -C (N0H ) -NH ₂ , = O, = NH, = NOH, = NR, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl and wherein the substituent is derived 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} R 1, R 1 'are H, alkyl, alkenyl alkynyl, aryl, aralkyl, acetyl, acyl sulfonyl;

The chemical bond between Z ₃ and Z ₄ or Z ₄ and Z ₅ is obtained from CC, C = C, CN, C = N, NN, N = N, CS, NS;

X and Y are obtained independently from H, OH, NH _; , F, Cl, Br, I, N ₃ , -S-NH ₂ , -S (O) -NH ₂ , -CN, COOR ':, -OR', -NR ':, -SR', -NHNH: , -NHOH, alkyl, alkenyl, alkynyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl and wherein the substituent is derived from F, Cl, Br, I, N ₃ , -CN, -OR , NO :, -NR :, SR, -NHNH, -NHOH, and R 'and R' are H, alkyl, alkenyl, alkynyl, aryl, aralkyl.

Example II.

The compounds of formula I-A are 8-substituted βL- or D-guanosine variants of the structure:

(IA) wherein X is obtained H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR ₂ , -NHNH ₂ , -NHOH, -CHO, -CONH ₂ , - COOR and -LA is R obtained from alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl; L is a bond obtained from alkyl, alkenyl, alkynyl and aralkyl; and A is derived from H, -OR ', -SR', -NR ' ₂ ,

NHNR'i, CHO, CONR's, wherein R 'is obtained from H, Me, Et, allyl, acetyl, -COCF ₃ ;

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

Z is N or CH;

R1, R; and R ₃ are obtained independently from H, -OH, -OAc, -OBz, -OP (O;) H.

Example III.

Compounds of formula I-B are 7-substituted-8 oxo or β-L-L-guanosine variants of the structure:

wherein X is derived from H, R, NH; ₍ -CHO, -COOR and -LA is R is selected from alkyl, alkenyl, alkynyl, aryl and aralkyl; L is a bond obtained from alkyl, alkenyl, alkynyl, and aralkyl; A is selected from H, F, Cl, Br, I, -OR ', -SR', -NR ' _: , -NHNH ;, -NHOH, N ₃ , -CHO, -CONH ;, -COOR' and -CN, wherein R 'is derived from the groups containing Me, Et, allyl, acetyl and -COCF ₃ ;

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

Z is N or CH; and

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

Example IV.

The compounds of formula I-B are 7-deaza-7,8-monosubstituted or β-L- or D-guanosine variants of the structure:

wherein X 1 and X ₂ are independently obtained H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR 2, -NHN 2 H, -NHOH, -CHO, -CONH ₂ , - COOR and -LA; wherein R is derived from alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl; L is a bond obtained from alkyl, alkenyl, alkynyl and aralkyl; and A is obtained from H, -OR ', -SR', -NR ' ₂ , -NHNR'o, -CHO, -COOR', -CONR '_; and wherein R 'is derived from Me, Et, allyl, acetyl, -COCF ₃ ;

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

Z is N or CH;

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

Example V.

The compounds of formula I-D are 7-deaza-8-aza-7-substituted or β-L- or D-quanosine variants of the structure:

(ID) wherein X is selected from H, R, F, Cl, Br, I, _N3, -CN, -OR, -SR, -NR _{2 Z} :, -NHNH -NHOH, -CHO, _-CONH: - COOR and -LA; wherein R is derived from alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, sulfonyl; L is a bond and is derived from alkyl, alkenyl, alkynyl and aralkyl; and A is derived from H, -OR ', -SR', -NR ' _: , -NHNR' :, -CHO, -COOR ', -CONR': and wherein R 'is derived from H, Me, Et, allyl , acetyl, -COCF ₃ ;

Y is obtained from H, R, F, Cl, Br, I, N ₃ , -CN, -OR, -SR, -NR. and wherein R is derived from H, alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl and sulfonyl;

Z is N or CH;

· R., _R: and R ₃ are independently selected from H, -OH, -OAc, -OBz, -OP (O,) H.

Example VI.

