AU736075B2 - Cytokine related treatments of disease - Google Patents

Description

P:\OPERUMS\60231-98.CLM 3/2/00 -1- CYTOKINE RELATED TREATMENTS OF DISEASE FIELD OF THE INVENTION The present invention relates to the field of nucleosides.

BACKGROUND OF THE INVENTION Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells), which originate in the bone marrow; and T lymphocytes (T cells) which originate in the thymus. B cells are largely responsible for humoral immunity antibody production), while T cells are largely responsible for cell-mediated immunity.

15 T cells are generally considered to fall into two subclasses, helper T cells and cytotoxic :macrophages, by releasing soluble protein mediators called cytokines which are involved in cell-mediated immunity. As used herein, lymphokines are a subset of cytokines.

20 Helper T cells are also generally considered to fall into two subclasses, Thl and Th2.

Th cells (also known as Type 1 cells) produce interleukin 2 tumor necrosis factor (TNFa) and interferon gamma (IFNy), and are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. In contrast, Th2 cells (also known as Type 2 cells) produce interleukins, IL4, IL-5, IL-6, IL-9, L-10 and EL-13, and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and lgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7:145-173).

As used herein, the terms Thl and Th2 "responses" are meant to include the entire o range of effects resulting from induction of Thl and Th2 lymphocytes, respectively. Among \other things, such responses include variation in production of the corresponding cytokines WO 98/30223 PCT/US98/00634 -2through transcription, translation, secretion and possibly other mechanisms, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including motility effects.

The priority applications, each of which is incorporated herein by reference, relate to aspects of our recent discoveries involving the effect of various nucleosides (which are defined herein to include derivatives and analogs of native nucleosides) on selectively modulating lymphocyte responses relative to each other. Among other things, we have shown that either of Th and Th2 responses can be selectively suppressed while the other is either induced or left relatively unaffected, and either of Th or Th2 responses can be selectively induced while the other is either suppressed or left relatively unaffected. We have also discovered the surprising fact that nucleosides effective in selectively modulating Thl and Th2 responses relative to one another tend to have a bimodal effect. Among other things, nucleosides which tend to generally suppress or induce both Thl and Thl activity at a relatively higher dose, tend to selectively modulate Thi and Th2 relative to each other at relatively lower doses.

The mechanisms by which nucleosides and other compounds selectively modulate Thl and Th2 responses relative to each other are still unclear. One possibility contemplated by the present inventors is that effective nucleosides alter the pool of guanosine triphosphate (GTP), which in turn affects the rate at which cytokines are produced. In this theory, relatively large variations in available GTP are sufficient to affect concentrations of both Thl and Th2 cytokines, while relatively smaller variations in available GTP tend to affect concentrations of Thl and Th2 cytokines to different extents.

The effects of 2-P-D-ribofuranosylthiazole-4-carboxamide (Tiazofurin), a synthetic Cnucleoside analogue, on GTP levels supports this view. Tumor cells are characterized by high levels of inosine monophosphate dehydrogenase (IMP DH) activity, and it is known that IMP DH is the rate-limiting enzyme of GTP biosynthesis. Weber, IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment, Adv. Exp. Med. Biol. 309B:287-292 (1991). Tiazofurin has been shown to selectively block IMP DH activity and deplete guanine nucleotide pools, which in turn forces various tumors into remission. Weber, Critical WO 98/30223 PCT/US98/00634 -3- Issues in Chemotherapy with Tiazofurin, Adv. Enzyme Regul. 29:75-95 (1989). Typical initial doses of Tiazofurin are about 4,400 mg/m 2 with consolidation doses of about 1100 to 3300 mg/m 2 At these levels synthesis of both Thl and Th2 responses are greatly reduced, thereby essentially shutting down much of the immune system. In one aspect of the present invention it is contemplated that much smaller doses of Tiazofurin, in the range of 1/10th to one-half that set forth above, would be sufficient to specifically suppress either a Thl response or a Th2 response without greatly reducing the other response.

The effects of 1-b-D-ribofuranosyl-1, 2 ,4-triazole-3-carboxamide (Ribavirin) also supports the present theory. Ribavirin is a potent, broad-spectrum antiviral agent, which has also been shown to inhibit IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Tiazofurin and Ribavirin on Purified IMP Dehydrogenase, Biochem. 27:2193-2196 (1988).

Ribavirin proceeds under a different mechanism than Tiazofurin in inhibiting IMP DH, however, acting on a different site on the enzyme molecule. Ribavirin is converted to its active metabolite, ribavirin-monophosphate (RMP), which inhibits the enzyme at the IMP- XMP site of IMP DH. As with Tiazofurin, the affinity of Ribavirin's active form to the enzyme is higher than that of the natural metabolite. At relatively high doses, approximately 2200 mg/m 2 or about 1200 1500 mg/day for an adult, Ribavirin reduces IMP DH activity to such an extent that both Thl and Th2 responses are inhibited. At relatively lower dosages of approximately 600 to 1000 mg/day, Ribavirin promotes a Thl response and suppresses a Th2 response.

Despite the existence of as-yet undefined mechanisms, we have discovered that enormous potential benefits can be derived from selective modulation of Thl and Th2 responses relative to each other. We have concluded, for example, that specific modulation of Thl relative to Th2 can be useful in treating a wide variety of conditions and diseases, ranging from infections, infestations, tumors and hypersensitivities to autoimmune diseases.

