Thiosemicarbazones as anti-virals and immunopotentiators Number:7,521,062 from the United States Patent and Trademark Office (PTO) owispatent The present invention is directed to novel immune potentiators, novel vaccine adjuvants, novel compounds and pharmaceutical compositions, novel methods for treating viral infections, including HCV, by administering the compounds, and novel methods for modulating an immune response by administering the compounds.<H immunopotentiators, Thiosemicarbazones, Thiosemicarbazo, 7521062.html, Patent, pto, 7521062

Title: Thiosemicarbazones as anti-virals and immunopotentiators

Abstract: The present invention is directed to novel immune potentiators, novel vaccine adjuvants, novel compounds and pharmaceutical compositions, novel methods for treating viral infections, including HCV, by administering the compounds, and novel methods for modulating an immune response by administering the compounds.

Patent Number: 7,521,062 Issued on 04/21/2009 to Barsanti, et al.

Inventors: Barsanti; Paul A. (Pleasant Hill, CA), Brammeier; Nathan (Walnut Creek, CA), Diebes; Anthony (Minnetonka, MN), Lagniton; Liana Marie (Berkeley, CA), Ng; Simon (Walnut Creek, CA), Ni; Zhi-Jie (Fremont, CA), Pfister; Keith B. (San Ramon, CA), Philbin; Casey (Columbus, OH), Valiante; Nicholas (Walnut Creek, CA), Wagman; Allan S. (Belmont, CA), Wang; Weibo (Moraga, CA), Weiner; Amy J. (Fairfield, CA)
Assignee: Novartis Vaccines & Diagnostics, Inc. (Emeryville, CA)

Appl. No.: 10/748,071

Filed: December 29, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60436472	Dec., 2002
60436638	Dec., 2002
60438987	Jan., 2003

Current U.S. Class: 424/278.1 ; 424/184.1; 514/357; 514/408; 514/582; 552/517

Current International Class: A61K 39/00 (20060101); A61K 31/175 (20060101); A61K 31/40 (20060101); A61K 39/095 (20060101); A61K 45/00 (20060101); A61K 31/44 (20060101)

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6613803	September 2003	Wang et al.
6638947	October 2003	Wang et al.
2003/0045568	March 2003	Altamura et al.
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Foreign Patent Documents


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Blantz, et al. Carcinostatic Activity of Thiosemicarbazones of Formyl Heteroaromatic Compounds. VII. 2-Formylpyridine Deriviatives Bearing Additional Ring Substitituents. J Med Cehm. 1970; 13(6)1124-1130. cited by examiner .
Edelman, "An Update on Vaccine Adjuvants in Clinical Trial," Aids Research and Human Retroviruses 8(8): 1409-1411 (1992). cited by examiner .
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Dickson and Iddon, "Condensed Thiophene Ring Systems. Part XII. Synthesis and Antiviral Activity of Some Benzo [b] Thiophene-2- and -3-Carbaldehyde Thiosemicarbazones" Int. J. Sulfur Chem. 8(2) :233-242, 1973. cited by other .
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Primary Examiner: Campell; Bruce
Assistant Examiner: Snyder; Stuart W
Attorney, Agent or Firm: Morrison & Foerster LLP

Parent Case Text

This application claims benefit of priority to the following US Provisional Patent Applications, Ser. No. 60/436,472, filed Dec. 27, 2002; Ser. No. 60/436,638, filed Dec. 30, 2002; and Ser. No. 60/438,987 filed Jan. 10, 2003; each of which is incorporated herein by reference in its entirety for any purpose.

Claims

What is claimed is:

1. A composition comprising: a vaccine in an amount effective to stimulate a cell--mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, wherein the thiosemicarbazone is a compound of formula I: ##STR00927## wherein: E is absent or selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; L is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl; W is absent or selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; X is a absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl; Y is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; Y' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; Y'' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; R' is H, alkyl, or substituted alkyl; R'' is H, or R' and R'' are taken together to form a heterocyclic ring; Z and Z' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxy, substituted alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyl sulfonyl, methanesulfonyl, and substituted or unsubstituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, heteroarylamino, alkylcarbonylamino, alkylaminocarbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, cycloamidino, cycloalkyl, cycloimido, arylsulfonyl and arylsulfonamido; or Z and Z' are taken together to form a heterocyclic group, which may be optionally substituted; the tautomers and the pharmaceutically acceptable salts, esters, or prodrugs thereof.

2. The composition of claim 1 wherein R' is H.

3. The composition of claim 1 wherein the thiosemicarbazone is a compound of formula III, ##STR00928## wherein: W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl groups; X and L are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl; R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino; Y is an aryl or heteroaryl group; Y' is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; Y'' is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; Z is hydrogen, or if Y is furanyl, then Z may be selected from the group consisting of alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; and salts, prodrugs, or tautomers thereof.