Compounds of formula I-E are thiazolo [4,5-d] pyrimidine or β-L- or D-nucleosides of the structure:

(Ι-Ε) where Χι = Ο, Se, = ΝΗ, ΝΝΗ ² , = ΝΗΟΗ, = NR and where R is alkyl, alkenyl, alkynyl, aralkyl and acyl; X; is S, O, Se;

Y is obtained from H, R, F, Cl, Br, I, N ₃ , -CN, -OR, wherein R is obtained from H, alkyl, alkenyl, alkynyl, acetyl, acyl and sulfonyl;

Z is N or CH;

R1, R _; and R ₃ are obtained independently from H, -OH, -OAc, -OBz,

Example VII.

The compounds of formula I-F are β-L nucleosides of purine of the structure:

obtained from

SR, NR _2, and aralkyl,

-OP _(O:) H.

or D-

wherein X is derived from H, R, -SNH _{2 /} -S (O) NH ₂ , -SO ₂ NH ₂ , F, Cl, Br, I, N ₃ ,

-CN, -OR, -SR, -NR ₂ and wherein R is obtained from alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl;

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

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

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

Example VIII.

Compounds of formula II, structures:

r ₂

R 3 (Π) wherein A is obtained independently from N or C;

B, C, E, F are independently obtained from CH, CO, N, S, Se, O, NR 1, CCONH 2, CCH ₃ , CR ₂ or P;

R 1 is independently H, short alkyl, short alkylamines, COCH ₃ , short alkyl alkenyls, short alkyl vinyl or short alkyl aryl. R ₂ is independently H, OH, halogens, CN, N ₃ , NH ₂ , C (= O) NH ₂ , C (= S) NH ₂ , C (= NH) NH ₂ .HCl, C (= NOH) NH ₂ , C (= NH) OMe, short alkyls, short alkylamines, short alkyl alkenyls, short alkyl vinyls, short alkylaryls or substituted heterocycles;

D is independently selected from CH, CO, N, S, Se, O, NR, CCONH _2, CCH _3, CR _{2 Z} L, or is not wherein R is independently H, 0, lower alkyl, lower alkylamines, _COCH3, short alkyl alkenyls, short alkyl vinyls, short alkyl aryls and R ₂ is independently H, OH, halogens, CN, N ₃ , NH ₂ , short alkyls, short alkylamines, short alkyl alkenyls, short alkyl vinyls, short alkyl aryls or substituted heterocycles;

X is independently O, S, _CH2 or NR; wherein R is COCH ₃ ;

R 1 and R 4 are obtained independently from H, CN, N ₃ , CH ₂ OH, short alkyls and short alkyl amines;

R _2, R _3, R / D / R? and R ₈ are obtained independently from H, OH, CN, N ₃ , halogens, CH ₂ OH, NH ₂ , OCH ₃ , NHCH ₃ , ONHCH ₃ , SCH ₃ , SPh, alkenyl, short alkyl, short alkyl amines and substituted heterocycles ; and

R 1, R 2 / R 3 / R 4 / R 5, R e, R 1 and R ₈ are not all substituted at the same time such that:

when R ₂ = R ₃ = H, then R ₇ and R ₈ are hydrogen or not at all; when R 1, R ₄ or R ₅ are substituted, then R ₇ = R ₈ = H and R ₂ = R ₃ = OH;

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

when R ₇ and R ₈ are substituted, then R ₂ and R ₃ are H or OH; when R ₇ and R ₈ is hydroxyl, then R ₂ and R ₃ are not OH;

when A = N; B = CO; C = N or NH; D = CO or C-NH ₂ ; E is CH or substituted C; F = CH; X = O, S or CH ₂ then R ₂ cannot be H, OH, CH ₃ , halogens, 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 heterocycles; 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 then R ₂ cannot 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 is 0 or _CH2, then _R2 will not be H or OH;

when A = N, B = N, CO or CH; C = CH, C-Cl or C-OCH ₃ ; D = CH or C-Ph; E is CH, C-Cl or C-Ph; F = N or CO; X = O, then _R2 will not be 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 _R2 will not be H or OH; and when A = C; B = CH; C = NH; D = CO, CS or C-NH ₂ ; E is N or NH; F = CO or CH; X = O, then R> cannot be H or OH;