These discoveries are especially significant because modern treatment strategies for many of the above-listed diseases have either limited effectiveness, significant side effects, or both. Treatment of autoimmune disease, for example, is frequently limited to palliative WO 98/30223 PCT/US98/00634 -4measures, removal of toxic antibodies (as in myasthenia gravis), and administration of hazardous drugs including corticosteroids, chloroquine derivatives, and antimetabolic or antitumor drugs, and drugs such as cyclosporines which target immune system cells.

SUMMARY OF THE INVENTION This application relates to the use of nucleosides in the relatively low dosage range to selectively modulate Thl 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 Thl 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 Thl or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result.

Examples of nucleosides contemplated to be effective in this manner are D- and Lforms of: bicyclic nucleosides corresponding to any of Formulas 1, 1-A through 1-F; and monocyclic nucleosides nucleosides corresponding to any of Formulas 2 through Examples of primary drugs contemplated to be effective in this manner are anti-viral agents such as Ribavirin, acyclovir, and AZTrM; anti-fungal agents such as tolnaftate, FungizoneTM, Lotrimin,TM Mycelex,TM, Nystatin and Amphoteracin; anti-parasitics such as MintezolTM, NiclocideTM, VermoxTM, and FlagylTM; bowel agents such as ImmodiumTM, LomotilTM and PhazymeM; anti-tumor agents such as AdriamycinTM, CytoxanTM, ImuranTM, Methotrxate, MithracinTM, TiazofurinTM, TaxolTM; dermatologic agents such as AclovateTM, CyclocortTM, DenorexTM, FloroneTM, OxsoralenTM, coal tar and salicylic acid; migraine preparations such as ergotamine compounds; steroids and immunosuppresants not listed WO 98/30223 PCT/US98/00634 above, including cyclosporins, DiprosoneTM, hydrocortisone; FloronTM, LidexTM, Topicort and Valisone; and metabolic agents such as insulin.

DETAILED DESCRIPTION Definitions Where the following terms are used in this specification, they are used as defined below.

The terms and indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn.

The term "abnormality" refers to a condition associated with a disease. Thus, Th and/or Th2 responses resulting from an autoimmune disease are considered herein to be abnormalities of the corresponding cytokine(s) even though such cytokine responses may commonly result from the disease.

The term "aryl" refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring phenyl) or two condensed rings naphthyl), which can optionally be substituted with hydroxyl, lower alky, chloro, and/or cyano.

The term "effective amount" refers to the amount of a compound of formula which will restore immune function to normal levels, or increase immune function above normal levels in order to eliminate infection.

The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers, in a 1:1 ratio, is a "racemic" mixture.

The term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, O or S, within the ring each available position of which can be optionally substituted, independently, with, hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within this class of substituents are purines, pyrimidines.

The term "immunomodulators" refers to natural or synthetic products capable of modifying the normal or aberrant immune system through stimulation or suppression.

The term "isomers" refers to different compounds that have the same formula.

"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

The term "L-configuration" is used throughout the present invention to describe the chemical configuration of the ribofuranosyl moiety of the compounds that is linked to the nucleobases. The L-configuration of the sugar moiety of compounds of the present invention contrasts with the D-configuration of ribose sugar moieties of the naturally occurring nucleosides such as cytidine, adenosine, thymidine, guanosine and uridine.

The term "lower alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, Ibutyl or n-hexyl. This term is further exemplified to a cyclic, branched or straight chain from one to six carbon atoms.

The term "monocyclic" refers to a monovalent saturated carbocyclic radical having at least one hetero atom, such as O, N, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with a sugar moiety or any other groups like bromo, chloro and/or cyano, so that the monocyclic ring system eventually aromatized, The term "nucleoside" refers to a compound composed of any pentose or modified 5 pentose moiety attached to a specific position of a heterocycle or to the natural position of a purine 9 -position) or pyrimidine (1-position) or to the equivalent position in an analog, including especiall both D- and L- forms of nitrogenous bicyclic and monocyclic heterocycles depicted in Figures 1, 1-A through 1-F, and 2 through 5 herein.

The term "C-nucleosides" is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base. In C-nucleosides, the linkage originates from the C-l position of the ribose sugar moiety and joins the carbon of the heterocyclic base. The linkage that forms in C-nucleosides are carbon to carbon type.

The term "D-nucleosides" refers to nucleoside compounds that have a D-ribose sugar moiety Adenosine).

The term "L-nucleosides" refers to nucleoside compounds that have an L-ribose sugar moiety.

The term "N-nucleosides" is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base. In N-nucleosides, the linkage originates from the C-l position of the ribose sugar moiety and joins the nitrogen of the heterocyclic base. The linkage that forms in N-nucleosides are carbon to nitrogen type.

Z_ A' I NI WO 98/30223 PCT/US98/00634 -7- The term "nucleotide" refers to a phosphate ester substituted on the 5'-position of a nucleoside.

The term "pharmaceutically acceptable salts" refers to any salt derived from inorganic and organic acids or bases.

The term "protecting group" refers to a chemical group that is added to, oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

The term "purine" refers to nitrogenous bicyclic heterocycles depicted in Figures 1, 1- A through 1-F herein.

The term "pyrimidine" refers to nitrogenous monocyclic heterocycles depicted in Figures 2 through 5 herein.

The term "tumor" refers broadly to all manner of autonomous morbid growth of tissue which may or may not become malignant, including all manner of neoplasms and cancers.