4. The composition of claim 3 wherein W is an optionally substituted phenyl.

5. The composition of claim 3 wherein W is substituted with at least one member selected from the group consisting of Br, Cl, F, and CF.sub.3.

6. The composition of claim 1 wherein Y is selected from the group consisting of phenyl, furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, imidazolyl and pyrimidinyl.

7. The composition of claim 6 wherein Y is phenyl, furanyl, or pyrimidinyl.

8. The composition of claim 3 wherein Z is hydrogen.

9. The composition of claim 3 wherein Y' is F or nitro.

10. The composition of claim 3 wherein W is phenyl optionally substituted with --CF.sub.3 or Cl; Y is phenyl; Y' is F or nitro; and Z is H.

11. The composition of claim 1 wherein the thiosemicarbazone is a compound of formula IV, ##STR00929## wherein: W is an optionally substituted phenyl or pyridinyl group; X is alkoxy or alkylamino; Y' is H or fluoro; Y'' is dialkylamino, fluoro, or nitro; and salts, prodrugs, or tautomers thereof.

12. The composition of claim 11 wherein W is an optionally substituted phenyl.

13. The composition of claim 11 wherein W is an optionally substituted pyridinyl group.

14. The composition of claim 11 wherein W is substituted with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; --CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3.

15. The composition of claim 11 wherein the thiosemicarbazone is ##STR00930## wherein: W is phenyl substituted with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; --CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3; X is alkoxy; and salts, prodrugs, or tautomers thereof.

16. The composition of claim 15 wherein X is --OCH.sub.2--.

17. The composition of claim 15 wherein the compound is ##STR00931## wherein: W is pyridinyl or is phenyl substituted with at least one member selected from the group consisting of Cl, F, and CF.sub.3; X is alkylamino; and salts, prodrugs, or tautomers thereof.

18. The composition of claim 17 wherein X is --NHCH.sub.2CH.sub.2-- or NHCH.sub.2--.

19. The composition of claim 17 wherein W is pyridinyl.

20. The composition of claim 17 wherein W is phenyl substituted with Cl, F, and CF.sub.3.

21. The composition of claim 1 wherein the thiosemicarbazone is a compound of Formula IVc ##STR00932## wherein: W is phenyl substituted with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; --CH.sub.3; N(CH.sub.3).sub.2; and --OCF.sub.3; X is alkoxy; and n is an integer from 1 to 3.

22. The composition of claim 1 wherein the thiosemicarbazone is a compound of Formula V ##STR00933## wherein: R is an alkyl group; X is alkoxy; and salts, prodrugs, or tautomers thereof.

23. The composition of claim 22 wherein R is methyl.

24. The composition of claim 22 wherein X is --OCH.sub.2--; --OCH.sub.2CH.sub.2--; --CH.sub.2O--; or --CH.sub.2CH.sub.2O--.

25. The composition of claim 1 wherein the thiosemicarbazone is a compound of Formula VI ##STR00934## wherein: X is absent or an alkylene; Y' is absent or is an alkyl group; and R is a halogen; and salts, prodrugs, or tautomers thereof.

26. The composition of claim 25 wherein X is --CH.sub.2CH.sub.2--; Y' is absent or is methyl, and R is Cl.

27. The composition of claim 1 wherein the thiosemicarbazone is a compound of Formula VII ##STR00935## wherein: R is nitro and Z is H; or R is Cl and Z is selected from the group consisting of alkyl, pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperazinylalkylene; and salts, prodrugs, or tautomers thereof.

28. The composition of claim 27 wherein Z is methyl, pyridylmethylene, piperidinylethylene, morpholinylethylene, piperazinylmethylene, piperazinylethylene, and morpholinylbutylene.

29. The composition of claim 1 wherein the thiosemicarbazone is a compound of formula VIII and salts, prodrugs, or tautomers thereof: ##STR00936## wherein: W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group; X is absent or is selected from the group consisting of oxo, amino, alkylene, and substituted alkylene; and Y is an aryl or heteroaryl group.

30. The composition of claim 29 wherein Y is selected from the group consisting of phenyl, furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl.

31. The composition of claim 29 wherein Y is furanyl.

32. The composition of claim 29 wherein X is absent.

33. The composition of claim 29 wherein W is substituted with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; --CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3.

34. The composition of claim 1 wherein the thiosemicarbazone is a compound of formula IX: ##STR00937## wherein: R' is H or lower alkyl; Y is an aryl or heteroaryl group having one ring or two fused rings; Y' is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; and Y'' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.

35. The composition of claim 34 wherein Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl.

36. A composition comprising: a vaccine in an amount effective to stimulate a cell--mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or a derivative thereof, wherein the thiosemicarbazone is independently selected from Tables I, II, and III.

37. The composition of claim 36 wherein the thiosemicarbazone is selected from the group consisting of: ##STR00938## ##STR00939## ##STR00940##

38. The composition of claim 36 wherein the thiosemicarbazone is pyridine-2-carbaldehyde thiosemicarbazone or a pharmaceutically acceptable salt thereof.

