ZA200207336B - Antiviral prodrugs. - Google Patents

Description

ANTIVIRAL PRODRUGS

This application claims the benefit of U.S. provisional application number 60/189,672, , filed March 15, 2000, and U.S. utility application number 09/594,410, filed June 16, 2000, both of which are incorporated herein by reference in their entirety.

Field of the Invention

The present invention relates to the field of nucleoside analogs.

Background of the Invention

Ribavirin (1-S-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog that has demonstrated efficacy in treating viral diseases both in monotherapy [see e.g., Hall, C.

B. et al., Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection.

N. Engl. J. Med. (1983), 308, 1443-1447], and in combination therapy with interferon-alpha [Reichard, O. et al. Randomized, double blind, placebo controlled trial of interferon alpha 2B with and without ribavirin for chronic hepatitis C. Lancet (1998), 351, 83-87].

In addition to its well known role as a direct antiviral agent, Ribavirin™ also exhibits immunomodulatory properties [Hultgren, C., et al; The antiviral compound ribavirin modulates the T helper Typel/Type2 subset balance in hepatitis B and C virus-specific immune responses. J. Gen. Virol. (1998), 79, 2381-2391}, which has been demonstrated in vitro by measuring Type 1 cytokine concentrations produced by activated T cells from both humans and mice [Tam, R., et al. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J. Hepatol. (1999), 30, 376-382]. Such immunomodulatory properties may advantageously be employed in treatments of various diseases.

However, Ribavirin™ is also known to exhibit significant toxicity [see e.g., Joksic, G. et al. Influence of Ribavirin™ on the micronucleus formation and in vitro proliferation of human lymphocytes. Neoplasma (2000);47(5):283-7], and especially hematotoxicity [see e.g.,

Jarvis, S., et al. Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br J Pharmacol (1998) , Apr;123(8):1587-92], thereby substantially reducing its usefulness in long-term treatments and/or treatments in relatively high dosages.

To reduce at least some of the cytotoxic effects of Ribavirin™, the L-isomer of

Ribavirin™ (Levovirin) can be administered to a patient. For example, while oral administration of Ribavirin™ in rats at 180mg/kg over four weeks produced significant ' hemolytic anemia and leukopenia, Levovirin did not produce any observable clinical . 5 pathology. Administration of the L-isomer of Ribavirin™ reduces at least some aspects of cytotoxicity, however, conversion of Ribavirin™ into the corresponding L- isomer generally fails to improve target specificity with respect to a target cell and/or target organ. ~ Although various triazole-type nucleoside analogs for use in antiviral and antineoplastic treatments are known in the art, all or almost all of them suffer from one or more disadvantages. Therefore, there is still a need to provide methods and compositions for nucleosides with improved tolerability and specificity.

Summary of the Invention

The present invention is directed to nucleoside analogs and their prodrug forms, wherein in one aspect contemplated compounds have a structure according to formula (I):

Ri Oo

N

/

H “a

N

3

OR, ol ®

RyO ORs wherein R; is a masking group of the amino group; R; is H, -C(O)R, or -P(O)(OR’),, wherein

R is C;-Cy7 alkyl, alkenyl, or alkynyl, and R’ is a masking group of the phosphate group; R3 and Rj’ are independently H or C;-C;3 acyl, and R; and R; are not hydrogen at the same time,

In another aspect of the invention, contemplated nucleoside analogs have a structure according to formula (II):

Ry hy

N

/

H pe

N

3 ' ol (mn ) HO OH wherein R; is a masking group having any of the following structures: 0 i

R—C—0—(CHp)y—C— i i

R— Ex Hono 0 no

R—C—S—(CH,)y~0—C— 0

I

R—S—S—C— i

R—S§—S—(CHy);~0—C— i

R—C—X—CH;— inwhich Xis O or S, and R is C;-Cy; alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched.

In a further aspect of the inventive subject matter, contemplated compounds have a structure according to formula (III):

Ri 0

N

/ ! “y (um)

ND 0 oa P—OR,

OR,

HO OH wherein R; is H or an amino masking group, and R; is a masking group of the phosphate group having any of the following structures: : i

Rebx er R—S—S—(CH)— i

Ros—s—( cir R—C—X—CHy— in which X is O or S, and R is C;-C;3 alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched.