The terms "treating" or "treatment" of a disease refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Thus, "treating" or "treatment" do not require complete alleviation of signs or symptoms, do not require a cure, and specifically include protocols which have only marginal effect on the patient.

Combinations and Methods Contemplated combinations in one aspect of the present invention generally include a primary or "first" drug and another or "second" drug, and contemplated methods involve selecting and combining the first and second drugs in combination therapies. In preferred embodiments a disease is identified which is known to produce an abnormality in at least one cytokine in a patient, the first drug is selected from among those compounds demonstrated to treat the disease at a monotherapeutic dosage, and the second drug, which may be a bimodal nucleoside modulator as herein described, is selected from among those compounds known to exacerbate the very abnormality produced by the disease when administered within a given dosage range. The first drug is then administered at less than the monotherapeutic dosage and the second drug is administered in a dosage outside the dosage range which exacerbates the abnormality. Since the second drug has a bimodal activity with respect to at least some of the cytokines of interest, the combination is still effective to treat the disease, and administration of the second drug allows reduction in the administered dosage of the primary or first drug.

Examples of primary drugs contemplated to be effective in combination with a modulator selected from Figures 1, 1-A through 1-F, and 2-5, are anti-viral agents such as interferon, including but not limited to interferon a and y, Ribavirin, acyclovir, and AZTr; anti-fungal agents such as tolnaftate, FungizoneTM, Lotrimin, Mycelex, r Nystatin and Amphoteracin; anti-parasitics such as Mintezol", Niclocide

M

Vermox r and FlagylTM; bowel agents such as ImmodiumTM, LomotilTM and PhazymeTM; anti-tumor agents such as interferon a and y, AdriamycinT

M

CytoxanTM, Imuran™, Methotrexate, Mithracin

M

Tiazofurin m TaxolTM; dermatologic agents such as Aclovate'

M

CyclocortrM, Denorexm, Florone™

M

Oxsoralen r coal tar and salicylic acid; migraine preparations such as ergotamine compounds; steroids and immunosuppresants not listed above, including cyclosporins, Diprosone m hydrocortisone; Floron T M LidexM, Topicort and Valisone; and metabolic agents such as insulin, and other drugs which may not nicely fit into the above categories, including cytokines such as IL2, 1L4, 16, IL8, IO1 and L12. Especially preferred primary drugs are AZT, 3TC, 8-substituted guanosine analogs, 2',3'-dideoxynucleosides, interleukin II, interferons such as laB-interferons, tucaresol, levamisole, isoprinosine and cyclolignans.

Examples of secondary drugs contemplated to be effective in the invention are D- and L- forms of bicyclic nucleosides corresponding to generic Formula 1 and 1-A through 1-F, and monocyclic nucleosides nucleosides corresponding to Formulas 2 through 5. Other S nucleoside and non-nucleoside compounds effective in the invention are readily identified through screening of such compounds in vitro for effect on L-2, TNF-a, IFN-y, IL-4 and IL- Co 0 WO 98/30223 WO 9830223PCTIUS98/00634 -9- Formula I compounds are purine nucleosides having the structure:

Z

3

Z

4

R

RI R 3 Formula 1 wherein R,R 2 R(3, 1R4, R5, R2' and R(3' are independently selected from the group consisting of H, OH, NH 2 F, Cl, Br, 1, N 3 -CN, -NR! 2

-NHNT

2 -NHOH, CHO, COOR', CONR' 2 alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, 1, N 3 -CN, NO 2

-NR"

2 SR", -NHNH 2 -NHOH, COOR", CONR"' 2 and where R' and R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl;- W=0, S, CH 2 ,Se; ZI 2are independently selected from N, C, CH;

Z

3 Z, are independently selected from the group consisting of -CR=CR-, where R is selected from the group consisting of H, F, Cl, Br, 1, N3, -CN, -NR! 2

-NHNH-

2 -NHOH, -NO 2 CR0, COOR', CONH 2

-C(O)-NH

2

-C(S)-NH

2

-C(NH)-NH

2 -C(NOH)-N1 2 =NH, =NOH, =NR, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from H, -OH,

NH

2 F, Cl, Br, I, N 3 -CN, -COOR", -CONR" 2

-NR."

2

-NIHNII

2 -NHOH, -NO 2 and R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl; The Chemical bond between Z 3 and Z 4 or Z 4 and Z. is selected from C-C, C=C, C-N, C=N, N-N, N=N, C-S, N-S; S X and Y are independently selected from the group consisting of H, F, Cl, Br, L, N 3

-S-NH

2

-S(O)-NH

2 -S(02)-NH 2 -CN, -COOR', -CONR 2

-NR'

2

NIINH

2 NHOH, alkyl, alkenyl, alcylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, 1, N 3 -CN, NO2, -NR" 2 SR", -NHN}I,, -NHOH, and R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl.

Formula 1 -A compounds are 8-substituted a-or fl-L- or D- guanosine analogs having the structure: 0 N

NH

x- RI

RI

wherein X is selected from H, R, N 3 -CN, -OR, -SR, -NR 2

-NHINH

2 -NHOH, -CHO,

-CONH

2 -COOR, and where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -NR' 2 -NHfNR' 2 -CHO, -COORI, -CONR' 2 where R' is selected from H, Me, Et, allyl, acetyl, -COCF 3 P:\OPER\JMS\60238-98.CLM 28h2/00 -11 I- Y is selected from H, R, F, Cl, Br, 1, N 3 CN, OR, SR. NR 2 where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CH; and RI, R 2 and R 3 are independently selected from H, -OH, -OAc, -OBz, -OP(0 2

)H.

