U.S. patent number RE42,015 [Application Number 11/821,076] was granted by the patent office on 2010-12-28 for n4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections.
This patent grant is currently assigned to Pharmasset, Inc.. Invention is credited to Michael J. Otto, Junxing Shi, Kyoichi A. Watanabe.
United States Patent |
RE42,015 |
Watanabe , et al. |
December 28, 2010 |
N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral
infections
Abstract
The present invention is directed to a compound, method and
composition of treating or preventing viral infections, in
particular, human immunodeficiency virus (HIV) and hepatitis B
virus (HBV) infections, in human patients or other animal hosts,
comprising the administration of N.sup.4-acylcytosine-1,3-dioxolane
and pharmaceutically acceptable salts, prodrugs, and other
derivatives thereof.
Inventors: |
Watanabe; Kyoichi A. (Stone
Mountain, GA), Shi; Junxing (Duluth, GA), Otto; Michael
J. (East Windsor, NJ) |
Assignee: |
Pharmasset, Inc. (Princeton,
NJ)
|
Family
ID: |
23338072 |
Appl.
No.: |
11/821,076 |
Filed: |
June 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60341555 |
Dec 14, 2001 |
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Reissue of: |
10320350 |
Dec 16, 2002 |
06908924 |
Jun 21, 2005 |
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Current U.S.
Class: |
514/272; 544/320;
544/321; 544/242 |
Current CPC
Class: |
A61P
31/22 (20180101); A61P 31/20 (20180101); C07D
405/04 (20130101); A61P 31/14 (20180101); C07H
19/06 (20130101); A61P 43/00 (20180101); C07D
409/14 (20130101); A61P 31/18 (20180101); A61P
1/16 (20180101); A61P 31/12 (20180101); C07H
19/16 (20130101) |
Current International
Class: |
C07D
407/04 (20060101); A61P 31/22 (20060101); A61P
31/18 (20060101); A61K 31/506 (20060101) |
Field of
Search: |
;544/242,320,321
;514/272 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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99493 |
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Jan 1984 |
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EP |
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409 227 |
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May 1989 |
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EP |
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8901258 |
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Jan 1991 |
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NL |
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Other References
Bacheler Lt., et al. (1994), An assay for HIV RNIn infected cell
lysates, and its use for rapid evaluation of antiviral efficacy.
Antivir. Chem. Chemother. 5:111-121. cited by other .
Charvet, A.S., et al., (1994), Inhibition of human immunodeficiency
virus type 1 replication by phosphonoformate- an
phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates, J. Med.
Chem., 37:2216-2223. cited by other .
Chou T., et al., Adv. Enzyme Regul., 1984, 22, 27-55. cited by
other .
Glubis, et al., (1993), Structure of dideoxynucleside active
against the HIV (AIDS) virus, Acta Cryst. C49, 1095-1097,
N4-isopropyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine. cited
by other .
Hosteller, K.Y., et al., Greatly enhanced inhibition of human
immunodeficiency virus type 1 replication in CEM and HT4-6C cells
by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid
prodrug of 3'-deoxythymidine, Antimicrob. Agents Chemother., 1992,
36, 2025-2029. cited by other .
Hosteller, K.Y., et al., Synthesis and antiretroviral activity of
phospholipid analogs of azidothymidine and other antiviral
nucleosides, J. Biol. Chem., 1990, 265, 61127. cited by other .
Jadhav, P.K., et al., (1997), Cyclic urea amide: HIV-1 protease
inhibitors with low nanomolar potency against both wild types and
protease inhibitor resistant mutants of HIV J. Med. Chem.
40:181-190. cited by other .
Kawaguchi, et al., Studies on
2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides, II.
N4-benzoyl-2',3'-diddeoxy-2',3'-didehydrocytidine as a prodrug of
2',3'-didehydrocytidine (DDCN), Chem. Pharm. Bull. (1989), 37(9),
2547-9, N4-benzoyl-2'3'-dideoxycytidine. cited by other .
Kucera, L.S., et al., Novel membrane-interactive ether lipid
analogs that inhibit infectious HIV-1 production and induce
defective virus formation, AIDS Res. Hum. Retroviruses, 1990, 6,
491-501. cited by other .
Ladner, S.K., et al., Antimicro. Agents Chemother., 1997, 41,
1715-1720. cited by other .
Mauldin, et al., (1998), Synthesis and antiviral activity of
prodrugs of the nucleoside
1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-B-D-erythropentofuranosyl]
cytosine, Bioorg. Med. Chem., 6, 577-585. cited by other .
Plantadosi, C., et al., Synthesis and evaluation of novel ether
lipid nucleoside conjugates for anti-HIV activity, J. Med. Chem.,
1991, 34, 1408-1414. cited by other .
Schinazi, R.F., et al., Antimicrob. Agents Chemother., 1992, 36,
2423. cited by other .
Schinazi, R.F., et al., Antimicrob. Agents Chemother., 1990, 34,
1061-1067. cited by other .
Shi, et al., (1999), Synthesis and biological evaluation of
2',3'-dideoxy-5-fluorocytidine (d4FC) analogues: discovery of
carbocyclic nucleoside triphosphates with potent inhibitory
activity against HIV-1 reverse transcriptase, J. Med. Chem., 42,
859-867. cited by other .
Wolff, Burger's Medicinal Chemistry, 5ed, Part I, John Wiley &
Sons, 1995, pp. 975-977. cited by other .
Banker, et al., Modern Pharmaceutics, 3ed, Marcel Dekker, New York,
1996, pp. 451 and 596. cited by other .
Kim, et al., Journal of Medicinal Chemistry, 36(5), 519-28
(English) 1993. cited by other .
Lee, et al., Bioorganic & Medicinal Chemistry Letters, 5(17),
2011-14 (English) 1995. cited by other.
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Primary Examiner: Rao; Deepak
Attorney, Agent or Firm: Merchant & Gould, PC
Parent Case Text
The present application claims priority to U.S. Ser. No. 60/341,555
filed on Dec. 14, 2001.
Claims
We claim:
1. A compound of the formula: ##STR00023## or a pharmaceutically
acceptable salt thereof, wherein i) R.sup.1 is .[.chosen from
hydrogen and.]. halogen; ii) R.sup.2 is chosen from .Iadd.alkyl,
.Iaddend.alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl,
haloalkyl, thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6
where R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3,
NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl,
alkynyl, and aryl; iii) R.sup.3 is chosen from halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; iv)
R.sup.3' is chosen from H, halogen.Iadd., .Iaddend.methyl.Iadd.,
.Iaddend.or ethyl; and v) R.sup.4 is .Iadd.chosen from .Iaddend.H,
phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl,
sulfonate ester, a lipid, an amino acid, a peptide, or
cholesterol.
2. The compound of claim 1 wherein R.sup.1 is fluorine.
3. The compound of claim 1 wherein R.sup.3 is fluorine and R.sup.3'
is H.
4. A compound selected from the group consisting of
.beta.-D-N.sup.4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane,
.Iadd.and
.Iaddend..beta.-D-N.sup.4-p-t-butylbenzoyl-5-fluoro-cytidine-1,-
3-dioxolane.
5. A compound selected from the following, or its pharmaceutically
acceptable salt:
.beta.-D-5-fluoro-N.sup.4-(4-iodobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00024##
.beta.-D-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00025##
.beta.-D-N.sup.4-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00026##
.beta.-D-N.sup.4-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00027##
.beta.-D-5-fluoro-N.sup.4-(3-fluorobenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00028##
.beta.-D-N.sup.4-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00029##
.beta.-D-N.sup.4-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00030##
.beta.-D-5-fluoro-N.sup.4-(4-nitrobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00031##
.beta.-D-5-fluoro-N.sup.4-p-toluoylcytidine-1,3-dioxolane of the
structure: ##STR00032##
.beta.-D-5-fluoro-N.sup.4-(m-toluoyl)cylidine-1,3-dioxolane of the
structure: ##STR00033##
.beta.-D-N.sup.4-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00034##
.beta.-D-5-fluoro-N.sup.4-(4-propylbenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00035##
.beta.-D-N.sup.4-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00036##
.beta.-D-5-fluoro-N.sup.4-(2-thiophenecarbonyl)cytidine-1,3-dioxolane
of the structure: ##STR00037##
.beta.-D-N.sup.4-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-di-
oxolane of the structure: ##STR00038## and
.beta.-D-N.sup.4-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00039##
6. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(iodobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00040##
7. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00041##
8. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00042##
9. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00043##
10. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(3-fluorobenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00044##
11. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00045##
12. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00046##
13. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(4-nitrobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00047##
14. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-p-toluoylcytidine-1,3-dioxolane of the
structure: ##STR00048##
15. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(m-toluoyl)cytidine-1,3-dioxolane of the
structure: ##STR00049##
16. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00050##
17. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(4-propylbenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00051##
18. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00052##
19. The compound of claim 5 wherein the compound is:
.beta.-D-N.sup.4-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00053##
20. The compound of claim 5 wherein the compound is:
.beta.-D-5-fluoro-N.sup.4-(2-thiophenecarbonyl)cytidine-1,3-dioxolane
of the structure: ##STR00054##
21. The compound of claim 5 wherein the compound is;
.beta.-D-N.sup.4-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-di-
oxolane of the structure: ##STR00055##
22. A pharmaceutical composition that includes an effective HIV or
HBV treatment amount of a compound of claim 1 in a pharmaceutically
acceptable carrier or diluent.