Example IX.

where X is

COCH ₃ ;

Compounds of general structure:

R 'and R''are independently obtained from H, CN, C (= O) NH _{2 /} NH ₂ ,

C (= S) _NH2, C (= NH) NH? .HC1 C (= NHO) _NH2, C (= NH) OMe, heterocycles, halogens, lower alkyl or lower alkyl aryl;

heterocycles such that:

R 1 and R ₄ are obtained independently from H, CN, N ₃ , CH ₂ OH, short alkyls or short alkyl amines; and

R _2, R, RO, R, R? and R _g are independently obtained from H, OH, CN, N ₃ , halogens, CH ₂ OH, NH ₂ , OCH ₃ , NHCH ₃ , ONHCH ₃ , SCH, SPh, short alkyl alkenyl, short alkyl amines or substituent 20 when R ₂ = R ₃ = H, then R ₇ and R ₈ are hydrogen or not at all.

In compounds of Formula III, R 'is more preferably carboxamide or CN and R''is hydrogen or halogens; R 1 = R ₄ = R ₅ = R ₇ = R a = H and R ₂ = R ₃ = OH and a suitable X is oxygen.

Example X.

Compounds of formula IV, structures:

(W) wherein A is obtained independently from N or C;

B, C, E and F are independently obtained from CH, CO, N, S, SeO, NR ₂ , CCONH ₂ , CCH ₃ , CR ₂ or P; R _x is independently H, short alkyl, short alkylamines, COCH ₃ , short alkyl alkenyls, short alkyl vinyls or short alkyl aryls. R ₂ is independently H, OH, halogens, CN, N ₃ , NH ₂ , C (= O) NH ₂ , C (= S) NH ₂ , C (= NH) NH _2, HCl,

C (= NOH) NH ₂ , C (= NH) 0 Me, short alkyls, short alkylamines, short alkyl alkenyls, short alkyl vinyls, short alkyl aryls or substituted heterocycles;

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

R 1 and R ₄ are obtained independently from H, CN, N ₃ , CH ₂ OH, short alkyls and short allylalkyl amines; and

R; / R3 / Rs, Rez R? and R ₈ are obtained independently from H, OH, CN, N ₃ , halogens, NH ₂ , CH ₁ OH, OCH ₃ , NHCH ₃ , 0 NHCH ₃ , SCH ₃ , SPh, alkenyl, allyl, short alkyl, short alkyl amines and substituted heterocycles such that:

where R ₂ = R ₃ = H, then R? and R _g are hydrogen or not at all;

when A is carbon; B = E = N; C is N-Ph, then F is not CH; when A = N; C is CH; B = E = C-CH ₃ , then F is not nitrogen; and when A is carbon; B = N; C = _C-CONH2; E = CH; F = S, then X is not CH ₂ .

In the compound of formula IV, R _{x is} more preferably H, short alkyl or allyl; R ₂ is more preferably H, OH, halogens, CN, N ₃ , NH 2, C (= O) NH _; , C (= NH) NH ₂ .HCl, C (= NOH) _NH2 or C (-NH) OMe; and when R 1 = R ₄ = R ₅ = R? = R a = H, it is desirable that R ₂ = R ₃ = OH, and X is a suitable oxygen.

Example XI.

Compounds of formula V, structures:

(V) wherein A is obtained independently from N or C;

B, C, E, F are independently obtained from CH, CO, N, S, _SeO, NR _{1 -Z} CCONH ₂ , CCH ₃ , CR ₂ or P; R ₂ is independently H, short alkyl, short alkylamines, COCH ₃ , short alkyl alkenyls, short alkyl vinyls or short alkyl aryls. R ₂ is independently H, OH, halogens, CN, N ₃ NH ₂ , C (= O) NH 2, C (= S) NH ₂ , C (= NH) NH _2, HCl,

C (= NOH) _NH2, C (= NH) OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;