In a still further aspect of the inventive subject matter, contemplated compounds have a structure according to formula (IV):

N

H pen \ Iv) : N ~ OP of

HO OH wherein R; is H or a masking group of the amino group, and R; is a group having any one of the following structures: i i 0

R—C—S—(CHy);~ O—P— R—O—b—

R— ¢— S—(CHy),—O R—0 co 39 _p=0 M—C— 0” \ i gi ) M-— CH & o-m in which R is C;-Cys alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched, and in which M is selected from alkyl, alkenyl, alkynyl, aralkyl, aryl, and a hydrophobic group (e.g., cholesterol, a vitamin D derivative, or a cholic acid derivatives ) bearing a linker which can be covalently attached to the carbonyl group). ) 5 In yet another aspect of the invention, a pharmaceutical composition comprises a therapeutically effective amount of any one or a combination of Formulas I-IV, or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable carrier. Contemplated compositions are useful in treatment of various diseases, and particularly contemplated diseases include viral infections and cancer. 10 Detailed Description

Where the following terms are used in this specification, they are used as defined below. The terms "nucleoside" and "nucleoside analog" are used interchangeably, and refer to a compound comprising a sugar moiety covalently coupled to a heterocycle. Particularly preferred heterocycles include aromatic heterocycles, and even more preferred heterocycles 15 include a purine, a pyrimidine, or a purine/pyrimidine analog. Most preferred heterocycles include a triazole. The term "nucleotide" refers to a nucleoside that is coupled to at least one phosphate group.

The term "heterocycle" refers to a carbocyclic radical having at least one heteroatom within the ring (e.g., N, O or S), wherein each position in the heterocycle may be 20 independently substituted with a functional or non-functional group. Functional groups include nucleophilic groups, electrophilic groups, polar groups, (e.g., hydroxy, oxo, amino, imino groups), and non-functional groups include alkyl groups and halogens.

The term "protecting group" or "masking group" refers to a chemical group that is covalently bound to an oxygen or nitrogen atom of contemplated compounds to prevent 25 further reaction of the oxygen or nitrogen atom in the course of derivatization of other . functional groups in contemplated compounds. A wide variety of oxygen, phosphate, and nitrogen protecting groups are known to those skilled in the art of organic synthesis (see e.g,, ‘ Protecting Groups in Organic Synthesis by James R. Hanson, Blackwell Science Inc; ISBN: 063204506X, or Activating Agents and Protecting Groups, Handbook of Reagents for Organic

Synthesis by William R. Roush and Anthony J. Pearson; John Wiley & Son Ltd; ISBN: 0471979279, both incorporated by reference herein). . Particularly preferred masking groups of the amino group include groups having the following structures: i il

R—C—0—(CHp)y—C— i i rx Hoot , 0 i

R—C—8—(CHy),~0—C— 0

R—S—S—C— i

R—S—S—(CHy)»~0—C— and 9

R—C—X—CH,—

Further contemplated masking groups of the amino group include aliphatic ester-type masking groups (e.g., acetyloxypentanoic acid, acetyloxyhexanoic acid, or acetyloxypropanoic acid), para-acetyloxybenzyloxycarbonyl-type masking groups (e.g., para-hydroxybenzloxy- carbonyl, or para-acetyloxyxybenzloxycarbonyl), or para-acetyldisulfidecarbonyl-type masking groups.

Similarly, while various masking groups for the phosphate groups are suitable, particularly contemplated masking groups have the following structure: i

Reber cn , R—S—S—(CHa)— i - Ress cnr , and R—C—X—CHy—

However, in further alternative aspects, suitable masking groups may also include aliphatic ester-type masking groups (e.g., acetyloxypentanoic acid, acetyloxyhexanoic acid, or acetyloxypropanoic acid), para-acetyloxybenzyloxycarbonyl-type masking groups (e.g,

parahydroxybenzloxycarbonyl, or para-acetyloxyxybenzloxycarbonyl), or paraacetyldisulfidecarbonyl-type masking groups. ’ The term "lower alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl, or n-hexyl, and further includes a cyclic, branched or straight chain from one to six : 5 carbon atoms. The term "aryl" refers to an unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl), which may be substituted with a functional or non-functional group.