23. A pharmaceutical composition that includes an effective HIV or
HBV treatment amount of a compound selected from the group
consisting of
.beta.-D-N.sup.4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane,
.Iadd.and
.Iaddend..beta.-D-N.sup.4-p-t-butylbenzoyl-5-fluoro-cytidine-1,-
3-dioxolane.
24. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound of the
formula: ##STR00056## or a pharmaceutically acceptable salt
thereof, wherein iv) R.sup.1 is .[.chosen from hydrogen and.].
halogen; v) R.sup.2 is chosen from .Iadd.alkyl, .Iaddend.alkenyl,
alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,
thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6 where
R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3, NO.sub.2,
alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl,
and aryl; vi) R.sup.3 is chosen from .[.H,.]. halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; vii)
R.sup.3' is chosen from H, halogen.Iadd., .Iaddend.methyl.Iadd.,
.Iaddend.or ethyl; and viii) R.sup.4 is H, phosphate, carbonyl
substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a
lipid, an amino acid, a peptide, or cholesterol, in a
pharmaceutically acceptable carrier.
25. A method for the treatment of a host infected with HBV that
includes administering an effective amount of a compound of the
formula: ##STR00057## or a pharmaceutically acceptable salt
thereof, wherein ix) R.sup.1 is .[.chosen from hydrogen and.].
halogen; x) R.sup.2 is chosen from .Iadd.alkyl, .Iaddend.alkenyl,
alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,
thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6 where
R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3, NO.sub.2,
alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl,
and aryl; xi) R.sup.3 is chosen from .[.H,.]. halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; xii)
R.sup.3' is chosen from H, halogen.Iadd., .Iaddend.methyl.Iadd.,
.Iaddend.or ethyl; and xiii) R.sup.4 is H, phosphate, carbonyl
substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a
lipid, an amino acid, a peptide, or cholesterol, in a
pharmaceutically acceptable carrier.
26. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound of the
formula: ##STR00058## or a pharmaceutically acceptable salt
thereof, wherein xiv) R.sup.1 is .[.chosen from hydrogen and.].
halogen; xv) R.sup.2 is chosen from .Iadd.alkyl, .Iaddend.alkenyl,
alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,
thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6 where
R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3, NO.sub.2,
alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl,
and aryl; xvi) R.sup.3 is chosen from .[.H,.]. halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; xvii)
R.sup.3' is chosen from H, halogen, methyl.Iadd., .Iaddend.or
ethyl; and xviii) R.sup.4 is H, phosphate, carbonyl substituted
with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an
amino acid, a peptide, or cholesterol, in a pharmaceutically
acceptable carrier in combination with another anti-HIV agent.
27. A method for the treatment of a host infected with HBV that
includes administering an effective amount of a compound of the
formula: ##STR00059## or a pharmaceutically acceptable salt
thereof, wherein xix) R.sup.1 is .[.chosen from hydrogen and.].
halogen; xx) R.sup.2 is chosen from .Iadd.alkyl, .Iaddend.alkenyl,
alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,
thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6 where
R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3, NO.sub.2,
alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl,
and aryl; xxi) R.sup.3 is chosen from .[.H,.]. halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; xxii)
R.sup.3' is chosen from H, halogen.Iadd., .Iaddend.methyl.Iadd.,
.Iaddend.or ethyl; and xxiii) R.sup.4 is H, phosphate, carbonyl
substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a
lipid, an amino acid, a peptide, or cholesterol, in a
pharmaceutically acceptable carrier in combination with another
.[.anti-HIV.]. .Iadd.anti-HBV .Iaddend.agent.
28. The method of claims 24, 25, 26 or 27 wherein R.sup.1 is
fluorine.
29. The method of claims 24, 25, 26, or 27 wherein R.sup.3 is
fluorine and R.sup.3' is H.
30. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound selected
from the group consisting of
.beta.-D-N.sup.4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane,
.Iadd.and
.Iaddend..beta.-D-N.sup.4-p-t-butylbenzoyl-5-fluoro-cytidine-1,-
3-dioxolane.
31. A method for the treatment of a host infected with HBV that
includes administering an effective amount of a compound .[.of one
of claim 5 or 6-21.]. .Iadd.according to any one of claims 5-21
.Iaddend.in a pharmaceutically acceptable carrier.
32. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound .[.of one
of claim 5 or 6-21.]. .Iadd.according to any one of claims 5-21
.Iaddend.in a pharmaceutically acceptable carrier.
33. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound .[.of one
of claim 5 or 6-21.]. .Iadd.according to any one of claims 5-21
.Iaddend.in a pharmaceutically acceptable carrier in combination
with another anti-HIV agent.
34. A method for the treatment of a host infected with HBV that
.[.includes.]. .Iadd.comprises .Iaddend.administrating an effective
amount of a compound .[.of one of claim 5 or 6-21.].
.Iadd.according to any one of claims 5-21 .Iaddend.in a
pharmaceutically acceptable carrier in combination with another
anti-HBV agent.
.Iadd.35. A method for the treatment of a host infected with HBV
that comprises administering an effective amount of a compound of
the formula: ##STR00060## or a pharmaceutically acceptable salt
thereof, wherein i) R.sup.1 is hydrogen; ii) R.sup.2 is chosen from
alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl,
haloalkyl, thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6
where R.sup.6 is chosen from halogen, CN, CF.sub.3, N.sub.3,
NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl,
alkynyl, and aryl; iii) R.sup.3 is chosen from halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; iv)
R.sup.3' is chosen from H, halogen, methyl, or ethyl; and v)
R.sup.4 is chosen from H, phosphate, carbonyl substituted with
alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino
acid, a peptide, or cholesterol..Iaddend.
.Iadd.36. A method for the treatment of a host infected with HBV
that comprises administering an effective amount of a compound in a
pharmaceutically acceptable carrier in combination with another
anti-HBV agent, wherein the compound has the formula: ##STR00061##
or a pharmaceutically acceptable salt thereof, wherein i) R.sup.1
is hydrogen; ii) R.sup.2 is chosen from alkyl, alkenyl, alkynyl,
cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl,
heteroaryl, and C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen from
halogen, CN, CF.sub.3, N.sub.3, NO.sub.2, alkyl, haloalkyl,
aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl; iii)
R.sup.3 is chosen from halogen, CN, CF.sub.3, N.sub.3, NO.sub.2,
alkyl, alkenyl, and alkynyl; iv) R.sup.3' is chosen from H,
halogen, methyl, or ethyl; and v) R.sup.4 is chosen from H,
phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl,
sulfonate ester, a lipid, an amino acid, a peptide, or
cholesterol..Iaddend.
.Iadd.37. A compound of the formula: ##STR00062## or a
pharmaceutically acceptable salt thereof, wherein i) R.sup.1 is
hydrogen; ii) R.sup.2 is chosen from alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl,
and C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen from halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy,
thioalkyl, alkenyl, alkynyl, and aryl; iii) R.sup.3 is chosen from
halogen, CN, CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and
alkynyl; iv) R.sup.3' is chosen from H, halogen, methyl, or ethyl;
and v) R.sup.4 is chosen from H, phosphate, carbonyl substituted
with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an
amino acid, a peptide, or cholesterol..Iaddend.
.Iadd.38. The compound of claim 37 wherein R.sup.2 is
C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen from halogen, CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy,
thioalkyl, alkenyl, alkynyl, and aryl..Iaddend.