D is obtained independently from CH, CO, N, S, Se, O, NR 1, CCONH 2, CCH ₃ , CR ₂ , P is or is not; R 1 is independently H, O, short alkyl, short alkylamines, COCH ₃ , short alkyl alkenyls, short alkyl vinyls or short alkyl aryls. R ₂ is independently H, OH, halogens, CN, N ₃ , NH ₂ , short alkyls, short alkylamines, short alkyl alkenyls, short alkyl vinyl, short alkyl aryls or substituted heterocycles;

X is independently 0, S, _CH2 or NR where R is _COCH3;

R 1 and R ₄ are obtained independently from H, CN, N ₃ , CH ₂ OH, short alkyls and short alkyl amines; and

R ₂ , R 3, R 5, R e, R e, R e, R e, R e, R e; and R ₈ are obtained independently from H, OH, CN, N ₃ , halogens, NH ₂ , CH ₂ OH, OCH ₃ , NHCH ₃ , ONHCH ₃ , SCH ₃ , SPh, alkenyl, allyl, short alkyl, short alkyl amines and substituted heterocycles such that:

when R ₂ = R ₃ = H, then R ₇ and R ₈ are hydrogen or not at all;

when A = N; B = CO; C = N or NH; D = CO or C-NH ₂ ; E is CH or substituted C; F = CH; X = O, S or CH ₂ then R ₂ cannot be H, OH CH ₃ , halogens, 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 heterocycles;

when A = N; B = CO; C = N or NH; S = CO or C-NH ₂ ; D = CH, C-CH ₃ or halogen; F = CH; X = N-COCH ₃ then R ₂ cannot 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 _CH2, then _R2 will not be H or OH;

when A = N; B = N, CO or CH; C = CH, C-Cl or C-OCH ₃ ; D = CH or C-Ph; E is CH, C-Cl or C-Ph; F = N or CO; X = O, then _R2 will not be 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 cannot be H or OH; and when A = C; B = CH; C = NH; D = CO, CS or C-NH ₂ ; E is N or NH; F = CO or CH; X = O, then _R2 will not be H or OH;

In another aspect, the manifestation of an abnormality in enhancing responses in one group of cytokines is treated by administering nucleosides or another compound that enhances responses in another group of cytokines. For this reason, for example, a commonly rapidly starting type of allergic manifestation manifests itself in an abnormally elevated Th2 response. Abnormality is treated by administering Ribavirin between 600 mg / day and 1000 mg / day (for a normal adult), at this dose the Th1 response is caused. The treatment is effective because Th1 and Th2 have a continuous wobble state in the example such that the Th2 response is suppressed.

In another aspect, a patient is treated preventively with nucleosides or other compounds that selectively limit Th1 activity without significantly limiting Th2 activity. For example, prophylaxis may prepare the patient for organ or tissue transplantation or for suspected contact with allergens.

In another aspect, a nucleoside or other compound is administered to a patient at a dose that reduces the patient's GTP stock to an amount that selectively reduces either the Th1 or Th2 response without significantly limiting the further response. Controlled drug delivery methods are particularly suitable to achieve the desired result, especially because of the fact that they maintain the same amount of compound in the serum for a suitable time. For example, for Ribavirin, the serum level should be maintained between 2 μΜ and 5 μΜ. Under such conditions to ensure a ratio, dosing is controlled and it may be desirable to have a ratio of solutes in vitro such that the measured USP Paddle Method at 100 rpm and 900 mL aqueous buffer (pH in the range 1.6-7.2) between 15% to 40% by weight of the compound after one hour, between 30% to 50% by weight of the compound after two hours, between 50% to 70% by weight of the compound after four hours and between 60% to 80% by weight of the compound after 6 hours.

Example of use

It is contemplated that the desired combinations will be used to treat many conditions and, in fact, a particular condition that responds positively to the administration of one or more such combinations. In particular, along with other considerations, it is contemplated that the combinations may be used to treat infection, infestation, tumor, hypersensitivity, or autoimmune disease.

