WO1990006671A2

WO1990006671A2 - Methods and compositions for the prophylaxis and treatment of hepatitis b virus infections

Info

Publication number: WO1990006671A2
Application number: PCT/US1989/005654
Authority: WO
Inventors: Peter M. Palese
Original assignee: Palese Peter M
Priority date: 1988-12-12
Filing date: 1989-12-11
Publication date: 1990-06-28
Also published as: EP0452360A4; KR910700054A; AU4829190A; EP0452360A1; CA2005192A1

Description

METHODS AND COMPOSITIONS FOR THE PROPHYLAXIS AND TREATMENT OF HEPATITIS B VIRUS INFECTIONS

TECHNICAL FIELD OF THE INVENTION

This invention relates to the prophylaxis and treatment of hepatitis B virus (HBV) infections. This invention relates more particularly to the use of carbocyclic analogues of purine and pyrimidine nucleosides in the prophylaxis and treatment of HBV viral infections.

BACKGROUND OF THE INVENTION

Hepatitis B virus ("HBV") infects humans at a very high rate. An estimated 200 million people are infected with HBV worldwide. In the United States it is estimated that 4% of the population have been infected.

The incubation period for HBV generally ranges from 50 to 160 days and HBV infections may either remain subclinical or result in severe illness, lasting for several months. Depending on the severity of the illness, recovery may be complete or a protracted illness leading to death may occur.

For patients who do not completely recover from an acute episode of viral hepatitis, a chronic form of the disease may develop. Patients with chronic hepatitis are more likely than others to develop chronic viral infections resulting from immunosuppressive therapy, lymphomatous disease, and chronic renal failure. Hepatocellular carcinoma is also a possible consequence of chronic HBV infection.

Chronic HBV infections may also result in the integration of HBV DNA into the genomic DNA of liver cells. Persons with such integrations are termed carriers and may have had no symptoms associated with the acute form of hepatitis. However, such persons, who collectively account for the largest concentration of HBV and may include between 0.5 to 1.0 million individuals in the United States, are prone to develop some of the more aggressive forms of the disease, such as cirrhosis and hepatocellular carcinoma.

Vaccines against HBV infections have been developed. They utilize the hepatitis B surface antigen (HBsAg) as imraunogen. The HBsAg of these vaccines is obtained either from plasma of human carriers of HBV or through recombinant DNA techniques. Although these surface antigen-based vaccines are generally effective in preventing hepatitis in individuals, not all individuals administered the vaccine develop protective levels of antibody. Factors such as the age of the individual to whom the vaccine is administered, the degree to which an individual's immune system is compromised or suppressed, as well as the site of injection influence the effectiveness of these vaccines. In addition, persons vaccinated have a small risk of developing hypersensitivity reactions. Finally, there is a prejudice against the plasma-derived vaccine because of the potential of AIDS and other serum contaminations.

Other agents are also presently in use to treat HBV infections. These include acycloguanosine (acyclovir), adenine arabinoside, and adenine arabinoside monophosphate. Acyclovir, which is effective against viruses which produce viral thymidine kinase and through mechanisms which are not completely understood, appears to be effective against some other viruses as well. Viral thymidine kinase phosphorylates acyclovir to the monophosphate form which is then converted by cellular kinases to the biologically active acyclovir triphosphate. For example, the antiviral activity of acyclovir against the

Herpes simplex virus results from the triphosphate's ability to interfere with Herpes simplex virus DNA polymerase and thereby to inhibit viral DNA replication. Acyclovir triphosphate also inhibits cellular alpha DNA polymerase, although to a lesser degree than the inhibition of viral DNA polymerase. This disadvantages the utility of acyclovir as a treatment for HBV because it reduces the ability of normal cells to replicate their own DNA. The antiviral activity of acyclovir triphosphate may also be related to its ability to be incorporated into growing chains of DNA which results in chain termination. Acyclovir induced-DNA chain incorporation and termination of cellular genes, however, may also lead to additional forms of toxicity, including chromosomal damage.