.Iadd.39. A pharmaceutical composition that comprises an effective
HIV or HBV treatment amount of a compound of claim 37 in a
pharmaceutically acceptable carrier or diluent..Iaddend.
.Iadd.40. A method for the treatment of a host infected with HIV
that comprises administering an effective amount of a compound of
claim 37..Iaddend.
.Iadd.41. A method for the treatment of a host infected with HBV
that comprises administering an effective amount of a compound of
claim 37..Iaddend.
.Iadd.42. A method for the treatment of a host infected with HIV
that comprises administering an effective amount of a compound of
claim 37 in a pharmaceutically acceptable carrier in combination
with another anti-HIV agent..Iaddend.
.Iadd.43. A method for the treatment of a host infected with HBV
that comprises administering an effective amount of a compound of
claim 37 in a pharmaceutically acceptable carrier in combination
with another anti-HBV agent..Iaddend.
Description
FIELD OF THE INVENTION
The present invention is directed to compounds, methods and
compositions for the treatment or prevention of viral infections
using nucleoside analogues. More specifically, the invention
describes N.sup.4-acyl-substituted cytosine nucleoside analogues,
pharmaceutically acceptable salts, prodrugs, or other derivatives
thereof, and the use thereof in the treatment of a viral infection,
and in particular a human immunodeficiency virus (HIV) or hepatitis
B virus (HBV) infection.
BACKGROUND OF THE INVENTION
In 1981, acquired immune deficiency syndrome (AIDS) was identified
as a disease that severely compromises the human immune system, and
that without exception leads to death. In 1983, the etiological
cause of AIDS was determined to be what is now known as human
immunodeficiency virus (HIV).
Another virus that causes a serious human health problem is the
hepatitis B virus (HBV). HBV is second only to tobacco as a cause
of human cancer. The mechanism by which HBV induces cancer is
unknown. It is postulated that it may directly trigger tumor
development, or indirectly trigger tumor development through
chronic inflammation, cirrhosis, and cell regeneration associated
with the infection.
After a 2- to 6-month incubation period, during which the host is
typically unaware of the infection, HBV infection can lead to acute
hepatitis and liver damage, resulting in abdominal pain, jaundice
and elevated blood levels of certain enzymes. HBV can cause
fulminant hepatitis, a rapidly progressive, often fatal form of the
disease in which large sections of the liver are destroyed.
Patients typically recover from the acute phase of HBV infection.
In some patients, however, high levels of viral antigen persist in
the blood for an extended, or indefinite, period, causing a chronic
infection. Chronic infections can lead to chronic persistent
hepatitis. Patients infected with chronic persistent HBV are most
common in developing countries. By mid-1991, there were
approximately 225 million chronic carriers of HBV in Asia alone,
and worldwide, almost 300 million carriers. Chronic persistent
hepatitis can cause fatigue, cirrhosis of the liver, and
hepatocellular carcinoma, a primary liver cancer.
In Western, industrialized countries, the high-risk group for HBV
infection includes those in contact with HBV carriers or their
blood samples. The epidemiology of HBV is very similar to that of
HIV/AIDS, which is a reason why HBV infection is common among
patients infected with HIV or suffering from AIDS. However, HBV is
more contagious than HIV.
In 1985, it was reported that the synthetic nucleoside
3'-azido-3'-deoxythymidine (AZT) inhibited the replication of HIV.
Since then, several other synthetic nucleosides, including but not
limited to 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC),
2',3'-dideoxy-2',3'-didehydrothymidine (d4T),
(-)-2',3'-dideoxy-3'-thiacytidine (3TC), and (-)-carbocyclic
2',3'-didehydro-2',3'-dideoxyguanosine (carbovir) and its prodrug
abacavir, have proven effective against HIV. After phosphorylation
to the 5'-triphosphate by cellular kinases, these synthetic
nucleosides are incorporated into a growing strand of viral DNA,
causing chain termination, because they lack a 3'-hydroxyl group.
Some nucleosides also inhibit the viral enzyme reverse
transcriptase.
3TC (lamivudine) and interferon are currently the only FDA-approved
drugs for the treatment of HBV infection. Viral resistance develops
within 6 months of 3TC treatment in about 14% of patients.
Cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC)
is currently in clinical trials for the treatment of HIV and
separately for HBV by Triangle Pharmaceuticals, Inc. See Schinazi
et al. (1992) Selective inhibition of human immunodeficiency
viruses by racemates and enantiomers of
cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine.
Antimicrob. Agents Chemother. 36, 2423-2431; U.S. Pat. Nos.
5,210,085; 5,914,331; 5,814,639; WO 91/11186; and WO 92/14743.
There has also been a signficant amount of research on
1,3-dioxolane nucleosides and their use to treat viral infections.
U.S. Pat. Nos. 5,210,085; 5,276,151; 5,852,027; and 5,179,104
disclose 5-fluorocytosine-1,3-dioxolane nucleoside and nucleoside
analogues for the treatment of viral infections.
The success of various synthetic nucleosides in inhibiting the
replication of HIV in vivo or in vitro has led a number of
researchers to design and test nucleosides that substitute a
heteroatom for the carbon atom at the 3'-position of the
nucleoside. Norbeck, et al., disclosed that
(+/-)-1-[(2-.beta.,4-.beta.)-2-(hydroxymethyl)-4-dioxolanyl]thymine
(referred to as (+/-)-dioxolane-T) exhibits a modest activity
against HIV (EC.sub.50 of 20 .mu.M in ATH8 cells), and is not toxic
to uninfected control cells at a concentration of 200 .mu.M.
Tetrahedron Letters 30 (46), 6246, (1989).
On Apr. 11, 1988, Bernard Belleau, Dilip Dixit, and Nghe Nguyen-Ba
at BioChem Pharma filed patent application U.S. Ser. No. 07/179,615
which disclosed a generic group of racemic
2-substituted-4-substituted-1,3-dioxolane nucleosides for the
treatment of HIV. The '615 patent application matured into European
Patent Publication No. 0 337 713; U.S. Pat. No. 5,041,449; and U.S.
Pat. No. 5,270,315 assigned to BioChem Pharma, Inc.
On Dec. 5, 1990, Chung K. Chu and Raymond F. Schinazi filed U.S.
Ser. No. 07/622,762, which disclosed an asymmetric process for the
preparation of enantiomerically pure .beta.-D-1,3-dioxolane
nucleosides via stereospecific synthesis, and certain nucleosides
prepared thereby, including
(-)-(2R,4R)-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]guanine (DXG),
and its use to treat HIV. This patent application issued as U.S.
Pat. No. 5,179,104. ##STR00001##
On May 21, 1991, Tarek Mansour, et al., at BioChem Pharma filed
U.S. Ser. No. 07/703,379 directed to a method to obtain the
enantiomers of 1,3-dioxolane nucleosides using a stereoselective
synthesis that includes condensing a 1,3-dioxolane intermediate
covalently bound to a chiral auxiliary with a silyl Lewis acid. The
corresponding application filed in Europe was EP 0 515 156.
On Aug. 25, 1992, Chung K. Chu and Raymond F. Schinazi filed U.S.
Ser. No. 07/935,515, disclosed certain enantiomerically pure
.beta.-D-dioxolanyl purine compounds for the treatment of humans
infected with HIV of the formula: ##STR00002## wherein R is OH, Cl,
NH.sub.2, or H, or a pharmaceutically acceptable salt or derivative
of the compounds optionally in a pharmaceutically acceptable
carrier or diluent. The compound wherein R is chloro is referred to
as
(-)-(2R,4R)-2-amino-6-chloro-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]purin-
e. The compound wherein R is hydroxy is
(-)-(2R,4R)-9-[(2-hydroxy-methyl)-1,3-dioxolan-4-yl]guanine. The
compound wherein R is amino is
(-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine.
The compound wherein R is hydrogen is
(-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4yl]purine.
This application issued as U.S. Pat. No. 5,925,643.
In 1992, Kim et al., published an asymmetric synthesis for selected
1,3-dioxolane pyrimidine nucleosides from 1,6-anhydro-D-mannose.
The specific synthesis resulted in .beta.-D and .alpha.-D
enantiomers of 1,3-dioxolane nucleosides. Kim et al.,
1,3-Dioxolanylpurine Nucleosides (2R,4R) and (2R,4S) with Selective
Anti-HIV-1 Activity in Human Lymphocytes, J. Med. Chem., 1993 36,
30-37.