The term "L-nucleoside" refers to nucleoside compounds having a sugar moiety in

L-configuration. The compounds of Formulas I-IV may have multiple asymmetric centers.

Accordingly, they may be prepared in either optically active form or as a racemic mixture. The scope of the invention as described and claimed encompasses the individual optical isomers and non-racemic mixtures thereof as well as the racemic forms of the compounds of Formulas

I-IV. Similarly, the term "o" and "8" indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn.

The term "pharmaceutically acceptable salt" refers to any salt derived from an inorganic and/or organic acid or base.

Contemplated compounds

It is generally contemplated that compounds according to the inventive subject matter include at least a portion of the L-isomer of Ribavirin™ (i.e., Levovirin), and it is preferred that contemplated compounds will be converted to Levovirin in vitro and/or in vivo. It is also contemplated that compounds according to the inventive subject matter may be prepared by covalently binding at least one modifying or masking group to at least one hydroxyl group on the sugar moiety and/or the amino group on the carboxamide function on the triazole ring.

Consequently, contemplated compounds of the inventive subject matter particularly include compounds according to formula (I), in which some or all of the hydroxyl groups and/or amino groups are modified by a protecting group:

Ry. ©

N

/ >, d) . fo) OR, 0 ‘ RO ORs wherein R, is a masking group of the amino group; R; is H, -C(O)R, or -P(O)(OR’),, wherein

Ris C;-Cy7 alkyl, alkenyl, or alkynyl, and R’ is a masking group of the phosphate group; R; and R3' are independently H or C;-Ci3 acyl, wherein R; and R; are not hydrogen at the same time.

In other contemplated nucleoside analogs, the amino group of the carboxamide function on the triazole ring is modified with a masking group, and such analogs may have a structure according to formula (II):

Ri J

N

/ oe

N. o uy oa

HO OH wherein R; is a masking group having any one of the following structures: i i

R—C—0—(CHy)y—C— i i

R— Ex Hcnro-t- i i

R—C—S—(CHz),-0—C— i

R—S—S—C— i

R—S—S8—(CH,);—0—C— i

R—C—X—CHy—

in which X is O or S, and R is C;-C3 alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched. : In still further contemplated compounds, the nucleoside analog is a nucleotide in which the amino group in the carboxamide group and/or the phosphate group on the Cs' oxygen are ‘ 5 modified with a masking group, and has a structure according to formula (III):

Ry \

N

/

H Be am

N_ :

N R ons

OR,’

HO OH wherein R; is H or a masking group of the amino group, and R, and R;' are independently a masking group of the phosphate group having any one of the following structures: i rbox( cue R—S8—5—(CHz),— 1

Ros—s—( cir R—C—X—CHr— in which X is O or S, and R is C;-C3 alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched.

Alternatively, contemplated compounds may have a structure according to formula (IV), in which the amino group of the carboxamide function in the triazole is optionally protected, and in which the Cs'-atom of the ribose moiety may be derivatized with various substituents:

Ri 0

N

’ oH < \ av)

N

. oP of

HO OH wherein R; is H or a masking group of the amino group, and R; is a group having any one of the following structures: . Q 2 0

R—C—§—(CH);~0—P—0— R—0—p—

R~C—S~—(CHzr—0 R—0 : 0 0 0 :

R _b=0 M—C— 0" a

Ooo

Wo

M-CH

V C. 0” “o-M in which R is C;-Cyg alkyl, alkenyl, alkynyl, aryl, or aralkyl, all of which may be straight or branched, and in which M is selected from alkyl, alkenyl, alkynyl, aralkyl, aryl, and a hydrophobic group (e.g., cholesterol, a vitamin D derivative, or a cholic acid derivative which may optionally comprise a linker).