Contemplated infections to be treated with the compounds of the present invention include respiratory syncytial virus (RSV), hepatitis B viruses (HBV), hepatitis C viruses (HCV), cold sores, herpes simplex type 1 and 2, genital cold sores, keratitis cold sores, encephalitis cold sores, herpes zoster, immunodeficiency viruses (HIV), influenza A viruses, hantannic viruses (haemorrhagic chills), human papilloma viruses (HPV), measles and mycosis. It is contemplated that the combination required in this application will be useful in the treatment of chronic viral and bacterial infections, including HIV, tuberculosis, leprosy and others.

Contemplated infestations to be treated with the compounds of the present invention include intercellular infestations with the elements, as well as helminthic or other parasitic infestations. The combination in this application appears to be useful in the treatment of chronic infestation.

It is contemplated that tumors will be treated, including viral causes, and the effect may suppress the conversion of the virus-infected cell to a neoplastic condition, suppress the spread of viruses from the converted cell to non-normal cells, and / or arrest the growth of the virus transformed cell.

Hypersensitivity including all types of allergies, including IgE and IgC allergies, hyper IgE syndrome, and dermatic conditions such as atopic dermatitis, are contemplated. It is contemplated that the desired combinations may be used to treat transplantation (transplant versus host disease) and to treat reactions that are caused by implantation.

Autoimmune diseases can be classified as either non-organ-specific or organ-specific. Non-organ-specific autoimmune diseases such as rheumatoid arthritis, gout, systemic lupus erythematosus (SLE), Sjorg's syndrome, scleroderma, muscle inflammation, skin inflammation, joint stiffness and rheumatic chills. Organ-specific autoimmune diseases are known to practically every organ, including insulin-dependent diabetes, thyroid disease (severe Hashimoto's thyroid disease), Addison's disease and various kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis , psoriasis, hepatitis and cirrhosis, celiac disease, intestinal inflammation and various types of male and female infertility. Autoimmune development may be triggered by viral infection, including HIV viruses, may be due to the consequences of transplant rejection, and may accompany some tumors or be accelerated by exposure to various chemicals.

It is contemplated that the abnormal manifestation of an increasing response in one group of cytokines can be treated by administering nucleosides that enhance the response in other groups of cytokines. In this way, for example, common IgE allergies are associated with a predominantly Th2 response, the allergy can be treated with Ribavirin, which increases the Th1 response at small doses of about 500 mg / day to 1000 mg / day.

In another aspect, a patient is treated preventively with a compound that selectively reduces Th1 activity without significantly limiting Th2 activity. Preventive treatment may be limited by anticipation of adverse events from previous cases, such as organ or tissue transplantation or reduction of symptoms from anticipated spring pulmonary inflammations by increasing the amount of pollen in the air.

synthesis

The synthesis of the compounds of formulas 1, 1-A to 1-F was performed in a pending PCT application PCT / US97 / 18387, which is in this application although not complete. The synthesis of compounds of formulas 2 to 5 was performed in a pending PCT application PCT / US97 / 00600.

Drug administration

It is contemplated that the compounds of the present invention may be administered in a suitable pharmaceutical form and by a convenient route. Where primary or first drugs are used for treatment as described above, monotherapeutic dosages and procedures for such drugs as set out in the PDR or at least available from the manufacturer or distributor are preferred. Preferred dosages and procedures for second drugs, such as the bimodal nucleosides described in this application, may advantageously be introduced during the experiment with particular patients. The experiments need not be extensive, and it is contemplated that the second nucleoside-containing medicaments described in this application will be administered in an amount of about 100 mg / day to about 5,000 mg / day.

Of course, the skilled practitioner may argue that the therapeutically effective amount will vary depending on the infection or the conditions of treatment, the severity of the disease, the diet during treatment, the pharmacokinetic agents used, as well as the treatment of the patient (animal or human). Therefore, the amount may range from 1 mg / day body weight or less, up to 25 mg / kg body weight or more. In a therapeutically active amount of the second medicament, an amount slightly less than 1 mg / kg to 25 mg / kg of the patient is contemplated, depending on the compound used, the condition or treatment of the infection, and the mode of administration of the medicament. This dose produces an effective blood level of active compound in the range of 0.04 to 100 micrograms / cc of the patient's blood. It is contemplated that appropriate nutrition of the patient will be manifested by administration of small doses and subsequent increase in the amount either until the very adverse side effects are induced or until the desired effect is achieved.