In 1992, Belleau et al., at BioChem Pharma, published a method to
obtain enantiomerically pure 1,3-dioxolane nucleosides via
L-ascorbic acid as a chiral auxiliary in the process. L-ascorbic
acid was used to produce a set of diastereomers which could be
separated. Belleau, et al., Oxidative Degradation of L-Ascorbic
Acid Acetals to 2',3'-Dideoxy-3'-Oxaribofuranosides Synthesis of
Enantiomerically Pure 2',3'-Dideoxy-3'-Oxaribofuranosides.
Synthesis of Enantiomerically Pure 2',3'-Dideoxy-3'-Oxacytidine
Stereoisomers as Potential Antiviral Agents. Tetrahedron Lett.
1992, 33:6949.
On Feb. 21, 1992, PCT/US92/01393 (WO 92/14729) by Liotta et al.
disclosed a method for the synthesis of 1,3-dioxolane nucleosides
that includes condensing a 2-O-protected-5-O-acylated-1,3-dioxolane
with a purine of pyrimidine base in the presence of a titanium
containing Lewis acid to provide predominately the desired O-isomer
in the C1'-position of a 1,3-dioxolane nucleoside. WO 92/14729 also
disclosed a process for the resolution of a racemic mixture of
1,3-dioxolane nucleoside enantiomers.
In 1992, Kim et al., published an article teaching how to obtain
(-)-L-.beta.-dioxolane-C and (+)-L-.beta.-dioxolane-T from
1,6-anhydro-L-.beta.-glucopyranose. Kim et al., Potent anti-HIV and
anti-HBV Activities of (-)-L-.beta.-Dioxolane-C and
(+)-L-.beta.-Dioxolane-T and Their Asymmetric Syntheses,
Tetrahedron Letters Vol 32(46), pp 5899-6902.
On Oct. 28, 1992, Raymond Schinazi filed U.S. Ser. No. 07/967,460
directed to the use of the compounds disclosed in U.S. Ser. No.
07/935,515 for the treatment of hepatitis B. This application has
issued as U.S. Pat. Nos. 5,444,063; 5,684,010; 5,834,474; and
5,830,898.
In 1993, Jin et al., at BioChem Pharma published an article that
concluded that Lewis acids play a crucial role in the preparation
1,3-dioxolane nucleosides. TiC.sub.4 and SnCl.sub.4 promote the
formation of dioxolane nucleosides with racemization in the
coupling of enantiomerically pure 2'-deoxy-3'-oxaribosides with
silylated N-acetylcytosine. The use of the Lewis acids
trimethylsilyltriflate, trimethylsilyl iodide, and
TiCl.sub.2(O-.sup.iPr).sub.2 furnished enantiomerically pure
cytosine dioxolane nucleosides in low diastereoselectivity.
Unexpected Effects of Lewis Acids in the Synthesis of Optically
Pure 2'-Deoxy-3'-Oxacytidine Nucleoside Analogs, Tetrahedron
Asymmetry vol 4, No. 2 pp 211-214 (1993).
In 1993, Siddiqui, et al., at BioChem and Glaxo published that
cis-2,6-diaminopurine dioxolane can be deaminated selectively using
adenosine deaminase. Siddiqui, et al., Antiviral Optically Pure
dioxolane Purine Nucleoside Analogues, Bioorganic & Medicinal
Chemistry Letters, Vol. 3 (8), pp 1543-1546 (1993).
(-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine
(DAPD) is a selective inhibitor of HIV-1 replication in vitro as a
reverse transcriptase inhibitor (RTI). DAPD is thought to be
deaminated in vivo by adenosine deaminase, a ubiquitous enzyme, to
yield (-)-.beta.-D-dioxolane guanine (DXG), which is subsequently
converted to the corresponding 5'-tri-phosphate (DXG-TP).
Biochemical analysis has demonstrated that DXG-TP is a potent
inhibitor of the HIV reverse transcriptase (HIV-RT) with a Ki of
0.019 .mu.M. ##STR00003##
Other nucleosides that have been successful in anti-viral
treatments include of 2',3'-dideoxy- and
2',3'-didehydro-2,3'-dideoxy-nucleosides (referred to as a "ddN" or
"d2N" nucleoside and a "d4N" nucleoside, respectively),
particularly, these nucleosides inhibit the replication of HIV in
vivo or in vitro, thus, has led a number of researchers to design
and test a variety of modified d2- and d4-nucleosides. One
modification has been the replacement of the 5-hydrogen on cytosine
nucleosides with fluorine, resulting in several 5-fluorocytosine
nucleosides with antiviral activity, including but not limited to
.beta.-D- and .beta.-L-2',3'-dideoxy-5-fluorocytine (.beta.-D-D2FC
and .beta.-L-D2FC) (U.S. Pat. Nos. 4,788,181 and 6,156,737).
.beta.-D-2',3'-Dideoxy-2',3'-didehydro-5-fluorocytidine (d4FC) and
its use to treat hepatitis B was first described in Example 2 of
European Pat. Application No. 0 409 227 A2 (Ajinomoto Co., Inc.).
Netherlands Pat. No. 8901258 (Stichting Rega V. Z. W.) discloses
generally 5-halogeno-2',3'-dideoxy-2',3'-didehydrocytidine
derivatives for use in treating HIV and HBV. .beta.-D- and
.beta.-L-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine were
further described in U.S. Pat. Nos. 5,703,058; 5.905,070;
6,232,300; and 5,561,120. U.S. Pat. No. 5,703,058 claims a method
for the treatment of HIV and/or HBV infection that includes
administering an effective amount of .beta.-L-d4FC in combination
or alternation with
cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane,
cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane,
9-[4-(hydroxymethyl)-2-cyclopenten-1-yl)-guanine (carbovir),
9-[(2-hydroxyethoxy)methyl]-guanine (acyclovir), interferon,
3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddI),
2',3'-dideoxycytidine (ddC),
(-)-2'-fluoro-5-methyl-.beta.-L-ara-uridine (L-FMAU) or
2',3'-didehydro-2',3'-dideoxythymidine (d4T). U.S. Pat. No.
5,905,070 claims a method for the treatment of HIV and HBV
infection that includes administering an effective amount of
.beta.-D-d4FC in combination or alternation with
cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane,
cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane,
9-[4-(hydroxy-methyl)-2-cyclopenten-1-yl)-guanine (carbovir),
9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon,
3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddI),
2',3'-dideoxycytidine (ddC),
(-)-2'-fluoro-5-methyl-.beta.-L-ara-uridine (L-FMAU) or
2',3'-didehydro-2',3'-dideoxythymidine (d4T). U.S. Pat. No.
6,232,300 claims a method to treat HIV with .beta.-D-d4FC.
Modification of the amino group of antiviral cytosine nucleosides
has not been fully explored. Only a few N.sup.4-substituted
cytosine 2',3'-dideoxy nucleosides and N.sup.4-substituted cytosine
2',3'-didehydro-2',3'-dideoxy nucleosides have been reported. These
include N.sup.4-benzoyl-2',3'-didehydro-2,'3-dideoxycytidine
(Kawaguchi et al., Studies on
2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides. II.
N4-benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine as a prodrug of
2',3'-dideoxy-2',3'-didehydrocytidine (DDCN), Chem. Pharm. Bull.
(1989), 37(9), 2547-9), N.sup.4-benzoyl-2',3'-dideoxycytidine
(Gulbis et al. (1993) Structure of a dideoxynucleoside active
against the HIV (AIDS) virus. Acta Cryst. C49, 1095-1097),
N.sup.4-acetyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, and
N.sup.4-isopropyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
(Shi et al. (1999)) Synthesis and biological evaluation of
2',3'-didehydro-2',3'-aideoxy-5-fluorocytidine (d4FC) analogues:
discovery of carbocyclic nucleoside triphosphates with potent
inhibitory activity against HIV-1 reverse transcriptase. J. Med.
Chem. 42, 859-867). Of the sugar-modified cytosine nucleosides,
some N.sup.4-acyl and imine-substituted
2',3'-dideoxy-3'-C-hydroxymethylcytidine analogues have been
synthesized (Mauldin et al. (1998) Synthesis and antiviral activity
of prodrugs of the nucleoside
1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-.beta.-D-erythropentofuranosyl]
cytosine. Bioorg. Med. Chem. 6, 577-585), and some N.sup.4-acetyl-
and phosphonoacetyl-2',3'-dideoxy-3'-thiacytidine nucleosides have
been prepared (Charvet et al. (1993) Inhibition of human
immunodeficiency virus type 1 replication by phosphonoformate- and
phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates. J. Med.
Chem. 37, 2216-2223).