In further alternative aspects of the inventive subject matter, substituents or ligands can be placed at different positions on the sugar or base of the compound. In preferred aspects, the substituents or ligands may be placed on the 2', 3, 4', or §', position of the sugar portion of the nucleoside. In other alternative aspects, the substituents or ligands can be placed on the base portion (i.e., the triazole) of the nucleoside to modify the base portion without disrupting the aromaticity or conjugation within the heterocyclic ring. Especially contemplated substituents include halogens, polar and non-polar groups, nucleophilic and electrophilic groups, and acidic and basic groups. For example, contemplated substituents include -CN, -Cl, -COOH, -CHO, -CH =CH, C(O)NH,, etc.

Alternatively, it should also be appreciated that omission of one or more substituents . may result in particularly desirable physico-chemical properties of contemplated molecules.

For example, where contemplated compounds interact with nucleoside/nucleotide metabolism, ‘ 20 2'-, and/or 3'-deoxyribose may be employed.

Various ligands may be covalently linked to a particular position on the sugar and/or base (i.e. the triazole ring) of contemplated compounds, wherein the ligands may comprise a drug or a non-drug. For example, contemplated drugs include cytostatic agents, antimetabolites, immunomodulators, antiviral agents, etc., while non-drugs include polymers (e.g., PEQG), resins, and various moieties that may alter solubility, polarity, charge, etc.

Contemplated ligands or substituents can also be designed to comprise a certain size or ' 5 length, or even to reflect a specific polarity. Consequently, contemplated ligands or substitu- ents may include alkyl, alkylene, alcohols, amines, amides, sulfones, sulfides, esters, ketones, carboxylic acids, metal ions, transition metal ions, aromatic compounds, heterocyclic aromatic compounds, cyclic compounds, heterocyclic compounds, heteroacyclic compounds, and amino acids.

In still further contemplated aspects of the inventive subject matter, compounds according to the inventive subject matter may also be designed to be "target-specific". For example, contemplated molecules, which may or may not include additional substituents or ligands, may be designed to target a particular part or organ of a patient, such as the liver, brain, or stomach. Alternatively, contemplated compounds may also be designed to target a particular subcellular compartment such as the nucleus or the mitochondria. Consequently, it is contemplated that suitable compounds may include substituents and or ligands to become reactive or to change biological activity with respect to a target molecule, target compartment, target cell, or target organ upon entry or exit of such compounds in he respective target.

Uses of contemplated compounds

It is contemplated that compounds according to formulae I-IV may be used to treat a wide variety of conditions, and in fact any condition which responds positively to administra- tion of one or more of such compounds. Among other things it is specifically contemplated that compounds according to the inventive subject matter may be used to treat an infection, an infestation, a cancer or tumor or an autoimmune disease. It is further contemplated that contemplated compounds may be used to target conditions or diseases in specific organs of a patient (typically a mammal, preferably a human), such as the liver or the heart.

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 genitals, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), measles, and fungus. Infestations contemplated to be treated with the compounds of the present invention include protozoan infestations, as well as helminth and other parasitic infestations.

Cancers or tumors contemplated to be treated include those caused by a virus, and the ) 5 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.

Autoimmune and other diseases contemplated to be treated include arthritis, psoriasis, bowel disease, juvenile diabetes, lupus, multiple sclerosis, gout and gouty arthritis, rheumatoid arthritis, rejection of transplantation, giant cell arteritis, allergy and asthma.

Consequently, a method of treating a mammal (preferably a human) having a cancer, a viral infection, an infestation, a cancer, or an autoimmune disease, comprises administering a therapeutically and/or prophylactically effective amount of a pharmaceutical containing a compound according to the inventive subject matter.

In yet another aspect, a method of treating a mammal (preferably a human) comprises administering a therapeutically and/or prophylactically effective amount of a pharmaceutical containing a compound of the present invention. In this aspect the effect may relate to modulation of some portion of the mammal’s immune system, especially modulation of lymphokines profiles of Type 1 and Type 2 with respect to one another. Where modulation of

Type 1 and Type 2 lymphokines occurs, it is contemplated that the modulation may include suppression of both Type 1 and Type 2, or reduction in expression of Type 1 cytokines and stimulation of expression of Type 2 cytokines.