Formula IlB compounds are 7-substituted-8-oxo-"-or 1-L-guanosine analogs having structure: x 0

N

0 N z _NH 0 R3 Formula 1-B wherein X is selected from a group comprising H, R, -NH- 2 -CHO, -COOR, and where .2, is selected from a group comprising alkyl, alkenyl, alkynyl, and aralkyl; L is a linker and selected from a group comprising alkyl, alkenyl, alkynyl, and aralkyl; A is selected from a group comprising H, F, Cl, Br, 1, -NR! 2 -Ni-NH 2 NHOH, N 3 -CHO, -CONi- 2 -COOR!, and -CN, where R' is selected from a group comprising Me, Et, allyl, acetyl, and -COCF 3 Y is selected from a group comprising H, R, F, Cl, Br, 1, N 3 -CN, -OR. -SR. and -NR 2 where R is selected from a group comprising H, alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, and sulfonyl; Z is N or CH; and RI, R 2 and R 3 are independently selected from a group comprising H, -OH, -OAc, -OBz, and -OP(0 2

)OH.

P:\OPERUJMS\60238-9g.CLM 29/2/00J -h1A- Formula I1-C com.pounds are. 7-deaza-7,8-mono- or disubstituted "-or P3- L- or Dguanosine analogs having the structure: Formula 1-C 9* WO 98/30223 WO 9830223PCT/US98/00634 -12wherein XI and X 2 are independently selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR, -NR 2

-NHNII

2 -NHOH, -CHO, -CONH 2 -COOR, and where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -NR' 2

-NIINR'

2 -CHO, COOR', -CONR' 2 where R'is selected from H, Me, Et, allyl, acetyl, -COCF 3 Y is selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR, -NR 2 where R is selected from H, alkyl, aikenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CH; RI, R 2 and R 3 are independently selected from H, -OH, -OAc, -OBz, -OP(0 2

)OH.

Formula I -D compounds are 7-deaza-8-aza-7-substituted %-or f3- L- or D- guanosine analogs having the structure: x

N

0

R

3

R

1 R 2 Formula 1-D X is selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR, -NR 2

-NIINH

2

-NHOH,-

CHO, -CONH 2 -COOR, and where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, SR', -NR' 2

-NHNR'

2 -CHO, -COOR', -CONR' 2 where R' is selected from H, Me, Et, allyl, acetyl, -COCF 3 Y is selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR, -Nk2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CH; PAPERJMS\6023 98-.d.d.W-I hoo 13 X i .s selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR. -NR 2

-NIINH

2 -NHOH, -CH-O,

CONE-

2 -COORt, and where R is selected from alkyl, alkenyl, alkyriyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -ORW, SR', -NR! 2 tINR' 2 -CHO, -COOR!, -CONR! 2 where R! is selected from H, Me, Et, allyl, acetyl, -COCF 3 Y is selected from H, R, F, Cl, Br, 1, N 3 -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CHP, RI. R 2 and R 3 are independently selected from H, -OH, -QAc, -OBz, -OP(0 2

)OH.L

Formula I1-E compounds are thiazolo[4,5-dlpyrimidine a-or f-L- or D- nucleosides having the structure: N ZY 0

R

is =NI- 2

R

2 X, sS N,=N2 =NHOH, or =NR where R is selected from alkyl, alkyenyl, alkynyl, and aralkyl, acyl;

X

2 is S, 0, or Se Y is selected from H, R, F, Cl, Br, I, N 3 -CN, -OR, -NR 2 where R is selected from H, **:alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CH; RI, R 2 and R 3 are independently selected from H, -OH, -QAc, -OBz, -OP(0 2

)OHL

Formula I1-F compounds are f3-L- or D- purine nucleosides having the structure: WO 98/30223 PCT/US98/00634 -14- X is selected from H, R, -SNH2, -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; 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

1

Z

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

R

1 R2, and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(0 2

)OH.

Formula 2 compounds have the structure: X R 6

/V

R, R 7 RS R 4

R

2 R 3 Formula 2 wherein: A is independently selected from N or C; B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR', CCONH 2

CCH

3

C-R

2 or P; R' is independently H, lower alkyl, lower alkylamines, COCH 3 lower alkyl alkenyl, lower alkyl vinyl or lower 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 .HC1, C(=NOH)NH 2 C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; D is independently selected from CH, CO, N, S, Se, O, NR', CCONH 2

CCH

3

C-R

2

P

or nothing, where R' is independently H, O, lower alkyl, lower alkylamines, COCH 3 lower WO 98/30223 WO 9830223PCTIUS98/00634 alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls, and W( is independently H, OH, halogens,

CNN

3 NI-1 2 lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; X is independently 0, S, CH 2 or NR; where R is COCH 3 R, and R(4 are independently selected from H, CN, N 3