Administration of the compounds of the present invention may be by oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion techniques), spray inhalation or rectal, topical, and the like, at a dosage of conventional non-toxic pharmaceutically acceptable carriers and carriers; vehicle.

It is also contemplated that the compounds of the present invention may be in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention may be administered orally as pharmaceutically acceptable salts. Since the compounds of the present invention are mostly water-soluble, they can be administered intravenously in saline (for example, a buffer at a pH of 7.2 to 7.5). Buffers commonly used for this purpose are phosphates, bicarbonates or citrates. Of course, the skilled practitioner may modify the treatment procedure to a knowledge basis, specify various treatments, especially the mode of administration of the drug, without changing the content of the present invention, or compromise its therapeutic activities. In particular, modifications of the present compounds result in substances that are more soluble in water or other carriers, for example, minor modifications (salt formation, esterification, etc.) which are known to the skilled chemist can be readily accomplished. Physicians also know how to adjust the route of administration and diet of particular agents to the good pharmacokinetics of the present drugs in order to achieve maximum effect for the patient.

In certain pharmaceutical dosage forms, the prodrug prodrug as a compound to be administered mainly comprises the presently preferred compounds: acyl (acetyl or other) derivatives, pyridine esters and various salt forms. The skilled chemist must know how to readily convert the present compounds to prodrugs to facilitate delivery of the active compounds to the target site within the host organism or patient. The skilled chemist may also utilize favorable pharmacokinetic indicators of drug professions to deliver the present compounds to a target site within the host organism or patient and to maximize the expected effects of the compound.

The compounds encompassed by the combination of the present invention may be administered alone or together. When administered alone, they may be administered in any order. The amount of active ingredient (s) and pharmaceutically active ingredient (s) and timing of administration will be obtained in order of the desired combined therapeutic effects to be accomplished.

The route of administration of the compounds of the present invention may range from continuous (intravenous) to several doses orally per day (e.g., QID) and may be oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal, buccal and lacee, along with other routes. administration.

In the therapy of the present invention, it is advantageous to intimately mix a therapeutically effective amount of the compound with a pharmaceutically acceptable carrier according to a conventional mixing technique, resulting in the manufacture of a dose. The carriers may take various forms depending on the desired form of preparation for dosage, for example, orally or parenterally. In prepared pharmaceutical compositions in oral form, pharmaceutical media can be used. Therefore, for a liquid formulation to be administered orally, it is appropriate to use substances such as suspensions, drinks and solutions, suitable carriers and additives, including water, glycols, oils, alcohols, essentials, preservatives, coloring agents and the like. For a solid preparation to be administered orally, it is suitable to use powder, tablets and capsules. For solid preparation, suppositories, suitable carriers and additives containing starch, sugar carriers such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like are suitable. The desired tablets or capsules may be coated or sustained with standard techniques.

For parenteral administration, the carriers will usually contain sterile water or aqueous sodium chloride solution, although these may be other ingredients, including those which allow for dispersion. Of course, where sterile water is used and kept sterile, carriers and compounds must also be sterilized. Suspensions suitable for injection may also be prepared using a suitable liquid carrier, suspending agent and the like.

It will also be appreciated that the most preferred example of use of the present invention is one in which the active compounds are relatively less cytotoxic to non-target host cells and relatively more active to the target site. In this regard, it may also be advantageous that Lnucleosides may have greater stability than D-nucleosides, which may lead to better pharmacokinetics. This finding means that L-nucleosides are not recognized by enzymes and therefore may have a longer half-life.

Thus, therapy has been discovered by those who have used nleosides and other compounds to selectively alter Th1 and Th2 responses relative to each other and to treat diseases. While specific embodiments have been disclosed in this application, the field of application is not limited to the interpretation of the appended claims.