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 is especially advantageous that * contemplated L-nucleosides 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.

It is further contemplated that compounds according to the present invention will be administered in any appropriate pharmaceutical formulation, and under any appropriate protocol. Thus, administration may take place orally, parenterally (including subcutaneous injections, intravenous, intramuscularly, by intrasternal injection or infusion techniques), by ] 5 inhalation spray, or rectally, topically and so forth, and in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

By way of example, 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 pharmacolo- gically acceptable salts. Because the compounds of the present invention are mostly water soluble, they can be administered intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5). 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.) that 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.

Thus contemplated compounds are presented to a cell (or target cell) in vivo or in vitro in a concentration range of between about 10nM to about 1mM, preferably between 100nM and 500uM, and most preferably between SuM and 500M. Where the administration of contemplated compounds is in vitro, admixing in any suitable form is contemplated. For example, where compounds according to the inventive subject matter are solid, admixing may be performed by adding the solid (e.g., as powder or tablet) to the medium. Alternatively, } where contemplated are dissolved or are liquid, admixing may be done in a continuous or discontinuous form (e.g., by pipetting). Similarly, where the administration of contemplated compounds is in vivo, presentation of contemplated compounds is contemplated in any suitable form and/or formulation (supra). For example, where compounds according to the

Claims (30)

1. \ PCT/US01/08769 “$ AMENDED CLAIMS .. [received by the International Bureau on 18 January 2002 (18.01.02): ’ original claims 1. 7. 10. 13. 16 and 18 amended: remaining claims unchanged (4 pages))

   I. A compound according to formula (I) Rig 0 ) r= H N i 1 ND 0) oh R‘O OR, wherein R, is a masking group of the amino group; wherein R» is H. an amino acid radical, -C(O)R. or -P(O)(OR");, wherein R is C;-C;5 alkyl. alkenyl, or alkynyl, and R’ is a masking group of the phosphate group; R; and R;' are independently H or C;-C,3 acyl; and wherein R, and R; are not hydrogen at the same time.
2. 2. The compound of claim 1 wherein R) is selected from the group consisting of acetyloxypentanoic acid, para-acetyloxybenzyloxycarbonyl, para- acetyldisulfidecarbonyl; and wherein Rj, R3 and Ry' are independently H or acetyl.
3. 3. The compound of claim 2 wherein R3 and Ry' are H.
4. 4. The compound of claim 2 wherein R; is hydrogen.
5. 35. The compound of claim 2 wherein R, is a masking group comprising a carbonyl function.
6. 6. The compound of claim 1 wherein Riz and Rj; are hydrogen, and wherein R, comprises a phosphate.
7. 7. A compound according to formula (II) Ri, 0 ae H % NP (1 ol E HO OH 34 AMENDED SHEET (ARTICLE 19) CLEAN COPY

   ” ~ PCT/US01/08769 wherein R, is a masking group of the amino group having a structure selected from the group consisting of 0 0 i 1 R—C—0—(CHy)}y—C— 0 0 nox Hcneo-t— i 0 i R—C—S—(CH;—0—C— 0 il : R—S—S—C— i R—S—S—(Clly);=0—C— _ 0 R—C—X~CH:— .,q : wherein X is O or S, and R is a C-Cy3 alkyl, alkenyl, alkynyl, aryl, or aralkyl.
8. 8. The compound of claim 7 wherein the masking group comprises a disulfide bond. :
9. 9. The compound of claim 7 wherein the masking group is selected from the group consisting of lo) 0 I fl R—C—0—(CHyy—C— 0 0 Rox H—cnro-t and 7 7 R—C—S8—(CHy»—-0—C— and wherein X is O or S, and R is a C,-C;; alkyl. alkenyl, alkynyl, aryl. or aralkyl.
10. 10. A compound according to formula (I
11. II) Ri 0 — / H N Cy hn (11) of P—OR;