39. A method of administering a vaccine comprising simultaneously administering a vaccine in an amount effective to stimulate a cell--mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof of claim 1 or 36.

40. A method of administering a vaccine comprising separately administering a vaccine in an amount effective to stimulate a cell--mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof of claim 1 or 36, wherein said vaccine adjuvant is administered either prior to or subsequent to administration of the vaccine.

Description

FIELD OF THE INVENTION

This invention relates to compounds and compositions, as well as uses of the compounds as immunopotentiators and use of the compounds in methods for treating and preventing viral infections including HCV. More particularly, the invention relates to compounds that are used alone or combined with other agents for which the immune response is desired, in the treatment or modulation of cancer, allergic diseases, asthma, as well as amelioration of viral, bacterial, and fungal infections.

BACKGROUND OF THE INVENTION

It is known that immune response to certain antigens which are otherwise weakly immunogenic can be enhanced through the use of vaccine adjuvants. Such adjuvants potentiate the immune response to specific antigens and are therefore the subject of considerable interest and study within the medical community.

Research has permitted development of vaccines possessing antigenic epitopes that were previously impossible to produce. For example, currently available vaccine candidates include synthetic peptides mimicking streptococcal, gonococcal, and malarial antigens. These purified antigens are generally weak immunogens, however, that require adjuvants in order to evoke protective immunity. However, conventional vaccine adjuvants possess a number of drawbacks, which limit their overall use and effectiveness.

It is also common knowledge that substances, which stimulate immune cells in vitro exhibit similar immuno-stimulatory effects in vivo. These compounds, such as recombinant cytokines, pathogen products (e.g. toxins, lipids, proteins/peptides, carbohydrates and nucleic acids) and other mammalian-derived immunostimulatory molecules (e.g. heat shock proteins, complement, immune complexes and proteoglycans) all induce a measurable pro-inflammatory response both in vitro and in vivo.

Historically, the classic adjuvants have been Freund's complete or incomplete (i.e., without mycobacteria) adjuvants. Edmund Coley, the inventor of Coley's Toxin, described this potential for cancer immuno-therapy.

Other adjuvants have been compared to Freund's. However, clinical use of such adjuvants in animals or humans is precluded because they produce granulomas at the site of injection; fever and other toxic effects; and tuberculin hypersensitivity. Other materials, such as mineral oil and aluminum hydroxide, have also been used as adjuvants, but they invariably suffer from disadvantages. For example, mineral oil is known to produce tissue irritation and to be potentially oncogenic. Aluminum hydroxide, the only approved adjuvant in the United States, also induces granulomas at the inoculation site and furthermore it does not effectively induce cell-mediated immunity. Moreover, many of the adjuvants currently available have limited utility because they contain components, which are not metabolizable in humans. Additionally, most adjuvants are difficult to prepare in that they may require time consuming procedures and the use, in some cases, of elaborate and expensive equipment to formulate a vaccine and adjuvant system.

For a thorough discussion of various immunological adjuvants, see "Current Status of Immunological Adjuvants", Ann. Rev. Immunol., 1986, 4, pp. 369-388, and "Recent Advances in Vaccine Adjuvants and Delivery Systems" by Derek T O'Hagan and Nicholas M. Valiente, both of which are hereby incorporated by reference in its entirety. See also U.S. Pat. Nos. 4,806,352; 5,026,543; and 5,026,546 for disclosures of various vaccine adjuvants appearing in the patent literature all of which are hereby incorporated by reference in its entirety.

There has been an effort to find new adjuvants for vaccines that would overcome the drawbacks and deficiencies of conventional adjuvants. In particular, an adjuvant formulation which elicits potent cell-mediated and humoral immune responses to a wide range of antigens in humans and domestic animals, but lacking the side effects of conventional adjuvants, such as Freund's complete adjuvant, would be highly desirable.

It is also desirable to identify small molecules, which stimulate a proinflammatory response for use as vaccine adjuvants.

Hepatitis is a systemic disease, which predominantly affects the liver. The disease is typified by the initial onset of symptoms such as anorexia, nausea, vomiting, fatigue, malaise, arthralgias, myalgias, and headaches, followed by the onset of jaundice. The disease may also be characterized by increased serum levels of the aminotransferases AST and ALT. Quantification of these enzymes in serum indicates the extent of liver damage.

There are five general categories of viral agents which have been associated with hepatitis: the hepatitis A virus (HAV); the hepatitis B virus (HBV); two types of non-A, non-B (NANB) agents, one blood-borne (hepatitis C) and the other enterically transmitted (hepatitis E); and the HBV-associated delta agent (hepatitis D).