CH

2 OH, lower alkyl and lower alkyl amines;

R(

2

R

3 R(5, R(7 and are independently selected from H, OH, CN, N 3 halogens,

CH

2 OH, NH 2

OCH

3

NHCH

3

ONI{CH

3 S CH 3 SPh, alkenyl, lower alkyl, lower alkyl amines and substituted heterocycles; and RI, R 2 1(3, R(4, R5, R6, R(7 and R, are not all substituted at the same time; such that when R2 R(3 then R(7 and are hydrogens or nothing; when RJ, or R,5 are substituted, then R(7 Rg= H and R2 =1R3 =OH; when R2 or R 3 are substituted, then R(7 and R, are H or OH; when R(7 or R, are substituted, then R2 and R(3 are H or OH; when R(7 and R8 are hydroxyl, then R2 and R 3 are not OH; when A N; B CO; C N or NH; D =COor C-NH 2 E is CH or C-substituted; F CH; X 0, S or CH 2 then R2 will not be H, OH, CH 3 halogens, N 3 CN, SH, SPh, CH 2

OH,

CH,OCH

3

CH

2 SH, CH 2 F7, CH 2

N

3 aryl, aryloxy or heterocycles; when A B CO; C N or NH-D =CO or C-N 2 E is CH, C-CH 3 or halogen; F CH;X =N-COCH 3 then R2 will not be H or OH;when A B =CH; C CHor CH 3 D =CHor C-CH 3 E isCH, C-CH 3 or C-

CONH

2 F =CH; X=O0, or CH 2 then R2 will not be H or OH; whenA N; B COor CH; C =CHC-C1or C.OCH 3 ;D =CH or CPh; Eis CH, C-Cl or C-Ph F N or CO- X =0 then R2 will not be Hor OH; whenA=N; B =CO orCS;C =N orNH; D= CO or C-NH.Eis CH orN; F=N or CH; X 0, then R, will not be H or OH; and when A B =CH; C =NH- D= CO, CS orC-NH 2 Eis Nor NH;TF= CO orCH; X 0, then R2 will not be H or OH.

Formula 3 compounds have the structure: WO 98/30223 PCT/US98/00634 -16- R

N

N R N Rs X R 6 R, R 7

R

8 R4

R

2

R

3 Formula 3 wherein: X is independently 0, S, CH 2 and NR, where R is COCH 3 R' and R" are independently selected from H, CN, C(=O)NH2, NH2, C(=S)NH 2

C(=NH)NH

2 .HCI, C(=NOH)NH 2 C(=NH)OMe, heterocycles, halogens, lower alkyl or lower alkyl aryl; R, and R4 are independently selected from H, CN, N 3 CH20OH, lower alkyl or lower alkyl amines; and R2, R 3 R5, R 6 R7 and R8 are independently selected from H, OH, CN, N 3 halogens,

CH

2 OH, NH2, OCH3, NHCH 3

ONHCH

3

SCH

3 SPh, alkenyl, lower alkyl, lower alkyl amines or substituted heterocycles; such that when R 2

R

3 H, then R 7 and R, are hydrogens or nothing.

In compounds of Formula 3, R' is preferably carboxamide or CN and R" is hydrogen or halogens; R, R4 R5 R7 R, H and R2 R3 OH, and preferably X is oxygen.

Formula 4 compounds have the structure: WO 98/30223 WO 9830223PCT/US98/00634 -17c -E R6 R, 1171R8

R

4 R12 R13 Formula 4 wherein: A is independently selected from N or C; B, C, E and F are independently selected from CH, CO, N, S, Se, 0, NR', CCONH- 2 CCH,, C-R 2 or P; R' is independently H, lower alkyl, lower alkylamines, COCR 3 lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R 2 is independently H, OH, halogens, CN, N 3 N2, C(=O)NH 2 C(=S)N4 2 C(=Ni-)NI- 2 .HCI, C(=NOH)NH 2 C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; X is independently 0, S, CH 2 or NR; where R is COCH- 3 R, and R(4 are independently selected from H, CN, N 3

CH

2 OH, lower alkyl or lower alkyl amnines; and

R

2 R(3, R 5 R6, R(7 and R, are independently selected from H, OH, CN, N 3 halogens,

NH

2

CH

2 OH, OCH 3

NHCH

3

ONHCH

3

SCH

3 SPh, alkenyl, allyl, lower alkyl, lower alkyl amines or substituted heterocycles; such that when R2 R3= H, then R 7 and R, are hydrogens or nothing; when A is carbon; B E N; C is N-Ph, then F is not CH; when A Cis CH; B C-CH then F is not nitrogen; and when A is carbon, B N; C C-CONI- 2 E CH; F S, then X is not CH 2 In compounds of Formula 4, R' is preferably H, lower alkyl or allyl; W( is preferably H, OH, halogens, CN, N 3 N11I 2 C(0)NH 2

C(=S)NH

2

C(=N)NH

2 .HCI, C(=NOH)NH 2 or WO 98/30223 PCT/US98/00634 -18- C(=NH)OMe; and when R R 4 R R Rg H, then preferably R R OH and preferably X is oxygen.