    OR. HO OH AMENDED SHEET (ARTICLE J9) CLEAN COP

    - PCT/US01/08769 wherein R; is H or a masking group of the amino group. and wherein R, and R,' are a independently a masking group of the phosphate group having a structure selected from the group consisting of i redox cn . R—S—8§-—(CH5)y— , 0 Res—s—(_ one , R—C—X—CH.— cand cr wherein X is O or S, and R is C,-C 5 alkyl, alkenyl, alkynyl, aryl. or aralkyl. IL The compound of claim 10 wherein R is a masking group.
12. 12. The compound of claim 10 wherein R; is a masking group comprising a disulfide bond.
13. 13. A compound according to formula (IV) Ri, 0

    N . / . H Ty

    N. Iv N av) oa HO OH wherein R; is H or a masking group of the amino group, and wherein R; is a group having a structure selected from the group consisting of 0] 0 0] it Ti I R—C—S~—(CHa),~0— P—, R—O— P— R=C—5—(CHy);—0 R—O 0 56 —0 P= ’ M—C— o” \ * and 0 i Aol NH M—CH PAN 0° o0-M 36 AMENDED SHEET (ARTICLE 19) CLEAN copy ) E

    . wherein R is C-C, alkyl, alkenyl, alkynyl, aryl or aralkyl, and wherein M is alkyl, alkenyl, alkynyl, aralkyl, aryl, or a hydrophobic group.
14. 14. The compound of claim 13 wherein the hydrophobic group is selected from the group consisting of a cholic acid, a bile acid, a cholesterol derivative and a vitamin D derivative.
15. 15. The compound of claim 14 wherein R, comprises a phosphate.
16. 16. Use of a compound selected from the group consisting of a compound according to claim 1, a compound according to claim 7, a compound according to claim 10, and a compound according to claim 13 in the manufacture of a preparation for treating a mammal having a viral infection.
17. 17. Use of claim 16 wherein the viral infection comprises an infection with an HCV virus or an HBV virus, and wherein the mammal is a human.
18. 18. A method of modulating a lymphokine profile in a mammal comprising: providing a composition that includes a compound selected from the group consisting of a compound according to claim 1, a compound according to claim 7, a compound according to claim 10, and a compound according to claim 13; and administering the composition to the mammal in a dosage effective to reduce expression of a type 1 cytokine and stimulate expression of a Type 2 cytokine.
19. 19. The method of claim 18 wherein the mammal is a human.
20. 20. Use of a compound selected from the group consisting of a compound according to claim 1, a compound according to claim 7, a compound according to claim 10, and a compound according to claim 13 in the manufacture of a preparation for modulating a lymphokine profile in a mammal. 37 AMENDED SHEET v ” “
21. 21. Use of claim 20 wherein the mammal is a human.
22. 22. A substance or composition for use in a method of treating a mammal having a viral infection, said substance or composition comprising a compound selected from the group consisting of a compound according to claim 1, a compound according to claim 7, a compound according to claim 10, and a compound according to claim 13; and said method comprising administering said substance or composition to the mammal.
23. 23. A substance or composition for use in a method of treatment of claim 22 wherein the viral infection comprises an infection with an HCV virus or an HBYV virus, and wherein the mammal is a human.
24. 24. A substance or composition for use in a method of modulating a lymphokine profile in a mammal, said substance or composition comprising a compound selected from the group consisting of a compound according to claim 1, a compound according to claim 7, a compound according to claim 10, and a compound according to claim 13; and said method comprising administering said substance or composition to the mammal in a dosage effective to reduce expression of a type 1 cytokine and stimulate expression of a Type 2 cytokine.
25. 25. A substance or composition for use in a method of treatment of claim 24 wherein the mammal is a human.
26. 26. A compound according to any one of claims 1 to 15, substantially as herein described and illustrated.
27. 27. Use according to claim 16, or claim 20, substantially as herein described and illustrated. 38 AMENDED SHEET
28. FE “ 28. A method according to claim 18, substantially as herein described and illustrated.
29. 29. A substance or composition for use in a method of treatment according to claim 22, or claim 24, substantially as herein described and illustrated.
30. 30. A new compound, a new use of a compound as claimed in any one of claims 1 to 15, a new non-therapeutic method of treatment, or a substance or composition for a new use in a method of treatment, substantially as herein described. 39 AMENDED SHEET