There are two general clinical categories of hepatitis, acute hepatitis and chronic hepatitis. Symptoms for acute hepatitis range from asymptomatic and non-apparent to fatal infections. The disease may be subclinical and persistent, or rapidly progress to chronic liver disease with cirrhosis, and in some cases, to hepatocellular carcinoma. Acute hepatitis B infection in adult Caucasians in the United States progresses to chronic hepatitis B in about 5% to 10% of the cases. In the remainder of the cases, approximately 65% are asymptomatic. In the Far East, infection is usually perinatal, and 50% to 90% progress to the chronic state. It is likely that the different rates of progression are linked to the age at infection rather than genetic differences in the hosts. In the United States, about 0.2% of the population is chronically infected, with higher percentages in high-risk groups such as physicians, drug addicts and renal dialysis patients. In countries such as Taiwan, Hong Kong and Singapore, the level in the population with hepatitis infection may be as high as 10%.

In the United States, about 20% of patients with chronic hepatitis die of liver failure, and a further 5% develop hepatitis B-associated carcinoma. In the Far East, a large percentage of the population is infected with HBV, and after a long chronic infection (20 to 40 years), approximately 25% of these will develop hepatocellular carcinoma.

After the development of serologic tests for both hepatitis A and B, investigators identified other patients with hepatitis-like symptoms, and with incubation periods and modes of transmission consistent with an infectious disease, but without serologic evidence of hepatitis A or B infection. After almost 15 years, the causative agent was identified as an RNA virus. This virus (designated "hepatitis C") has no homology with HBV, retroviruses, or other hepatitis viruses.

Hepatitis C(HCV) appears to be the major cause of post-transfusion and sporadic non-A, non-B (NANB) hepatitis worldwide, and plays a major role in the development of chronic liver disease, including hepatocellular carcinoma (Kuo et al., Science 244:362-364, 1989; Choo et al., British Medical Bulletin 46(2):423441, 1990). Of the approximately 3 million persons who receive transfusions each year, approximately 150,000 will develop acute hepatitis C (Davis et al., New Eng. J. Med. 321(22):1501-1506, 1989). In addition, of those that develop acute hepatitis C, at least one-half will develop chronic hepatitis C.

Until recently, no therapy has proven effective for treatment of acute or chronic hepatitis B or C infections, and patients infected with hepatitis must generally allow the disease to run its course. Most anti-viral drugs, such as acyclovir, as well as attempts to bolster the immune system through the use of corticosteroids have proven ineffective (Alter, "Viral hepatitis and liver disease," Zuckerman (ed.), New York: Alan R. Liss, pp. 537-42, 1988). Some anti-viral activity has been observed with adenosine arabinoside (Jacyna et al., British Med. Bull. 46:368-382, 1990), although toxic side effects, which are associated with this drug render such treatment unacceptable.

One treatment that has provided some benefit for chronic hepatitis B and C infections is the use of recombinant alpha interferon (Davis et al., New Eng. J. Med. 321(22):1501-1506, 1989; Perrillo et al., New Eng. J. Med. 323:295-301, 1990). However, for patients with hepatitis B infections only about 35% of infectees responded to such treatment, and in perinatal infectees only about 10% responded to treatment. For hepatitis C infections, despite apparent short-term success utilizing such therapy, six months after termination of treatment half of the patients who responded to therapy had relapsed. In addition, a further difficulty with alpha interferon therapy is that the composition frequently has toxic side effects such as nausea, and flu-like symptoms, which require reduced dosages for sensitive patients.

A disease related to hepatitis B and hepatitis C infections is hepatocellular carcinoma. Briefly, hepatocellular carcinoma is the most common cancer worldwide. It is responsible for approximately 1,000,000 deaths annually, most of them in China and in sub-Saharan Africa. There is strong evidence of an etiologic role for hepatitis B infection in hepatocellular carcinoma. Carriers of the HBV are at greater than 90 times higher risk for the development of hepatocellular carcinoma than noncarriers. In many cases, hepatitis B virus DNA is integrated within the cellular genome of the tumor. Similarly, hepatitis C virus has also recently been found to be associated with hepatocellular carcinoma, based upon the observation that circulating HCV antibodies can be found in some patients with hepatocellular carcinoma. At present, surgical resection offers the only treatment for hepatocellular carcinoma, as chemotherapy, radiotherapy, and immunotherapy have not shown much promise (Colombo et al., Lancet 1006-1008, 1989; Bisceglie et al., Ann. of Internal Med. 108:390401, 1988; Watanabe et al., Int. J. Cancer 48:340-343, 1991; Bisceglie et al., Amer. J. Gastro. 86:335-338, 1991).

Therefore, therapeutics that could serve to augment natural host defenses against hepatitis, or against tumor induction and progression, with reduced cytotoxicity, or that allows treatment of interferon non-responsive individuals would be very beneficial. The present invention provides such therapeutic agents, and further provides other related advantages.

BRIEF SUMMARY OF THE INVENTION

The invention provides novel immune potentiators, novel vaccine adjuvants, novel compounds and pharmaceutical compositions, novel methods for treating viral infections, including HCV, by administering the compounds, and novel methods for modulating the immune response by administering the compounds.