Formula 5 compounds have the structure:

D

E

BF

SRS

X

R

6

R

1

R

7 R R 4

R

2 R 3 Formula wherein: A is independently selected from N or C; B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR', CCONH2,

CCH

3

C-R

2 or P; R' is independently H, lower alkyl, lower alkylamines, COCH 3 lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R 2 is independently H, OH, halogens, CN, N 3

NH

2

C(=O)NH

2 C(=S)NH2, C(NH)NH 2 .HC1, C(=NOH)NH 2 C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; D is independently selected from CH, CO, N, S, Se, O, NR', CCONH 2

CCH

3

C-R

2

P

or nothing; R' is independently H, O, lower alkyl, lower alkylamines, COCH 3 lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R 2 is independently H, OH, halogens, CN, N3,

NH

2 lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; X is independently O, S, CH 2 or NR where R is COCH 3 R, and R 4 are independently selected from H, CN, N 3

CH

2 OH, lower alkyl and lower alkyl amines; and WO 98/30223 PCT/US98/00634 -19-

R

2 R, R, R 7 and R, are independently selected from H, OH, CN, N 3 halogens,

CH

2 OH, NH2, OCH 3

NHCH

3

ONHCH

3

SCH

3 SPh, alkenyl, lower alkyl, lower alkyl amines and substituted heterocycles; such that when R 2

R

3 H, then R 7 and R, are hydrogens or nothing.

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 then R 2 will not 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 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 then R 2 will not be H or OH; when A N; B N, CO or CH; C CH, C-CI or C-OCH3; D CH or C-Ph; E is CH, C-CI or C-Ph; F N or CO; X O, then R 2 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 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 2 will not be H or OH.

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. Thus, for example, a common rapid onset type of allergy results in an abnormally elevated Th2 response. The abnormality is treated by administering Ribavirin at between 600 mg/day and 1,000 mg/day (for a typical adult), at which dose the Thl response is induced. The treatment is effective because Thl and Th2 have a teeter-totter type relationship in this instance, such that the Th2 response is suppressed.

In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Thl activity without significantly reducing Th2 activity. The prophylaxis can, for example, prepare the patient for organ or tissue transplant, or for anticipated contact with allergens.

WO 98/30223 PCT/US98/00634 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 Thl or Th2 response without significantly reducing the other response.

Controlled release dosage forms are particularly contemplated to achieve that result, especially formulations which maintain the dose of the compound in the serum within a desirable range.

In the case of Ribavirin, for example, the serum level should be maintained between about 2 jpM and about 5 ptM. In terms of delivery rates, a controlled release formulation may advantageously have an in vitro dissolution rate when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) between about 15% and 40% by weight of the compound after 1 hour, between about 30% and about 50% by weight of the compound after 2 hours, about 50% and 70% by weight of the compound after 4 hours, between about 60% and about 80% by weight of the compound after 6 hours It is contemplated that the claimed combinations will be used to treat a wide variety of conditions, and in fact any condition which responds positively to administration of one or more such combinations. Among other things it is specifically contemplated that such combinations may be used to treat an infection, an infestation, a tumor, a hypersensitivity or an autoimmune disease.

Infections contemplated to be treated with the compounds of the present invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), measles and fungus. It is especially contemplated that combinations claimed herein will be useful in treating chronic viral and bacterial infections, including HIV, Tuberculosis, leprosy and so forth.

Infestations contemplated to be treated with the compounds of the present invention include intracellular protozoan infestations, as well as helminth and other parasitic infestations.

Again, it is especially contemplated that combinations claimed herein will be useful in treating chronic infestations.

WO 98/30223 PCT/US98/00634 -21- Tumors contemplated to be treated include those caused by a virus, and the effect may involve inhibiting the transformation of virus-infected cells to a neoplastic state, inhibiting the spread of viruses from transformed cells to other normal cells and/or arresting the growth of virus-transformed cells.

Hypersensitivities contemplated to be treated include all types of allergies, including IgE and IgG allergies, hyper IgE syndrome, and dermatic conditions such as atopic dermatitis.

It is also contemplated that claimed combinations can be used to treat transplant rejection, (graft vs. host disease) and implant reactions.

Autoimmune diseases can be classified as either non-organ-specific or organ-specific.

Non-organ-specific autoimmune diseases include rheumatoid arthritis, gout and gouty arthritis, Systemic Lupus Erythematosus (SLE), Sjogren syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis, and rheumatic fever. Organ-specific autoimmune diseases are known for virtually every organ, including insulin-dependent diabetes, thyroid diseases (Graves disease and Hashimoto thyroiditis), Addison disease, and some kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, forms of hepatitis and cirrhosis, celiac disease, inflammatory bowel disease, and some types of male and female infertility. Autoimmune processes may also be stimulated by viral infections including the HIV virus, may result from rejection of transplantation, and may accompany certain tumors, or be precipitated by exposure to some chemicals.

It is also contemplated that an abnormality reflected in increased response in one group of cytokines can be treated by administering a nucleoside which increases response in another group of cytokines. Thus, for example, since common IgE allergies are associated with a predominantly Th2 response, allergies can be treated with Ribavirin, which increases Thl response at low dosages of about 500 mg/day to about 1,000 mg/day.

In yet another aspect of the invention, a patient is prophylactically treated by administering a compound which selectively reduces Thl activity without significantly reducing Th2 activity. The prophylactic treatment may be to reduce expected undesirable WO 98/30223 PCT/US98/00634 -22effects from an upcoming event, such as an organ or tissue transplant, or to reduce symptoms from an expected pulmonary insult, as from the onset of increase in airborne pollen levels in Spring.

Synthesis Synthesis of compounds according to Formulas 1, and I-A through I-F were set forth in co-pending PCT application PCT/US97/18387, which is incorporated herein as though set forth in full. Synthesis of compounds according to Formulas 2 through 5 were set forth in copending PCT application PCT/US97/00600.