Claims (64)

PATENT CLAIMS A method for determining an effective amount of a first compound and a second compound used in combination in a system comprising: identifying a desired concentration of the first compound that is significantly effective in discriminating imbalances; identifying a second compound known to activate the imbalance when added over a concentration range over time; and adding to the system both, wherein the amount of the first compound is less than the desired concentration and the amount of the second compound is outside the concentration range. Second The method of claim 1 is chronic characterized disease. by that imbalance Third The method of claim 1, characterized the by that imbalance results from viral disease. 4th The method of claim 1, characterized the by that imbalance results from insulin dependent diabetes. The method of claim 1, wherein the imbalance comprises allergy. The method of claim 1, wherein the imbalance comprises atopic dermatitis. • ····························· The method of claim 1, wherein the imbalance comprises intercellular elemental infection. 8th The method of claim 1 results from hyper IgE characterized syndrome. the by that imbalance 9th The method of claim 1 characterized the by that imbalance results from HIV. 10th The method of claim 1 characterized the by that imbalance results from transplantation versus host disease. The method of claim 1, wherein the imbalance results from systemic lupus erythematosus. 12. The method of claim 1, wherein the imbalance results from the tumor. The method of claim 1, wherein the imbalance comprises abnormally increasing Th1 activity. «* 14. The method of claim 1, wherein the imbalance comprises abnormally decreasing Th1 activity. The method of claim 1, wherein the imbalance comprises an abnormally increasing Th2 activity. The method of claim 1, wherein the imbalance comprises abnormally decreasing Th2 activity. 17. The method of claim 1, wherein the second compound comprises a pharmaceutically acceptable form of leukide. The method of claim 1, wherein the second compound comprises a pharmaceutically acceptable form of Dnucleoside. The method of claim 1, wherein the second compound comprises a pharmaceutically acceptable form of Lnucleoside. The method of claim 1, wherein the second compound comprises a pharmaceutically acceptable form of ribavirin. The method of claim 1, wherein the second compound comprises a pharmaceutically acceptable form of interferon. The method of claim 1, wherein the second compound comprises a nucleoside according to at least one of formulas 1, 1A, 1B, 1C, 1D, 1E or IF. The method of claim 1, wherein the second compound comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. Use of a medicament as a medicament for modulating the activity of the first cytokine phenotype in a system comprising: associating the activity of the first cytokine phenotype with the disease; combining administration of the pharmaceutical composition with dose-dependent enhancement of the activity of the second cytokine phenotype; and providing the pharmaceutical composition to the system in a first dosage range. 25. The method of claim 24, wherein the disease comprises a chronic disease. 26. The method of claim 24, wherein the disease comprises a viral disease. The method of claim 24, wherein the disease comprises insulin-dependent diabetes. 28. The method of claim 24, wherein the disease comprises allergy. 29. The method of claim 24, wherein the disease comprises atopic dermatitis. 30. The method of claim 24, wherein the disease comprises intercellular elemental infection. e l 31. The method of claim 24, wherein the disease comprises hyper IgE syndrome. 32. The method of claim 24, wherein the disease comprises HIV. 33. The method of claim 24, wherein the disease comprises transplantation versus host disease. 34. The method of claim 24, wherein the disease comprises systemic lupus erythematosus. 35. The method of claim 24, wherein the disease comprises a tumor. 36. The method of claim 24, further comprising combining a decrease in the activity of the second cytokine phenotype with administration of the pharmaceutical composition in a second dose. The method of claim 35, wherein the pharmaceutical composition comprises a pharmaceutically acceptable form of ribavirin. 38. The method of claim 35, wherein the pharmaceutical composition comprises a pharmaceutically acceptable form of interferon. 39. The method of claim 24, further comprising identifying a therapeutic agent that is effective for treating the disease at the recommended dose and administering it at the lowest recommended dose in combination with the medicament. 40. The method of claim 39, wherein the therapeutic agent is selected from the group consisting of antiviral agents, antifungal agents, intestinal agents, antitumor agents, dermatological agents, antimigraine agents, steroids, immune suppressants, and metabolic agents. 