The compounds used in the methods and compositions of the invention are small molecules. They have greater potential for finer specificity thus providing improved efficacy and safety profiles compared to existing immuno-stimulants and antivirals.

As adjuvants, the compounds are combined with numerous antigens and delivery systems to form a final vaccine product.

As immuno-therapeutics, the compounds are used alone or combined with agents or other therapies for which the immune response is desired for treatment or modulation of cancer, allergic diseases, asthma, and chronic infections such as coronavirus, SARS-associated coronavirus (SARS-CoV), HIV, HCV, HBV, HSV, and H. pylori.

One embodiment of the invention is a composition comprising:

a vaccine in an amount effective to stimulate a cell-mediated immune response; and

a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.

In another embodiment, the invention is an composition according to claim 1, wherein the thiosemicarbazone is a compound of formula I:

##STR00001##

wherein:

E is absent or selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; L is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl;

W is absent or selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl; X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl; Y is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;

Y' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

Y'' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

R' is H, alkyl, or substituted alkyl;

R'' is H, or

R' and R'' are taken together to form a hetercyclic ring;

Z and Z' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxy, substituted alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyl sulfonyl, methanesulfonyl, and substituted or unsubstituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, arylamino-carbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, heteroarylamino, alkylcarbonylamino, alkylaminocarbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, cycloamidino, cycloalkyl, cycloimido, arylsulfonyl and arylsulfonamido; or

Z and Z' are taken together to form a heterocyclic group, which may be optionally substituted;

the tautomers and the pharmaceutically acceptable salts, esters, or prodrugs thereof.

Other embodiments include methods of treating a viral infection comprising the step of administering to a subject a composition as described above.

Still other embodiments include a method of treating a viral infection or potentiating a cell-mediated immune response comprising administering to a subject a compound of formula II:

##STR00002##

wherein:

W is selected from substituted and unsubstituted aryl, or a substituted and unsubstituted heteroaryl group having one ring or two fused rings;

X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl, wherein if X is absent, Y and W together form an optionally substituted aryl or heteroaryl group having at least two fused rings;

Y is selected from substituted and unsubstituted aryl, or a substituted and unsubstituted heteroaryl group having one ring or two fused rings;

Y' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

Y'' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

R' is H or CH.sub.3,

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, and optionally substituted heterocyclylalkyl;

salts, prodrugs, or tautomers thereof.

Still other embodiments include compounds of formula III,

##STR00003##

wherein:

W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl groups;

X and L are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl;

R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino;

Y is an aryl or heteroaryl group;

Y' is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; Y'' is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; Z is hydrogen, or if Y is furanyl, then Z may be selected from the group consisting of alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; and salts, prodrugs, or tautomers thereof.

Yet other embodiments include compounds of formula IV,

##STR00004##

wherein: W is an optionally substituted phenyl or pyridinyl group; X is alkoxy or alkylamino; Y' is H or fluoro; Y' is dialkylamino, fluoro, or nitro; and

salts, prodrugs, or tautomers thereof.

Another embodiment includes compounds of Formula IVc

##STR00005##

wherein:

W is phenyl substituted with at least one member selected from the group consisting of --Cl; --F; --Br; --CF3; --OCH.sub.3; --NO.sub.2; --CH.sub.3; N(CH.sub.3).sub.2; and --OCF.sub.3;

X is alkoxy; and

n is an integer from 1 and 3.

Another embodiment includes compounds of Formula V

##STR00006##

wherein:

R is an alkyl group;

X is alkoxy; and

salts, prodrugs, or tautomers thereof.

Still another embodiment includes compounds of Formula VI

##STR00007##

wherein: X is absent or an alkylene; Y' is absent or is an alkyl group; and R is a halogen; and

salts, prodrugs, or tautomers thereof.

Another embodiment includes compounds of Formula VII

##STR00008##

wherein:

R is nitro and Z is H; or

R is Cl and Z is selected from the group consisting of alkyl, pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperizinylalkylene; and

salts, prodrugs, or tautomers thereof.

Other embodiments include compounds of formula VIII and salts, prodrugs, or tautomers thereof:

##STR00009##

wherein: W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group; X is absent or is selected from the group consisting of oxo, amino, alkylene, and substituted alkylene; and Y is an aryl or heteroaryl group.

Another embodiment includes compounds of formula IX:

##STR00010## wherein; Y is an aryl or heteroaryl group having one ring or two fused rings; Y' is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; and Y'' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.

Yet another embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III, IV, IVc, V, VI, VII, VIII, or IX and a pharmaceutically acceptable carrier.

Another embodiment includes a method of treating a viral infection comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds, salts and tautomers thereof, and a pharmaceutically suitable carrier.

In some embodiments, the viral infection is HCV.

Some embodiments involve a method of treating viral infections in a subject comprising administering to the subject any one or more of the compounds described herein or, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer.