Administration It is contemplated that compounds according to the present invention will be administered in any appropriate pharmaceutical formulation, and under any appropriate protocol. Where primary or "first" treatment drugs are employed as discussed above, preferred monotherapeutic dosages and protocols for such drugs are set forth in the PDR, or are at least available from the manufacturer or distributor. Preferred dosages and protocols for the "second" drugs, such as bi-modal nucleosides described herein, may best be established through experimentation with particular patients. Such experimentation need not be extensive, and it is contemplated that "second" drugs comprising nucleosides as described herein will be administered at between about 100 mg/day and about 5,000 mg/day.

Of course, one of ordinary skill in the art will recognize that a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated. Thus, effective dosages may range from 1 mg/kg of body weight, or less, to 25 mg/kg of body weight or more. In general a therapeutically effective amount of the "second" drug is contemplated to range from slightly less than about 1 mg./kg. to about mg./kg. of the patient, depending upon the compound used, the condition or infection treated and the route of administration. This dosage range generally produces effective blood level concentrations of active compound ranging from about 0.04 to about 100 micrograms/cc of blood in the patient. It is contemplated, however, that appropriate patient-specific regimens WO 98/30223 PCT/US98/00634 -23will be developed by administering a small amount, and then increasing the amount until either the side effects become unduly adverse, or the intended effect is achieved.

Administration of compounds according to the present invention may take place orally, parenterally (including subcutaneous injections, intravenous, intramuscularly, by intrasternal injection or infusion techniques), by inhalation spray, or rectally, topically and so forth, and in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

It is contemplated that compounds according to the present invention can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally as pharmacologically acceptable salts. Because the compounds of the present invention are mostly water soluble, they can be administered intravenously in physiological saline solution buffered to a pH of about 7.2 to Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.

In certain pharmaceutical dosage forms, the pro-drug form of administered compounds, especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred. One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient. One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of WO 98/30223 PCTUS98/00634 -24the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.

In addition, compounds included in combinations according to the present invention may be administered separately or together, and when administered separately this may occur in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

Administration routes of compounds according to the present invention may range from continuous (intravenous drip) to several oral administrations per day (for example, and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.

To prepare therapies according to the present invention, a therapeutically effective amount of a compound is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.

A carrier may take a wide variety of forms depending on the form of preparation desired for administration, oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carrier, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques.

For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may P:\OPERUMS\60238-98.CLM i8/2/00 be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

It will also be appreciated that in general, the most preferred uses according to the present invention are those in which the active compounds are relatively less cytotoxic to the non-target host cells and relatively more active against the target. In this respect, it may also be advantageous that L-nucleosides may have increased stability over D-nucleosides, which could lead to better pharmacokinetics. This result may attain because L-nucleosides may not be recognized by enzymes, and therefore may have longer half-lives.

Thus, therapies have been disclosed which employ nucleosides and other compounds to selectively modulate Thl and Th2 responses relative to each other in the treatment of S 15 disease. While specific embodiments have been disclosed herein, the scope of the invention is not be limited except through interpretation of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and or variations such as "comprises" or "comprising", will S 20 be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

s page is followed by page 33 This page is followed by page 33

Claims (58)

1. A method of reducing an administered dosage of a first drug in the treatment of a disease which is known to produce an abnormality in at least one cytokine in a patient, comprising: identifying a monotherapeutic dosage of the first drug which is effective to treat the disease; identifying a second drug as one that exacerbates the abnormality when administered as a monotherapy within a dosage range; and administering a combination therapy comprising the first drug at less than the monotherapeutic dosage and the second drug outside the dosage range.

2. The method of claim I wherein the disease comprises a chronic disease.

3. The method of claim I wherein the disease comprises chronic viral disease.

4. The method of claim 1 wherein the disease comprises insulin dependent diabetes. The method of claim 1 wherein the disease comprises allergy.

6. The method of claim 1 wherein the disease comprises atopic dermatitis.

7. The method of claim 1 wherein the disease comprises intracellular protozoan infection.

8. The method of claim 1 wherein the disease comprises hyper IgE syndrome.

9. The method of claim 1 wherein the.disease comprises HIV. The method of claim 1 wherein the disease comprises graft versus host disease.

11. The method of claim 1 wherein the disease comprises Systemic Lupus Erythematosus.

12. The method of claim 1 wherein the disease comprises a tumor. AMENDED SHEET (ARTICLE 19) wo98/0223 13 AUG 1998

13. The method of any of claims 1-12 wherein the abnormality comprises an abnormal increase in Thl activity.

14. The method of any of claims 1-12 wherein the abnormality comprises an abnormal decrease in ThI activity. The method of any of claims 1-12 wherein the abnormality comprises an abnormal increase in Th2 activity.

16. The method of any of claims 1-12 wherein the abnormality comprises an abnormal decrease in Th2 activity.

17. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of a nucleoside.

18. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of a D-nucleoside.

19. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of an L-nucleoside. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of Ribavirin.

21. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically 'acceptable form of an interferon.

22. The method of any of claims 1-12 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, ID, IE or 1F.

23. The method of any of claims 1-12 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or PCT8 9 8 00 63 4 ,13 AUG 1996

24. A method of treating a disease in a patient, comprising: recognizing that the disease is associated with an increase in activity of a first lymphokine phenotype; recognizing that a particular pharmaceutical is capable of both increasing and decreasing a second lymphokine phenotype depending on the dosage; and administering the pharmaceutical to treat the disease at least in part by affecting the activity of the second lymphokine phenotype. The method of claim 24 wherein the disease comprises a chronic disease.'