Therefore, it is an object of the present invention to provide a
compound, method and composition for the treatment or prevention of
HIV infection in human patients.
It is another object of the present invention to provide a
compound, method and composition for the treatment or prevention of
HBV infection in human patients or other host animals.
It is still another object of the present invention to provide a
compound, method and composition for the treatment or prevention of
HIV and HBV infection in human patients or other host animals.
SUMMARY OF THE INVENTION
It has been found that certain N.sup.4-acyl-cytosine 1,3-dioxolane
nucleosides, and in particular,
N.sup.4-acyl-5-fluorocytidine-1,3-dioxolane, show improved
inhibitory activity against HIV and HBV. Therefore, a method for
the treatment or prevention of HIV and/or HBV infection in a host,
and in particular, a human, is provided that includes administering
an effective amount of a N.sup.4-acyl-cytosine nucleoside.
In one embodiment of the present invention, the active compound is
of formula (A): ##STR00004## wherein R.sup.1 is chosen from
hydrogen, halogen (F, Cl, Br, I), alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF.sub.3,
N.sub.3, NO.sub.2, aryl, heteroaryl and acyl; R.sup.3 and R.sup.3'
are chosen independently from H, halogen (F, Cl, Br, I), CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; R.sup.4
is H, phosphate (including but not limited to monophosphate,
diphosphate, triphosphate, or a stabilized phosphate prodrug),
carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other
pharmaceutically acceptable leaving group, which, when administered
in vivo, is capable of providing a compound wherein R.sup.3 and
R.sup.3' are H or phosphate, sulfonate ester (including but not
limited to alkyl or arylalkyl sulfonyl including but not limited to
methanesulfonyl), benzyl (wherein the phenyl group is optionally
substituted with one or more substituents as described in the
definition or aryl given above), a lipid (including but not limited
to a phospholipid), an amino acid, a peptide, or cholesterol; and
R.sup.2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl,
and C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen from halogen (F,
Cl, Br, I), CN, CF.sub.3, N.sub.3, NO.sub.2, alkyl, haloalkyl,
aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
The compound of the present invention can be in the form of the
isolated .beta.-L- or .beta.-D-configuration, or a mixture thereof,
including but not limited to a racemic mixture.
In addition, the N.sup.4-acylcytosine-1,3-dioxolane nucleosides are
inhibitors of HBV. Therefore, these compounds can also be used to
treat patients that are co-infected with both HIV and HBV.
The present invention provides a compound, method and composition
for treating an HIV infection in a host comprising administering a
therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a compound, method and composition
for preventing an HIV infection in a host comprising administering
a therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a compound, method and composition
for treating an HBV infection in a host comprising administering a
therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a compound, method and composition
for preventing an HBV infection in a host comprising administering
a therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a use of a compound for the
treatment of HIV and/or HBV infection in a host comprising
administering a therapeutically effective amount of at least one
compound as described in the present application.
The present invention provides a method of manufacture for a
therapeutically effective compound for the treatment of an HIV
and/or HBV infection.
In another aspect, there is provided a pharmaceutical formulation
comprising a compound of the invention in combination with a
pharmaceutically acceptable carrier or excipient for the treatment
of a host infected with HIV or HBV.
In still another aspect, there is provided a compound, method and
composition for treating or preventing an HIV infection in a host
comprising administering to the subject a combination comprising at
least one compound of the invention and at least one further
therapeutic agent.
In still another aspect, there is provided a method and composition
for treating or preventing an HBV infection in a host comprising
administering to the subject a combination comprising at least one
compound of the invention and at least one further therapeutic
agent.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that N.sup.4-acyl-cytosine-1,3-dixolane
nucleosides, and in particular,
N.sup.4-acyl-5-fluorocytidine-1,3-dioxolane, show improved
inhibitory activity against HIV and HBV. Therefore, a method for
the treatment or prevention of a host, and in particular, a human,
infected with HIV and/or HBV, is provided that includes
administering an effective amount of an
N.sup.4-acyl-cytosine-1,3-dioxolane nucleosides.
The present invention also provides a compouind, method and
composition for treating an HIV infection in a host comprising
administering a therapeutically effective amount of at least one
compound as described in the present application.
The present invention provides a compound, method and composition
for preventing an HIV infection in a host comprising administering
a therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a compound, method and composition
for treating an HBV infection in a host comprising administering a
therapeutically effective amount of at least one compound as
described in the present application.
The present invention provides a compound, method and composition
for preventing an HBV infection in a host comprising administering
a therapeutically effective amount of at least one compound as
described in the present application.
In another aspect, there is provided a pharmaceutical formulation
comprising a compound of the invention in combination with a
pharmaceutically acceptable carrier or excipient.
In still another aspect, there is provided a method and composition
for treating or preventing an HIV infection in a host comprising
administering to the subject a combination comprising at least one
compound of the invention and at least one further therapeutic
agent.
In still another aspect, there is provided a method and composition
for treating or preventing an HBV infection in a host comprising
administering to the subject a combination comprising at least one
compound of the invention and at least one further therapeutic
agent.
I. Active Compound
In one embodiment of the present invention, the active compound is
of formula (A): ##STR00005## wherein R.sup.1 is chosen from
hydrogen, halogen (F, Cl, Br, I), alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF.sub.3,
N.sub.3, NO.sub.2, aryl, heteroaryl and acyl; R.sup.3 and R.sup.3'
are chosen independently from H, halogen (F, Cl, Br, I), CN,
CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl, and alkynyl; R.sup.4
is H, phosphate (including but not limited to monophosphate,
diphosphate, triphosphate, or a stabilized phosphate prodrug),
carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other
pharmaceutically acceptable leaving group, which, when administered
in vivo, is capable of providing a compound wherein R.sup.3 and
R.sup.3' are H or phosphate, sulfonate ester (including but not
limited to alkyl or arylalkyl sulfonyl including but not limited to
methanesulfonyl), benzyl (wherein the phenyl group is optionally
substituted with one or more substituents as described in the
definition or aryl given above), a lipid (including but not limited
to a phospholipid), an amino acid, a peptide, or cholesterol; and
R.sup.2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl,
and C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen from halogen (F,
Cl, Br, I), CN, CF.sub.3, N.sub.3, NO.sub.2, alkyl, haloalkyl,
aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
The compound of the present invention can be in the form of the
isolated .beta.-L- or .beta.-D-configuration, or a mixture thereof,
including but not limited to a racemic mixture.
In one embodiment of the present invention, the active compound is
.beta.-D-N.sup.4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane,
.beta.-D-N.sup.4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane,
and
.beta.-D-N.sup.4-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.
In one embodiment of the present invention, the active compound is
of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I), CN, CF.sub.3, N.sub.3,
NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl,
alkynyl, or aryl in the ortho position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with I in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkyl in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with methyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with ethyl in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-propyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with iso-propyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-butyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with sec-butyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with tert-butyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-pentyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with iso-pentyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with neo-pentyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with cyclo-pentyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-hexyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with a cyclohexyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CN in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CF.sub.3 in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with N.sub.3 in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with haloalkyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aminoalkyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkoxy in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thioalkyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkenyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkynyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aryl in the ortho position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thiophenyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with furanyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with naphthyl in the ortho
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzoyl in the ortho
position.
In one embodiment of the present invention, the active compound is
of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I), CN, CF.sub.3, N.sub.3,
NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl,
alkynyl, or aryl in the meta position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with I in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkyl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with methyl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with ethyl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-propyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula, its pharmaceutically acceptable salts or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with iso-propyl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-butyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with sec-butyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with tert-butyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-pentyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with iso-pentyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with neo-pentyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with cyclo-pentyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-hexyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with a cyclohexyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CN in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CF.sub.3 in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A); its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with N.sub.3 in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with haloalkyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aminoalkyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkoxy in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thioalkyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkenyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkynyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aryl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzyl in the meta position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thiophenyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with furanyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with naphthyl in the meta
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzoyl in the meta
position.