Still other embodiments involve the methods described above wherein the infection is an HCV infection.

Some embodiments of a method of adminstering a vaccine comprise simulatneously administering a vaccine in an amount effective to stimulate a cell-mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.

Other embodiments of a method of adminstering a vaccine comprise separately administering a vaccine in an amount effective to stimulate a cell-mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine, wherein the vaccine adjuvant is adminstered either prior to or subsequent to administration of the vaccine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows candidate small molecule immuno-potentiators identified in vitro by measuring TNF-alpha production by human PBMC.

FIG. 2 shows thiosemicarbazone cytokine induction at several concentrations.

FIG. 3 depicts a high throughput assay for small molecule immune potentiator screen.

FIG. 4 depicts dual functional HCV anti-virals and immune potentiators. TNF-alpha production is represented by black bars and IL-12 p40 is represented by gray bars, presented as the % of LPS (1 mg/ml) activity.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention is directed to a method of inducing an immunostimulatory effect in a patient comprising administering a thiosemicarbazone compound in an amount effective to stimulate a cell-mediated immune response.

One preferred embodiment of the method of inducing an immunostimulatory effect in a patient is directed to a vaccine adjuvant composition comprising a vaccine in an amount effective to stimulate a cell-mediated immune response and, as a vaccine adjuvant, a thiosemicarbazone or derivatives thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.

As is well-understood in the art, a vaccine may be prophylactic and/or therapeutic in nature. The vaccines and vaccine compositions disclosed herein likewise may be used prophylactically or therapeutically.

When the thiosemicarbazone is administered as a vaccine adjuvant, it may be administered simultaneously with the vaccine, prior to the vaccine, and even after vaccine administration.

Preferably, the thiosemicarbazone is a compound of formula I, the tautomers thereof, and the pharmaceutically acceptable salts, esters, or prodrugs thereof:

##STR00011##

E is absent or selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;

L is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and arbonyl;

W is absent or selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;

X is absent or is selected from the group consisting og oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl;

Y is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;

Y' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

Y'' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;

R' is H, alkyl, or substituted alkyl;

R'' is H, or

R' and R'' are taken together to form a heterocyclic ring;

Z and Z' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxy, substituted alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyl sulfonyl, methanesulfonyl, and substituted or unsubstituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, arylamino-carbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, heteroarylamino, alkylcarbonylamino, alkylaminocarbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, cycloamidino, cycloalkyl, cycloimido, arylsulfonyl and arylsulfonamido.

Alternatively, Z and Z' are taken together to form a heterocyclic group or substituted heterocyclic group.

The above method of inducing an immunostimulatory effect in a patient includes the administration of the thiosemicarbazone compound to enhance the efficacy of a therapeutic treatment by stimulating a local immune response in selected cells or tissues of the patient.

The above method of stimulating a local immune response in selected cells or tissues of a patient includes the stimulation of a local immune response wherein the selected cells or tissues are infected or cancerous. In one embodiment the selected cells or tissues are infected with a fungus or bacterium. In another embodiment the selected cells are infected with an allergen. In another embodiment the selected cells are infected with a virus. In still a more particular embodiment the virus is the as coronavirus, SARS-associated coronavirus (SARS-CoV), HCV, HIV, HBV, HSV, H. pylori, HSV Type 1 or 2, or Human Papilloma Virus.

The vaccine adjuvant compositions of the invention can contain further pharmaceutically acceptable ingredients, excipients, carriers, and the like well known to those skilled in the art.

The invention is also directed to administering the vaccine adjuvant composition. The vaccine is administered in an amount effective to stimulate an immune response. The amount that constitutes an effective amount depends, inter alia, on the particular vaccine used, the particular adjuvant compound being administered and the amount thereof, the immune response that is to be enhanced (humoral or cell mediated), the state of the immune system (e.g., suppressed, compromised, stimulated), and the desired therapeutic result. Accordingly it is not practical to set forth generally the amount that constitutes an effective amount of the vaccine. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.

The vaccine adjuvant compositions of the invention can be administered to animals, e.g., mammals (human and non-human), fowl, and the like according to conventional methods well known to those skilled in the art (e.g., orally, subcutaneously, nasally, topically).

Suitable vaccines include, but are not limited to, any material that raises either humoral or cell mediated immune response, or both. Suitable vaccines include live viral and bacterial immunogens and inactivated viral, tumor-derived, protozoal, organism-derived, fungal, and bacterial immunogens, toxoids, toxins, polysaccharides, proteins, glycoproteins, peptides, and the like. Conventional vaccines, such as those used in connection with BCG (live bacteria), cholera, plague, and typhoid (killed bacteria), hepatitis B, influenza, inactivated polio, and rabies (inactivated virus), measles, mumps, rubella, oral polio, and yellow fever (live virus), tetanus and diphtheria (toxoids), hemophilus influenzae b, meningococcal, and pneumococcal (bacterial polysaccharides) also can be used.