Although viral thymidine kinase is absent from the hepatitis B virus, acyclovir has been

reported to be active against hepatitis B replication. Reports suggest that some other cellular enzymes phosphorylate acyclovir to its active form. Inhibtion of HBV replication may then occur by mechanisms similar to those by which acyclovir is thought to inhibit thymidine kinase viruses, including inhibition of HBV DNA polymerase as well as integration into DNA and subsequent chain termination. Although the use of acyclovir against HBV infections is

disadvantaged by the same potential side effects described above, there are even more problems with its use against HBV - - while it is effective during short-term administration in reducing markers associated with HBV replication, such as plasma levels of HBV DNA polymerase, cessation of drug administration often results in the return to pretreatment levels of virus replication.

Adenine arabinoside (ara-A) and adenine arabinoside monophosphate (ara-AMP, a form of the drug which allows it to be administered intramuscularly) are also effective alone or in combination in decreasing levels of circulating HBV DNA polymerase activity in patients infected with HBV.

However, complete inhibition of HBV may not result from these treatments, as DNA polymerase activity has been demonstrated to increase following cessation of drug therapy.

Furthermore, both ara-A and ara-AMP are associated with substantial toxicity. Untoward effects of these drugs commonly experienced by patients include nausea, anorexia, fatigue, diarrhea, vomiting, and reversible bone marrow suppression with thrombocytopenia. In addition, a peculiar neuromuscular pain syndrome that produces pain and cramping, most pronounced at the site of injection, and which may last for months following cessation of drug administration has been described. Payne, John A. "Chronic Hepatitis: Pathogenesis and Treatment", Disease a Month, March, pp. 117-59 (1988).

SUMMARY OF THE INVENTION

This invention relates to compositions and methods for the prevention and treatment of HBV infections, in animals and man, characterized by an antiviral effective amount of a compound selected from the group consisting of formulae:

wherein:

R ¹ and R⁴ are independently either hydrogen, hydroxyl, acyloxy or together form a bond;

R ² is selected from the group consi.sting of hydrogen, acyloxy and hydroxyl;

R ³ is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR⁶;

R⁵ is selected from the group consisting of hydrogen and acyl, a C_1-6 alkanoyl group and an aroyl group;

R⁶ is selected from the group consisting of hydrogen, a C_1-6 alkanoyl group and an aroyl group;

R⁷ is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R⁸ is hydrogen; or

selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R⁸ is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of position 6;

Y is selected from the group consisting of CH and nitrogen (N);

R⁹ is selected from the group consisting of hydrogen and amino;

R¹⁰ is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R ¹¹ is hydrogen; and NR¹²R¹³ when R¹¹ is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;

R¹² and R¹³ are independently hydrogen or a C_1-6 alkyl group;

X¹ is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C_1-6 alkyl group, and

NHR¹⁴ wherein R¹⁴ is a C_1-6 alkyl group;

R ¹⁵ is selected from the group consisting of hydrogen, a C_1-6 alkyl group or halogen

(including fluorine, chlorine, bromine or iodine).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel methods and compositions for the prophylaxis and treatment of infections caused by the hepatitis B virus. The present invention particularly relates to the treatment and prophylaxis of HBV infections using methods and compositions characterized by certain carbocyclic analogues of nucleosides .

The term "carbocyclic analogue of a nucleoside" refers to compounds which possess a cyclopentane ring in place of the tetrahydrofuran ring of the analogous nucleoside. The substitution of cyclopentane for the tetrahydrofuran moiety is thought to increase the resistance of the carbocyclic analogues of nucleosides to the action of degradative enzymes and may also increase the selectivity of their biologic actions.

United States patent 4,396,623 (Shealy et al.) refers to the use of certain carbocylic analogs of uracil nucleosides for the treatment of various human and animal diseases caused by DNA viruses, such as Herpes simplex virus. United States patents 4,177,348 (Shealy et al.) and 4,232,154

(Shealy et al.) refer to carbocyclic analogues of cytosine nucleosides and their activity against DNA viruses, such as herpes simplex virus Type 1 and vaccinia virus, and RNA viruses such as rhinovirus Type 1A and influenza virus. United States patents 4,543,255 (Shealy et al.) and 4,728,736 (Shealy et al.) refer to carbocyclic analogues of purine 2'-deoxyribofuranosides and ribofuranosides, respectively, and their activity against DNA viruses, exemplified by herpes simplex virus Type 1.