In one embodiment of the present invention, the active compound is
of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I), CN, CF.sub.3, N.sub.3,
NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl,
alkynyl, or aryl in the para position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with I in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is
fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are independently
hydrogen or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkyl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with methyl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with ethyl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-propyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with iso-propyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-butyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with sec-butyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with tert-butyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-pentyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with iso-pentyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with neo-pentyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with cyclo-pentyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with n-hexyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with a cyclohexyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CN in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with CF.sub.3 in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with N.sub.3 in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with haloalkyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aminoalkyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkoxy in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thioalkyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkenyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with alkynyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with aryl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzyl in the para position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with thiophenyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with furanyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with naphthyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with benzoyl in the para
position.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,6-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,5-dihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,5-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,5-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,6-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5,6-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4,5-trihalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4,5-tetrahalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4,5,6-pentahalo.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,6-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,5-dialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,5-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,5-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,6-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5,6-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4,5-trialkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4,5-tetraalkyl.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4,5,6-pentaalkyl. In yet
another embodiment of the present invention, the active compound is
of formula (A), its pharmaceutically acceptable salts or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a phenyl moiety optionally
substituted with 2,3-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,6-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,5-di-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,4-tri-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,3,5-tri-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,5-tri-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,4,6-tri-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 2,5,6-tri-NO.sub.2.
In yet another embodiment of the present invention, the active
compound is of formula (A), its pharmaceutically acceptable salts
or prodrugs thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1
is fluorine or hydrogen; iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; and iv) R.sup.2 is a phenyl
moiety optionally substituted with 3,4,5-tri-NO.sub.2. In another
embodiment of the present invention, the active compound is of
formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a thienyl moiety optionally
substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl
in the 2-position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a thienyl moiety optionally
substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl
in the 3-position or the 4-position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a benzothiophenyl optionally
substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl
on the benzene ring.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a benzothiophenyl moiety optionally
substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl
on the thienyl ring.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a cyclohexyl optionally substituted
with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl,
hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or
3-position.
In another embodiment of the present invention, the active compound
is of formula (A), its pharmaceutically acceptable salt or prodrugs
thereof, wherein: i) R.sup.4 is hydrogen; ii) R.sup.1 is fluorine
or hydrogen; iii) R.sup.3 and R.sup.3' are independently hydrogen
or fluorine; and iv) R.sup.2 is a cyclohexyl moiety optionally
substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl,
aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl
in the 4-position.
In one preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(4-iodobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00006## or a pharmaceutically acceptable salt
or prodrug thereof.
In another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine-1,3-dioxolaneof
the structure: ##STR00007## or a pharmaceutically acceptable salt
or prodrug thereof.
In still another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00008## or a pharmaceutically acceptable
salt or prodrug thereof.
In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00009## or a pharmaceutically acceptable salt
or prodrug thereof.
In another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(3-fluorobenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00010## or a pharmaceutically acceptable
salt or prodrug thereof.
In still another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00011## or a pharmaceutically acceptable
salt or prodrug thereof.
In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00012## or a pharmaceutically acceptable salt
or prodrug thereof.
In another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(4-nitrobenzoyl)cytidine-1,3-dioxolane of
the structure: ##STR00013## or a pharmaceutically acceptable salt
or prodrug thereof.
In still another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-p-toluoylcytidine-1,3-dioxolane of the
structure: ##STR00014## or a pharmaceutically acceptable salt or
prodrug thereof.
In one preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(m-toluoyl)cytidine-1,3-dioxolane of the
structure: ##STR00015## or a pharmaceutically acceptable salt or
prodrug thereof.
In another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of
the structure: ##STR00016## or a pharmaceutically acceptable salt
or prodrug thereof.
In still another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(4-propylbenzoyl)cytidine-1,3-dioxolane
of the structure: ##STR00017## or a pharmaceutically acceptable
salt or prodrug thereof.
In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00018## or a pharmaceutically acceptable
salt or prodrug thereof.
In still another preferred embodiment, the active compound is
.beta.-D-5-fluoro-N.sup.4-(2-thiophenecarbonyl)cytidine-1,3-dioxolane
of the structure: ##STR00019## or a pharmaceutically acceptable
salt or prodrug thereof.
In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-di-
oxolane of the structure: ##STR00020## or a pharmaceutically
acceptable salt or prodrug thereof.
In another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane
of the structure: ##STR00021## or a pharmaceutically acceptable
salt or prodrug thereof. II. Stereoisomerism and Polymorphism
The compounds of the present invention have asymmetric centers and
occur as racemates, racemic mixtures, individual diastereomers or
enantiomers, with all isomeric forms being included in the present
invention. Some compounds may exhibit polymorphism. The present
invention encompasses racemic, optically-active, polymorphic, or
stereoisomeric form, or mixtures thereof, of a compound of the
invention, which possess the useful properties described herein.
The optically active forms can be prepared by, for example,
resolution of the racemic form by recrystallization techniques, by
synthesis from optically-active starting materials, by chiral
synthesis, or by chromatographic separation using a chiral
stationary phase or by enzymatic resolution.
Examples of methods to obtain optically active materials include at
least the following. i) physical separation of crystals: a
technique whereby macroscopic crystals of the individual
enantiomers are manually separated. This technique can be used if
crystals of the separate enantiomers exist, i.e., the material is a
conglomerate, and the crystals are visually distinct; ii)
simultaneous crystallization: a technique whereby the individual
enantiomers are separately crystallized from a solution of the
racemate, possible only if the latter is a conglomerate in the
solid state; iii) enzymatic resolutions: a technique whereby
partial or complete separation of a racemate by virtue of differing
rates of reaction for the enantiomers with an enzyme; iv) enzymatic
asymmetric synthesis: a synthetic technique whereby at least one
step of the synthesis uses an enzymatic reaction to obtain an
enantiomerically pure or enriched synthetic precursor of the
desired enantiomer; v) chemical asymmetric synthesis: a synthetic
technique whereby the desired enantiomer is synthesized from an
achiral precursor under conditions that produce asymmetry (i.e.,
chirality) in the product, which may be achieved using chiral
catalysts or chiral auxiliaries; vi) diastereomer separations: a
technique whereby a racemic compound is reacted with an
enantiomerically pure reagent (the chiral auxiliary) that converts
the individual enantiomers to diastereomers. The resulting
diastereomers are then separated by chromatography or
crystallization by virtue of their now more distinct structural
differences and the chiral auxiliary later removed to obtain the
desired enantiomer; vii) first- and second-order asymmetric
transformations: a technique whereby diastereomers from the
racemate equilibrate to yield a preponderance in solution of the
diastereomer from the desired enantiomer or where preferential
crystallization of the diastereomer from the desired enantiomer
perturbs the equilibrium such that eventually in principle all the
material is converted to the crystalline diastereomer from the
desired enantiomer. The desired enantiomer is then released from
the diastereomer; viii) kinetic resolutions: this technique refers
to the achievement of partial or complete resolution of a racemate
(or of a further resolution of a partially resolved compound) by
virtue of unequal reaction rates of the enantiomers with a chiral,
non-racemic reagent or catalyst under kinetic conditions; ix)
enantiospecific synthesis from non-racemic precursors: a synthetic
technique whereby the desired enantiomer is obtained from
non-chiral starting materials and where the stereochemical
integrity is not or is only minimally compromised over the course
of the synthesis; x) chiral liquid chromatography: a technique
whereby the enantiomers of a racemate are separated in a liquid
mobile phase by virtue of their differing interactions with a
stationary phase (including but not limited to via chiral HPLC).
The stationary phase can be made of chiral material or the mobile
phase can contain an additional chiral material to provoke the
differing interactions; xi) chiral gas chromatography: a technique
whereby the racemate is volatilized and enantiomers are separated
by virtue of their differing interactions in the gaseous mobile
phase with a column containing a fixed non-racemic chiral adsorbent
phase; xii) extraction with chiral solvents: a technique whereby
the enantiomers are separated by virtue of preferential dissolution
of one enantiomer into a particular chiral solvent; xiii) transport
across chiral membranes: a technique whereby a racemate is placed
in contact with a thin membrane barrier. The barrier typically
separates two miscible fluids, one containing the racemate, and a
driving force such as concentration or pressure differential causes
preferential transport across the membrane barrier. Separation
occurs as a result of the non-racemic chiral nature of the membrane
that allows only one enantiomer of the racemate to pass
through.
Chiral chromatography, including but not limited to simulated
moving bed chromatography, is used in one embodiment. A wide
variety of chiral stationary phases are commercially available.
III. Definitions
The term "independently" is used herein to indicate that the
variable, which is independently applied, varies independently from
application to application. Thus, in a compound such as R''XYR'',
wherein R'' is "independently carbon or nitrogen," both R'' can be
carbon, both R'' can be nitrogen, or one R'' can be carbon and the
other R'' nitrogen.
As used herein, the term "substantially free of" or "substantially
in the absence of" refers to a nucleoside composition that includes
at least 95% to 98% by weight, and even more preferably 99% to 100%
by weight, of the designated enantiomer of that nucleoside. In a
preferred embodiment, in the methods and compounds of this
invention, the compounds are substantially free of enantiomers.