Furthermore, it is contemplated that certain currently experimental vaccines, especially materials such as recombinant proteins, glycoproteins, and peptides that do not raise a strong immune response, will also find use in connection with the thiosemicarbazone. Exemplary experimental subunit immunogens include those related to viral disease such as adenovirus, AIDS, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, hepatitis A, hepatitis B, hepatitis C, HSV-1, HSV-2, hog cholera, influenza A, influenza B, Japanese encephalitis, measles, parainfluenza, rabies, respiratory syncytial virus, rotavirus, wart, and yellow fever.

Specific antigens for use with the invention include, but are not limited to, those listed below. The number(s) in parenthesis indicate representative resources of the antigen. The resource list follows the antigen list and each resource is incorporated by reference in its entirety.

Specific antigens include: a protein antigen from N. meningitides serogroup B (1-7); an outer-membrane vesicle (OMV) preparation from N. meningitides serogroup B. (8, 9, 10, 11); a saccharide antigen from N. meningitides serogroup A, C W135 and/or Y, such as the oligosaccharide (12) from serogroup C (13); a saccharide antigen from Streptocaccus pneumoniae (14, 15, 16); an antigen from N. gonorrhoeae (1, 2, 3); an antigen from Chlamydia pneumoniae (17, 18, 19, 20, 21, 22, 23); an antigen from Chlamydia trachomatis (24); an antigen from hepatitis A virus, such as inactive virus (25, 26); an antigen from hepatitis B virus, such as the surface and/or core antigens [e.g. 26, 27]; an antigen from hepatitis C virus (28); an antigen from Bordetella pertussis, such as petussis holotoxin (PT) and filamentous haemagglutinin (FHA) from B. pertussis, optionally also combination with pertactin and/or agglutinogens 2 and 3 (29, 30); a diphtheria antigen, such as a diphtheria toxoid (31:chapter 3) e.g. the CRM197 mutant (32); a tetanus antigen, such as a tetanus toxioid (31:chapter 4); a protein antigen from Helicobacter pylori such as CagA (33), VacA (33), NAP (34), HopX (5), HopY (35) and/or urease; a saccharide antigen from Haemophilus influenzae B (13); an antigen from Porphyromonas gingivalis (36); polio antigen(s) (37, 38) such as IPV or OPV; rabies antigen(s) (39) such lyophilized inactivated virus (40, RabAvert.TM.); measles, mumps and/or rubella antigens (31: chapters 9, 10, & 11); influenza antigen(s) (31:chapter 19), such as the haemagglutinin and/or neuraminidase surface proteins; an antigen from Moraxella catarrhalis (41); an antigen from Streptococcus agalactiae (group B streptococcus) (42, 43); an antigen from Streptococcus pyogenes (group A streptococcus) (43, 44, 45); and an antigen from Staphylococcus aureus (46).

The composition may comprise one or more of the above antigens.

Where a saccharide or carbohydrate antigen is used, it is preferably conjugated to a carrier protein in order to enhance immunogenicity (47-6). Preferred carrier proteins are bacterial toxine or toxiods, such as diphtheria or tetanus toxoids. The CRM197 diphtheria toxoid is particularly preferred. Other suitable carrier proteins include the N. meningitides outer membrane protein (57), synthetic peptides (58, 59), heat shock proteins (60), pertussis proteins (61, 62), protein D from H. influenzae (63), toxin A or B from C. difficile (64) etc. Where a mixture comprises capsular saccharides from both serogroups A and C, it is preferred that the ratio (w/w) of MenA saccharide:MenC saccharide is greater than 1 (e.g. 2:1, 3:1, 4:4, 5:1, 10:1 or higher). Saccharides from different serogroups of N. meningitides may be conjugated to the same or different carrier proteins.

Any suitable conjugation reaction can be used, with any suitable liner where necessary. Toxic protein antigens may be detoxified where necessary (e.g. detoxification of pertussis toxin by chemical and/or genetic means (30)). Where a diphtheria antigen is included in the composition it is preferred also to include tetanus antigens and pertussis antigens. Similarly, where a tetanus antigen is included it is preferred also to include diphtheria and pertussis antigens. Similar, where pertussis antigen is included it is preferred also to include diphtheria and tetanus antigens.