The methods and compositions of this invention are characterized by an antiviral effective amount of a compound of the formulae:

wherein:

R ¹ and R⁴ are independently either hydrogen, hydroxyl, acyloxy or together form a bond (when R ¹ and R⁴ together form a bond, a double bond is formed between the carbons of the cyclopentane ring to which R ¹ and R⁴ are attached in formulae A and B);

R² is selected from the group consisting of hydrogen, acyloxy and hydroxyl;

R³ is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR⁶;

R⁷ is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R⁸ is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R⁸ is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of position 6;

Y is selected from the group consisting of

CH and nitrogen (N);

R⁹ is selected from the group consisting of hydrogen and amino;

R¹⁰ is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R¹¹ is hydrogen; and NR¹²R¹³ when R¹¹ is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4; R¹² and R¹³ are independently hydrogen or a C_1-6 alkyl group;

X¹ is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C_1-6 alkyl group, and NHR ¹⁴ wherein R¹⁴ is a C_1-6 alkyl group;

(including fluorine, chlorine, bromine or

iodine).

The above-described compositions and methods in addition to being useful in treating or preventing HBV infections are surprisingly advantageous

over presently available agents and methods. First, the carbocyclic analogues of this invention have not been observed to be incorporated into viral and host cell DNA. Therefore, the methods and compositions of the present invention are advantaged over prior methods and compositions which utilize compounds which are incorporated into host cell DNA and which may cause chromosomal damage. Furthermore, the methods and compositions of this invention are not plasma derived so they carry no risk of serum carried infections and infectious agents.

In the more preferred methods and compositions of this invention an antiviral effective amount of a compound of Formulae I-XI is employed, wherein Y is N or CH and X of Formulae I, III, V, VII, and IX is halogen, an amino group, an alkylamino group, an alkoxy group, or an alkylthio group, and X of

Formulae II, IV, VI, VIII, X, and XI is oxygen or sulfur:

In all of the above structures for Formulae I-XI, X represents the R⁷ moiety of structure A described supra.

The compounds represented by Formulae I-XI are carbocyclic analogues of various nucleosides:

Carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-purines, Formulae I and II.

Carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-8-azapurines, Formulae III and IV.

Carbocyclic analogues of 2'-deoxyribofuranosides of 2-amino-6-substituted-purines, Formulae V and VI.

Carbocyclic analogues of 2'-deoxyribofuranosides of 2-amino-6-substituted-8-azapurines,

Formulae VII and VIII.

Carbocyclic analogues of 3'-deoxyribofuranosides of 2-amino-6-substituted-purines, Formulae IX and X with Y = CH.

Carbocyclic analogues of 3'-deoxyribofuranosides of 2-amino-6-substituted-8-azapurines,

Formulae IX and X with Y = N.

Carbocyclic analogues of 2-amino-6-substituted purine 2',3'-didehydro-2',3'-dideoxy nucleosides represented by Formula XI.

Most preferably, the carbocyclic analogue useful in the methods and compositions of this invention is 2'-deoxyguanosine ("2'-CDG"), i.e., the compound of Formula VI where X = 0.

Preferably, in accordance with this invention, the above-described compounds are used against HBV infections and, more preferably, the above-described preferred compounds, and most preferably 2'-CDG, are used in methods and compositions of this invention against that infection.

The compounds used in the treatments of this invention can be synthesized from known and readily available materials by well known, conventional methods. For example, synthesis of carbocyclic analogues of nucleosides represented by Formulae

I-IV are described in following publications which are incorporated herein by reference:

Y. F. Shealy, J. D. Clayton, G. Arnett, and

W. M. Shannon, "Synthesis and Antiviral Evaluation of Carbocyclic Analogues of Ribofuranosides of 2-Amino-6-substituted-purines and of 2-Amino-6-substituted-8-Azapurines", Journal of Medicinal Chemistry, Volume 27, pages 670-74 (1984).

Y. F. Shealy and J. D. Clayton, United

States patent 4,728,736, March 1, 1988.

Syntheses of the carbocyclic analogue of guanosine is described in Y. F. Shealy and J. D.