Similarly, the term "isolated" refers to a nucleoside composition
that includes at least 85 or 90% by weight, preferably 95% to 98%
by weight, and even more preferably 99% to 100% by weight, of the
nucleoside, the remainder comprising other chemical species or
enantiomers.
The term "alkyl," as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic, primary,
secondary, or tertiary hydrocarbon. The term includes both
substituted and unsubstituted alkyl groups. The alkyl group may be
optionally substituted with any moiety that does not otherwise
interfere with the reaction or that provides an improvement in the
process, including but not limited to but limited to halo,
haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido,
carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy,
aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl,
sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide,
phosphonyl, phosphinyl, phosphoryl, phosphine, thioester,
thioether, acid halide, anhydride, oxime, hydrozine, carbamate,
phosphonic acid, phosphonate, either unprotected, or protected as
necessary, as known to those skilled in the art, for example, as
taught in Greene et al., Protective Groups in Organic Synthesis,
John Wiley & Sons, Second Edition, 1991, hereby incorporated by
reference. Specifically included are CF.sub.3 and
CH.sub.2CF.sub.3.
Alkyl groups include, but are not limited to the radicals of
methane, ethane, propane, cyclopropane, 2-methylpropane
(isobutane), n-butane, 2,2-dimethylpropane (neopentane),
cytobutane, 1,1 diraethylcyclopropane, 2-methylbutane,
trans-1,2-dimethylcyclopropane, ethylcyclopropane, n-pentane,
methylcyclobutane, cis-1,2-dimethylcyclopropane, spiropentane,
cyclopentane, 2,2-dimethylbutane, 1,1,2-trimethylcyclopropane,
2,3-dimethylbutane, 2-methylpentane, 3-methylpentane,
1,2,3-trimethylcyclopropane, n-hexane, ethylcyclobutane,
methylcyclopentane, 2,2dimethylpentane, 2,4-dimethylpentane,
cyclohexane, 2,2,3-trimethylbutane, 3,3-dimethylpentane,
1,1-dimethylcyclopentane, 2,3-dimethylpentane, 2-methylhexane,
trans-1,3-dimethylcyclopentane, cis-1,3-dimethylcyclopentane,
3-methylhexane, trans-1,2-dimethylcyclopentane, 3-ethylpentane,
quadricyclane (quadricyclo[2,2,1,0.sup.2,6,o.sup.3,5]heptane),
n-heptane, 2,2,4-trimethylpentane, cis-1,2-dimethylcyclopentane,
methylcyclohexane, ethylcyclopentane, 1,1,3-trimethylcyclopentane,
2,2-dimethylhexane, 2,5-dimethylhexane, 1,trans-2,
cis-4trimethylcyclopentane, 2,4-dimethylhexane,
2,2,3-trimethylpentane, 1,trans-2,cis-3-trimethylcyclopentane,
3,3-dimethylhexane, 2,3,4-trimethylpentane,
1,1,2-trimethylcyclopentane, 2,3,3-trimethylpentane,
2,3-dimethylhexane, 3-ethyl-2-methylpentane,
1,cis-2,trans-4-trimethylcyclopentane,
1,cis-2,trans-3trimethylcyclopentane, 2-methylheptane,
4-methylheptane, 3,4-dimethylhexane,
1,cis-2,cis-4trimethylcyclopentane, 3-ethyl-3-methylpentane,
3-ethylhexane, 3-methylheptane, cylotheptane (suberane),
trans-1,4-dimethylcyclohexane, 1,1-dimethylcyclohexane,
cis-1,3-dimethylcychohexane, trans-1-ethyl-3-methylcyclopentane,
trans-1-ethyl-2-methylcyclopentane,
cis-1-ethyl-3-methylcyclopentane, 1-ethyl-1-methylcyclopentane,
2,2,4,4-tetramethylpentane, 1,cis-2-cis-3-trimethylcyclopentane,
trans-1,2-dimethylcyclohexane, 2,2,5-trimethylhexane,
trans-1,3-dimethylcyclohexane, n-octane, isopropylcyclopentane,
2,2,4-trimethylhexane, cis-1-ethyl-2-methylcyclopentane,
cis-1,2-dimethylcyclohexane, 2,4,4-trimethylhexane,
n-propylcyclopentane, 2,3,5-trimethylhexane, ethylcyclohexane,
2,2-dimethylheptane, 2,2,3,4-tetramethylpentane,
2,4-dimethylheptane, methylcycloheptane, 2,2,3-trimethylhexane,
4-ethyl-2-methylhexane, 3-ethyl-2.2-dimethylpentane,
4,4-dimethylheptane, 2,6-dimethylheptane, 2,5-dimethylheptane,
3,5-dimethylheptane, bicyclo[4.2.0]octane,
cis-bicyclo[3.3.0]octane, 2,4-dimethyl-3-ethylpentane,
1,1,3-trimethylcyclohexane, 3,3-dimethylheptane,
2,2,5,5-tetramethylhexane, 2,3,3-trimethylhexane,
3-ethyl-2-methylhexane, trans-1,3,5-trimethylcyclohexane,
2,3,4-trimethylhexane, cis-1,3,5-trimethylcyclohexane,
trans-1,2,4-trimethylcyclohexane, 2,2,3,3-tetramethylpentane,
4-ethyl-3-methylhexane, 3,3,4-trimethylhexane, 2,3-dimethylheptane,
3,4-dimethylheptane, 3-ethyl-3-methylhexane, 4-ethylheptane,
2,3,3,4-tetramethylpentane, 2,3-dimethyl-3-ethylpentane,
trans-1,2,3-trimethylcyclohexane, 1-isopropyl-e-methylcyclopentane
(pulegan), 4-methyloctane, 1-isopropyl-2-methylcyclopentane,
3-ethylheptane, 2-methyloctane, cis-1,2,3-trimethylcyclohexane,
3-methyloctane, 2,4,6-trimethylheptane,
cis-1,2,4-trimethylcyclohexane, 3,3-diethylpentane,
2,2-dimethyl-4-ethylhexane, 2,2,4-trimethylheptane,
2,2,4,5-tetramethylhexane, 2,2,5-trimethylheptane,
2,2,6-trimethylheptane, 2,2,3,5-tetramethylhexane, nopinane
(7,7-dimethylbicyclo[3.1.1]heptane),
trans-1-ethyl-r-methylcyclohexane, cycloctane,
1-ethyl-2-methylcyclohexane, n-nonane,
1,3,3-trimethylbicyclo[2.2.1]heptane (fenchane),
trans-1-ethyl-4-methylcyclohexane,
cis-1,1,3,5-tetramethylcyclohexane,
cis-1-ethyl-4-methylcyclohexane, 2,5,5-trimethylheptane,
2,4,4-trimethylheptane, 2,3,3,5-tetramethylhexane,
2,2,4,4-tetramethylhexane, isopropylcyclohexane,
1,1,2,2-tetramethylcyclohexane, 2,2,3,4-tetramethylhexane,
2,2-dimethyloctane, 3-ethyl-2,2,4-trimethylpentane,
3,3,5-trimethylheptane, 2,3,5-trimethylheptane, 2,4-dimethyloctane,
d,l-cis-1-ethyl-3-methylcyclohexane, d,l-2,5-dimethyloctane,
1,1,3,5-tetramethylcyclohexane, n-butylcyclopentane,
n-propylcyclohexane, 2,3,5-trimethylheptane,
2,5-dimethyl-3-ethylhexane, 2,4,5-trimethylheptane,
2,4-dimethyl-3-isopropylpentane, 2,2,3-trimethylheptane,
2,4-dimethyl-4-ethylhexane, 2,2-dimethyl-3-ethylhexane,
2,2,3,4,4-pentamethylpentane, 1,1,3,4-tetramethylcyclohexane,
5-ethyl-2-methylheptane, 2,7-dimethyloctane, 3,6-dimethyloctane,
3,5-dimethyloctane, 4-isopropylheptane, 2,3,3-trimethylheptane,
4-ethyl-2-methylheptane, 2,6-dimethyloctane,
2,2,3,3-tetramethylhexane, trans-1-isopropyl-4-methylcyclohexane
(p-menthane), 4,4-dimethyloctane, 2,3,4,5-tetramethylhexane,
5-ethyl-e-methylheptane, 3,3-dimethyloctne, 4,5-dimethyloctane,
3,4-diethylhexane, 4-propylheptane, 1,1,4-trimethylcycloheptane
(eucarvane), trans-1,2,3,5-tetramethylcyclohexane,
2,3,4,4-tetramethylhexane, 2,3,4-trimethylheptane,
3-isopropyl-2-methylhexane, 2,2,7-trimethylbicyclo[2.2.1]heptane
(a-frenchane), 3-methylheptane, 2,4-dimethyl-3-ethylhexane,
3,4,4-trimethylheptane, 3,3,4-trimethylheptane,
3,4,5-trimethylheptane, 2,3-dimemthyl-4-ethylhexane,
1-methyl-e-propylcyclohexane, 2,3-dimethyloctane, d,l-pinane,
2,3,3,4-tetramethylhexane, 3,3-dimethyl-4-ethylhexane,
5-methylnonane, 4-methylnonane, 3-ethyl-2-methylheptane,
3,4-dimethyloctane, d-a-pinane, d,l-1-isopropyl-3-methylcyclohexane