In another embodiment, the invention provides a method of treating a viral infection in a mammal comprising administering to the mammal a compound of formula II or its salts, prodrugs, or tautomers thereof:

##STR00012##

wherein:

W is an aryl, substituted aryl, heteroaryl or substituted heteroaryl group having one ring or two fused rings;

X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl. Preferably X is absent or is selected from the group consisting of piperizinyl, --O(CH.sub.2).sub.n--; --(CH.sub.2).sub.n--O--; --O--; --C(O)O--; --NH--(CH.sub.2).sub.m--; --(CH.sub.2).sub.m--NH--; --NH--(CH.sub.2).sub.m--NH--; --N(CH.sub.2).sub.n--(CH.sub.2).sub.m--NH--; --N(CH.sub.2).sub.n--(CH.sub.2).sub.m--N(CH.sub.2).sub.p--; --NH--(CH.sub.2).sub.m--N(CH.sub.2).sub.n and --O--(CH.sub.2).sub.p--O--, wherein n, m, and p are 1 to 3. More preferably, X is absent or is selected from the group consisting of --CH.sub.2--O--; --O--CH.sub.2--; --CH.sub.2; --O--; --C(O)O--; --NHCH.sub.2--; --NHCH.sub.2CH.sub.2; and --OCH.sub.2CH.sub.2O--;

Y is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having one ring or two fused rings. Preferably, Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, and imidazolyl;

Alternatively, X does not exist and Y and W together form an arly, substituted aryl, heteroaryl, or substituted heteroaryl group having at least two fused rings. Preferably, Y and W together form an unsubstituted or substituted nitrogen-containing fused heteroaryl group having at least two fused rings. More preferably an unsubstituted or substituted quinolinyl, indolyl, benzo[g]indolyl, benzindolyl, or benzofuranyl.

Y' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino. Preferably, Y' is absent or is selected from the group consisting of halo; --CH.sub.3; --OCH.sub.3; --N(CH.sub.2CH.sub.3).sub.2; -phenyl; --Br; and --NO.sub.2.

Y'' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.

R' is H or CH.sub.3;

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, and substituted heterocyclylalkyl. In one embodiment, Z is preferably hydrogen. In another embodiment, if Y is furanyl, then Z is selected from the group consisting of pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperizinylalkylene.

In one embodiment, W is phenyl or phenyl substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, preferably with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3.

In another embodiment, W is a heteroaryl or substituted heteroaryl selected from the group consisting of furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl, preferably pyridinyl. If substituted, the heteroaryl is preferably substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, more preferably at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3.

In one embodiment, if Y is pyrrol, the Y' and Y'' are alkyl. In another embodiment, if Y is phenyl, and Y' is alkoxy, then Y'' is a halogen. In another embodiment if Y is pyrazolyl, then Y' is aryl. In another embodiment, if Y is aryl with two fused rings, then Y' is alkoxy and Y'' is alkyl.

In one preferred embodiment, Y is pyrrol and Y' and Y'' are each --CH.sub.3, X is absent, and W is phenyl substituted with nitro, dimethylamine, Cl, F, or CH.sub.3.

In other preferred embodiments, Z is hydrogen, Y is furanyl, Y' does not exist, X is absent, and W is phenyl substituted with C.sub.1 or CF.sub.3; or Z is hydrogen, Y is phenyl, Y' is --OCH.sub.3, X is --OCH.sub.2-- and W is phenyl substituted with one or two Cl; or Z is hydrogen, Y is phenyl, Y' is nitro, X is --NHCH.sub.2-- and W is phenyl substituted with Cl.

In another embodiment, the invention provides a method of treating a patient with an HCV infection by administering to the patient a compound of formula II, or its salts, prodrugs, or tautomers thereof as described above.

The patient is preferably a mammal, and in some embodiments, a human. The compounds may be injected or taken orally.

In another embodiment, the invention provides a method of treating a patient with an HCV infection by administering to the patient a compound of formula II, or its salts, prodrugs, or tautomers thereof.

##STR00013##

R' is H or --CH.sub.3.

W is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having one ring or two fused rings. Preferably, W is phenyl or phenyl substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, preferably with at least one member selected from the group consisting of --Cl; --F; --Br; --CF.sub.3; --OCH.sub.3; --NO.sub.2; CH.sub.3; --N(CH.sub.3).sub.2; and --OCF.sub.3.

X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl.

Y is an aryl or heteroaryl group having one ring or two fused rings.

Alternatively, X does not exist and Y and W together form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having at least two fused rings.

Y' is absent or is selected from the group consisting of nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; Y'' is absent or is selected from the group consisting of nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, and substituted heterocyclylalkyl.

The patient is preferably a mammal, and in some embodiments, a human. The compounds may be injected or taken orally.

The invention is also directed to novel compounds as defined below by formulas III-VII, and salts, prodrugs, or tautomers thereof, as well as pharmaceutical compositions containing the compounds and methods of treating or preventing viral infections, in particular HCV, by administering such compounds to a mammal in need thereof.

The invention is also directed to novel compounds defined by formula III and salts, prodrugs, or tautomers thereof:

##STR00014##

W is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group. Preferably W is phenyl or substituted phenyl. If substituted, phenyl is preferably substituted with at least one member selected from the group consisting of Br, Cl, F, and CF.sub.3.

L and X are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl;

R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino.

Y is an aryl or heteroaryl group. Y is preferably selected from the group consisting of phenyl, furanyl, pyrridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, and imidazolyl. More preferably, Y is phenyl, furanyl, or pyrimidinyl.

Y' is absent or selected from the g