Clayton, Journal of Pharmaceutical Sciences, Volume 62, pages 1432-34 (1973), which is incorporated herein by reference.

Synthesis of carbocyclic analogues of nucleosides represented by Formulae V-VIII are

described in the following publications which are incorporated herein by reference:

Y. F. Shealy, C. A. O'Dell, W. M. Shannon and G. Arnett, "Synthesis and Antiviral Activity of Carbocyclic Analogues of 2'-Deoxyribofuranosides of 2-Amino-6-substituted-purines and of 2-Amino-6-substituted-8-azapurines", Journal of Medicinal

Chemistry, Volume 27, pages 1416-21 (1984).

Y. F. Shealy and C. A. O'Dell, United

States patent 4,543,255, September 24, 1985.

Syntheses of carbocyclic analogues of nucleosides represented by Formulae IX and X are described in the article by Y. F. Shealy, C. A.

O'Dell, and G. Arnett, "Synthesis and Antiviral

Evaluation of Carbocycyclic Analogues of

2-Amino-6-substituted-purine 3'-Deoxyribofuranosides", Journal of Medicinal Chemistry, Volume 30, pages 1090-94 (1987), which is incorporated herein by reference.

The synthesis of the carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir), was reported by R. Vince et al., "Second International Conference on Antiviral Research, Williamsburg,

Virginia, 1988". Abstract, Antiviral Research,

Volume 9, page 120 (1988), is incorporated herein by reference.

Syntheses of carbocyclic analogs of uracil nucleosides are described in the following publications which are incorporated herein by reference:

Y. F. Shealy, and C. A. O'Dell, "Synthesis of the Carbocyclic Analogs of Uracil Nucleosides",

Journal of Heterocyclic Chemistry, Volume 13,

pages 1015-20 (1976).

Y. F. Shealy, and C. A. O'Dell, "Acid-Catalyzed Cyclization of Alkoxyacryloylureas to

2,4(1H,3H)pyrimidinediones", Journal of Heterocyclic Chemistry, Volume 13, pages 1041-47 (1976).

Y. F. Shealy, C. A. O'Dell, W. M. Shannon, and G. Arnett, "Carbocyclic Analogues of 5-Substituted Uracil Nucleoside: Synthesis and Antiviral Activity", J. Med. Chem., Volume 26, pages 156-61 (1983).

United States patent 4,396,623 (Y. F.

Shealy, C. A. O'Dell and W. M. Shannon).

Syntheses of carbocyclic analogs of cytosine nucleosides are described in the following publications which are incorporated herein by reference:

United States patents 4,177,348 and

4,232,154 (Y. F. Shealy and C. A. O'Dell);

Y. F. Shealy and C. A. O'Dell, "The Carbocyclic Analog of Cytidine, Synthesis and Anti-neoplastic Activity", Journal of Heterocyclic Chem., Volume 13, pages 1353-54 (1976). Y. F. Shealy and C. A. O'Dell, J. of

Heterocyclic Chem., Volume 17, pages 353-58 (1980).

Syntheses of carbocyclic analogs of thymine nucleosides are described in the following publication which is incorporated herein by reference:

Y. F. Shealy, C. A. O'Dell, and M. C.

Thorpe, "Carbocyclic Analogs of Thymine Nucleosides and Related I-Substituted Thymines", J. Heterocyclic Chem., Volume 18, pages 383-89 (1981).

Depending on the route of administration, which could normally be either oral or parenteral, the compounds may be in the form of a solid, semi-solid, liquid, oil, or ingestible capsule and may either be present as the orginal compound or in the form of a pharmaceutically acceptable salt in

association with or without an appropriate pharmaceutical carrier.

The therapeutically antiviral effective amount of the compounds to be used in accordance with this invention to provide prophylaxis and treatment for individuals infected with, or at risk of being infected with HBV, can be determined by methods known in the art.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.