41. The method of claim 40, comprising combining a decrease in the activity of the second cytokine phenotype with administration of the pharmaceutical composition in a second dose. 42. The method of claim 39, wherein the pharmaceutical composition comprises a pharmaceutically acceptable form of ribavirin or interferon. 43. The method of claim 39, further comprising combining a decrease in the activity of the second cytokine phenotype with administration of the pharmaceutical composition in a second dose. The method of claim 24, wherein the second medicament comprises a nucleoside according to at least one of formulas 1, ΙΑ, 1B, 1C, 1D, 1E or IF. The method of claim 24, wherein the second medicament comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. The method of claim 39, wherein the second t medicament comprises a nucleoside according to at least one of formulas 1, ΙΑ, 1B, 1C, 1D, 1E or IF. 47. The method of claim 39, wherein the second medicament comprises a nucleoside according to at least one of formulas 2, 3, 4, or 5. 48. The use of a pharmaceutical composition for the prophylactic improvement of a patient's health that suppresses Th1 activity of a patient upon administration of the aforementioned dose and administration of the pharmaceutical composition to the patient with a lower indicated amount of dose. 49. The method of claim 48, wherein the prophylaxis comprises preparing the patient for an organ transplant. 50. The method of claim 48, wherein the prophylaxis comprises preparing a patient for tissue transplantation. 51. The method of claim 48, wherein the prophylaxis comprises preparing the patient for contact with allergens. 52. The method of claim 48, further comprising a pharmaceutical composition for inducing Th2 activity. The method of claim 48, wherein the pharmaceutical composition comprises a nucleoside according to at least one of formulas 1, ΙΑ, 1B, 1C, 1D, 1E or IF. 54. The method of claim 48, wherein the pharmaceutical composition comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. 55. The use of a compound for treating an abnormality in Th1 or A Th2 response in a system characterized by an abnormality of the Th1 and Th2 cytokine response by inverse mode38 by Th1 and Th2 responses comprising: identifying a compound and dose concentration thereof that reduces GTP stock systems to a level that selectively reduces one of the Th1 or Th2 responses without significant limitations on other responses; and adding the compound to the system during range regulation. 56. The method of claim 54, wherein the abnormality comprises a chronic disease. 57. The method of claim 54, wherein the abnormality comprises a viral disease. 58. The method of claim 54, wherein the abnormality comprises insulin-dependent diabetes. 59. The method of claim 54, wherein the abnormality comprises allergy. 60. The method of claim 54, wherein the abnormality comprises atopic dermatitis. 61. The method of claim 54, wherein the abnormality comprises intercellular elemental infection. 62. Method according to claim 54. characterized with that ab normality includes hyper IgE syndrome. 63. Method according to claim 54. characterized with that ab normality includes HIV. 64. The method of claim 54, wherein the abnormality comprises transplantation versus host disease. 65. The method of claim 54, wherein the abnormality comprises systemic lupus erythematosus. 66th process by Claim 54, characterized by the by that abnormalities malita It includes tumor. 67th process by Claim 54, characterized by the by that zlúče- nina comprises a nucleoside according to at least one from pattern- cov 1, 1Α, 1B, 1C, ID, IE, or 1F. 68th process by Claim 54, characterized by the by in the zlúče- nina comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. · 69. A controlled release formulation for oral administration comprising a compound that selectively modulates Th1 and Th2 responses with respect to each other during extent control. The controlled release preparation of claim 69, wherein the compound comprises a nucleoside according to at least one of formulas 1, ΙΑ, 1B, 1C, ID, IE, or 1F. The controlled release preparation of claim 69, wherein the compound comprises a nucleoside according to at least one of formulas 2, 3, 4 or 5. 72. The controlled release preparation of claim 69, wherein the compound comprises ribavirin. 73. The controlled release preparation of claim 69, wherein the compound comprises interferon. • 74. The controlled release preparation of claim 69, wherein the amount of compound in the patient's serum is maintained in the range of 2 μΜ to 5 μΜ. 75. The controlled release preparation of claim 69, wherein the preparation has an in vitro solubility ratio such that the measured USP Paddle Method at 100 rpm and 900 mL aqueous buffer (pH between 1.6 to 7.2) is between 15% to 40% by weight of the compound after one hour, between 30% to 50% by weight of the compound after two hours, between 50% to 70% by weight of the compound after four hours and between 60% to 80% by weight of the compound after six hours.