26. The method of claim 24 wherein the disease comprises chronic viral disease.

27. The method of claim 24 wherein the disease comprises insulin dependent diabetes mellitus..

28. The method of claim 24 wherein the disease comprises allergy.

29. The method of claim 24 wherein the disease comprises atopic dermatitis. The method of claim 24 wherein the disease comprises intracellular protozoan infection.

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 graft versus host disease.

34. The method of claim 24 wherein the disease comprises Systemic Lupus Erythematosus. The method of claim 24 wherein the disease comprises a tumor.

36. The method of any of claims 24 34 wherein the first phenotype is Th2 and the second phenotype is Thl. AMENDED SHEET (ARTICLE 19) ;,e PCT/ 9 8 G 63 4 wo 93223 13 AUG 1998

37. The method of claim 36 wherein the pharmaceutical comprises a pharmaceutically acceptable form of Ribavirin.

38. The method of claim 36 wherein the pharmaceutical comprises a pharmaceutically acceptable form of an interferon.

39. The method of any of claims 24 35 further comprising administering the pharmaceutical in a combination therapy with a therapeutic agent. The method of claim 39 wherein the therapeutic agent is selected from the list consisting of anti-viral agents, anti-fungal agents, bowel agents, anti-tumor agents, dermatologic agents, migraine preparations, steroids, immuno-suppresants and metabolic agents.

41. The method of claim 39 wherein the pharmaceutical comprises a pharmaceutically acceptable form of Ribavirin or an Interferon.

42. The method of claim 39 wherein the first phenotype is Th2 and the second phenotype is Thl.

43. The method of any of claims 24 35 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, ID, IE or IF.

44. The method of any of claims 24 35 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or The method of claim 39 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, lD, IE or 1F.

46. The method of claim 39 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 13 AUG 1998

47. A method of prophylactically treating a patient comprising: providing a pharmaceutical which suppresses Thl activity in the patient when administered above a given dosage level; and administering the pharmaceutical to the patient below the given dosage level.

48. The method of claim 47 wherein the prophylaxis comprises preparing the patient for an organ transplant.

49. The method of claim 47 wherein the prophylaxis comprises preparing the patient for a tissue transplant. The method of claim 47 wherein the prophylaxis comprises preparing the patient for expected contact with allergens.

51. The method of any of claims 47 49 further comprises providing the pharmaceutical at a dosage which induces Th2 activity.

52. The method of any of claims 47 49 wherein the pharmaceutical comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, ID, IE or IF.

53. The method of any of claims 47 49 wherein the pharmaceutical comprises a nucleoside according to at least one of Formulas 2, 3, 4 or AMENDED SHEET (ARTICLE 19)

54. o 56. 4

57. D

58.

59.

60. 0

61.

62.

63.

64.

66.

67. LtiK S ^I ^^jy~ A method of treating a disease having an elevated or suppressed Thl or Th2 response, comprising: identifying a compound and a dosage range for the compound as having efficacy in reducing the patient's GTP pool and thereby selectively reducing one of the Thl or Th2 response without significantly reducing the other response; and administering the nucleoside to the patient within the dosage range. The method of claim 54 wherein the disease comprises a chronic disease. The method of claim 54 wherein the disease comprises chronic viral disease. The method of claim 54 wherein the disease comprises insulin dependent diabetes mellitus. The method of claim 54 wherein the disease comprises allergy. The method of claim 54 wherein the disease comprises atopic dermatitis. The method of claim 54 wherein the disease comprises intracellular protozoan infection. The method of claim 54 wherein the disease comprises hyper IgE syndrome. The method of claim 54 wherein the disease comprises HIV. The method of claim 54 wherein the disease comprises graft versus host disease. The method of claim 54 wherein the disease comprises Systemic Lupus Erythematosus. The method of claim 54 wherein the disease comprises a tumor. The method of any of claims 54 65 wherein the compound comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, ID, 1E or 1F. The method of any of claims 54 65 wherein the compound comprises a nucleoside accordingto at least one of Formulas 2, 3, 4 or 0 P OPER JMS 002;S-9S-clin dloc O' 01

68. A controlled release preparation for oral administration including a compound effective to selectively modulate Thl and Th2 responses with respect to each other within a dosage range, the controlled release aspect of the preparation assisting in maintaining a serum level below that which would suppress both Thl and Th2 responses, wherein the compound comprises a nucleoside according to at least one of Formulas 1, 1A, 1B, 1C, ID, lE or IF, or a nucleoside according to at least one of Formulas 2, 3, 4 or

69. The controlled release preparation of claim 68 wherein the preparation also comprises Ribavirin. o

70. The controlled release preparation of claim 68 wherein the preparation also comprises an interferon.

71. The controlled release preparation according to any of claims 68-70 wherein the patient maintains a serum level of between about 2 pM and about 5 AM of the compound. S 72. The controlled release preparation according to any of claims 68-71 wherein the preparation has an in vitro dissolution rate when measured by o: the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) between about 15% and 40% by weight of the compound after 1 hour, between about 30% and about 50% by weight of the compound after 2 hours, about 50% and 70% by weight of the compound after 4 hours, between about 60% and about 80% by weight of the compound after 6 hours. Dated this 7 th day of May 2001. ICN Pharmaceutials, Inc. ApL By their Patent Attorneys I Davies Collison Cave