Claims

CLAIMS WE CLAIM:

1. A method for preventing or treating hepatitis B virus infections in animals and man, characterized by administering an antiviral effective amount of a compound of the formula:

wherein:

R ¹ and R⁴ are independently either hydrogen. hydroxyl, acyloxy or together form a bond;

R ² is selected from the group consisting of hydrogen, acyloxy and hydroxyl;

R⁶ is selected from the group consisting of hydrogen, a C_1-6 alkanoyl group and an aroyl group; R⁷ is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R⁸ is hydrogen; or

Y is selected from the group consisting of

CH and nitrogen;

R⁹ is selected from the group consisting of hydrogen and amino;

R¹⁰ is selected from the group consisting of oxygen bound through a double bond to

carbon 4 when R ¹¹ is hydrogen; and NR¹²R¹³ when R¹¹ is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;

R ¹² and R¹³ are independently hydrogen or a C_1-6 alkyl group;

(including fluorine, chlorine, bromine or iodine).

2. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R⁹ is amino; and Y is CH.

3. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ⁴, and R⁵ are hydrogen; R2 and R3 are hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R⁸ is hydrogen; R⁹ is amino; and Y is CH.

4. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R⁹ is ammo; and Y is N.

5. The method according to claim 1, wherein the compound has the formula (A) and R¹, R⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R⁸ is hydrogen; R⁹ is amino; and Y is N.

6. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R⁹ is ammo; and Y is CH.

7. The method according to claim 1, wherein the compound has the formula (A) and R ¹, R²,

R ⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R⁸ is hydrogen; R⁹ is amino; and Y is CH.

8. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group , an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R ⁹ is ammo; and Y is N.

9. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N.

10. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ³, R⁴, and R⁵ are hydrogen; R² is hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R ⁹ is ammo; and Y is N or CH.

11. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ³, R⁴, and R⁵ are hydrogen; R² is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N or

CH.

12. The method according to claim 1, wherein the compound has the formula (A) and R¹ and

R ⁴ together are a bond, R², R³, and R⁵ are hydrogen; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N or CH.

13. The method according to claim 1, wherein the compound has the formula (A) and R¹,

R ², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is oxygen; R ⁸ is hydrogen; R⁹ is amino; and Y is CH.

14. A pharmaceutical composition for use in preventing or treating hepatitis B virus infections in animals and man, characterized by an antiviral effective amount of a compound selected from the group consisting of formulae:

wherein:

R ² is selected from the group consist of hydrogen, acyloxy and hydroxyl; R³ is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR⁶

R ⁷ is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R⁸ is hydrogen; or

Y is selected from the group consisting of

CH and nitrogen;

R⁹ is selected from the group consisting of hydrogen and amino;

R ¹² and R¹³ are independently hydrogen or a C_1-6 alkyl group;

X is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C_1-6 alkyl group, and NHR ¹⁴ wherein R¹⁴ is a C_1-6 alkyl group;

(including fluorine, chlorine, bromine or iodine).

15. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R¹, R⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R ⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R⁹ is amino; and Y is CH.

16. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹, R⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino;

and Y is CH.

17. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;

R ⁹ is ammo; and Y is N.

18. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R¹, R⁴, and R⁵ are hydrogen; R² and R³ are hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino;

and Y is N.

19. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) ancl R¹, R², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R ⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;

R ⁹ is amino; and Y is CH.

20. A pharmaceutical composition according to claim 14, wherein the compound has the formula

( AA) and R ¹, R², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is

CH.

21. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹, R², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;

R ⁹ is ammo; and Y is N.

22. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹, R², R⁴, and R⁵ are hydrogen; R³ is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N.

23. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹, R³, R⁴, and R⁵ are hydrogen; R² is hydroxyl; R⁷ is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R⁸ is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;

R ⁹ is ammo; and Y is N or CH.

24. A pharmaceutical composition according to claim 14, wherein the compound has the formula (A) and R¹, R³ , R⁴, and R⁵ are hydrogen; R² is hydroxyl; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N or CH.

25. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹ and R⁴ together are a bond, R², R³, and

R ⁵ are hydrogen; R⁷ is selected from the group consisting of oxygen and sulfur; R ⁸ is hydrogen; R⁹ is amino; and Y is N or CH.

26. A pharmaceutical composition according to claim 14, wherein the compound has the formula

(A) and R ¹, R² , R⁴, and R⁵ are hydrogen; R³ is hydroxyl;

R ⁷ is oxygen; R⁸ is hydrogen; R⁹ is amino; and Y is CH.