(d,l-m-menthane), 2,2,3,3,4-pentamethylpentane,
trans-1,2,4,5-tetramethylcyclohexane, 3,3-diethylhexane,
2-methylnonane, d-1-isopropyl-3-methylcyclohexane (d-m-menthane),
3-ethyl-4-methylheptane, 4-ethyl-3-methylheptane,
4-ethyl-4-methylheptane, 1-.beta.-pinane, 3-methylnonane,
3-ethyloctane, 4-ethyloctane, 3-ethyl-2,2,3-trimethylpentane,
1-1-isopropyl-3-methylcyclohexane
(1-m-menthane)cis-1-isopropyl-4-methylcyclohexane (cis-p-menthane),
cis-1,2,3,5-tetramethylcyclohexane, 2,3-dimethyl-3-ethylhexane,
1-isopropyl-4-methylcyclohexane (p-menthane),
3,4-dimethyl-3-ethylhexane, 3,3,4,4-tetramethylhexane, cyclononane,
1-isopropyl-2-methylcyclohexane (o-menthane),
cis-1,2,4,5-tetramethylcyclohexane, 1-methyl-1-propylcyclohexane,
n-decane, 1-methyl-4-propylcyclohexane,
1-methyl-2-propylcyclohexane, n-pentrylcyclopentane,
n-butylcyclohexane, trans-decahydronaphthalene (trans-decalin),
isoamylcyclohexane, cis-decahydronaphthalene (cis-decalin),
n-undecane (n-hendecane), cyclodecane, n-pentylcyclohexane,
n-hexylcyclopentane, 9-methyl-trans-decahydronaphthalene,
1,10-dimethyl-trans-decahydronaphthalene,
9-methyl-cis-decahydronaphthalene, n-dodecane,
1,10-dimethyl-cis-decahydronaphthalene, n-hexycyclohexane,
n-heptylcyclopentane, 9-ethyl-trans-decahydronaphthalene,
9-ethyl-cis-decahydronaphthalene,
1-methyl-trans-decahydronaphthalene, n-tridecane, bicyclohexyl,
n-octylcyclopentane, n-heptylcyclohexane, n-tetradecane,
n-nonylcyclopentane, n-octylcyclohexane, n-pentadecane,
n-decyclopentane, n-nonylcyclohexane, n-undecylcyclopentane
(n-hendecylcyclopentane), n-decylcyclohexane, 2-methylheptadecane,
n-dodecylcyclopentane, n-undecylcyclohexane
(n-hendecylcyclohexane), n-tridecylcyclopentane,
n-dodecylcyclohexane, n-tetradecylcyclopentane,
pentadecyclcyclopentane, n-hexadecane (cetane),
tridecylcyclohexane, hexadecicyclopentane, n-heptadecane,
tetradecylcyclohexane, heptadecylcyclopentane, n-octadecane,
pentadecylcyclohexane, octadecylcyclopentane, n-nonadecane,
hexadecylcyclohexane, nonadecylcyclopentane, n-eicosane,
heptadecylcyclohexane, eicosylcyclopentane, n-heneicosane,
octadecylcyclohexane, heneicosylcyclopentane, n-docosane,
docosylcyclopentane, nonadecylcyclohexane, n-tricosane,
eicosylcyclohexane, tricosylcyclopentane, n-tetracosane,
tetracosylcyclopentane, heneicosylcyclohexane, n-pentacosane,
pentacosylcyclopentane, docosylcyclohexane, hexacosylcyclopentane,
notricyclene (tricyclo[2.2.1.0.sup.2,6]heptane), n-hexacosane,
cyclohexadecane, tricosylcyclohexane, heptacosylcyclopentane,
n-heptacosane, tetracosylcyclohexane, cyclopentadecane,
octacosylcyclopentane, n-octacosane, pentacosylcyclohexane,
nonacosylcyclopentane, n-nonacosane, hexacosylcyclohexane,
triacontylcyclopentane, d,l-isobornane
(2,2,3-trimethylbicyclo[2.2.2]heptane), n-triacontane,
heptacosylcyclohexane, hentriacontylcyclopentane, n-hentriacontane,
octacosylcyclohexane, dotriacontylcyclopentane, n-dotriacontane
(bicetyl), noncosylcyclohexane, tritriacontylcyclopentane,
tritriacontane, triacontylcyclohexane, tetratriacontylcyclopentane,
tetratriacontane, 28-methylnonacosane, hentriacontylcyclohexane,
pentatriacontylcyclopentane, pentatriacontane,
dotriacontylcyclohexane, hexatriacontylcyclopentane,
hexatriacontane, tritriacontylcyclohexane, heptatriacontane,
tetratriacontylcyclohexane, octatriacontane,
pentatriacontylcyclohexane, nonatriacontane,
hexatriacontylcyclohexane, tetracontane, norbornane
(bicyclo[2.2.1]heptane], 2,2,3,3-tetramethylbutane, bornane
(camphane), and adamantane. It is understood to those of ordinary
skill in the art that the relevant alkyl radical is named by
replacing the suffix "-ane" with the suffix "-yl".
The term "alkenyl" refers to an unsaturated, hydrocarbon radical,
linear or branched, in so much as it contains one or more double
bonds. The alkenyl group disclosed herein can be optionally
substituted with any moiety that does not adversely affect the
reaction process, including but not limited to but not limited to
alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,
amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino,
alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,
sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid,
amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester,
thioether, acid halide, anhydride, oxime, hydrozine, carbamate,
phosphonic acid or phosphonate, either unprotected, or protected as
necessary, as known to those skilled in the art, for example, as
taught in Greene et al., Protective Groups in Organic Synthesis,
John Wiley & Sons, Second Edition, 1991, hereby incorporated by
reference. Non-limiting examples of alkenyl groups include
methylene, ethylene, methylethylene, isopropylidene,
1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl,
1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon
radical, linear or branched, in so much as it contains one or more
triple bonds. The alkynyl group may be optionally substituted with
any moiety that does not adversely affect the reaction process,
including but not limited to but not limited to hydroxyl, halo (F,
Cl, Br, I), perfluoro alkyl including but not limited to
trifluoromethyl, amino, alkylamino, arylamino, alkoxy, aryloxy,
nitro, cyano, acyl, amido, carboxamido, carboxylate, thiol,
alkylthio, azido, sulfonic acid, sulfate, phosphonic acid,
phosphate, or phosphonate, either unprotected, or protected as
necessary, as known to those skilled in the art, for example, as
taught in Greene et al., Protective Groups in Organic Synthesis,
John Wiley & Sons, Second Edition, 1991, hereby incorporated by
reference. Non-limiting examples of suitable alkynyl groups include
ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl,
pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl,
hexyn-1-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-1-yl
radicals.
The term "alkylamino" or "arylamino" refers to an amino group that
has one or two alkyl or aryl substituents, respectively.
The term "protected" as used herein and unless otherwise defined
refers to a group that is added to an oxygen, nitrogen, or
phosphorus atom to prevent its further reaction or for other
purposes. A wide variety of oxygen and nitrogen protecting groups
are known to those skilled in the art of organic synthesis.
The term "aryl", alone or in combination, means a carbocyclic
aromatic system containing one, two or three rings wherein such
rings may be attached together in a pendent manner or may be fused.
Non-limiting examples of aryl include phenyl, biphenyl, or
naphthyl, or the following aromatic group that remains after the
removal of a hydrogen from the aromatic ring: benzene, toluene,
ethylbenzene, 1,4-xylene, 1,3-xylene, 1,2-xylene, isopropylbenzene
(cumene), n-propylbenzene, 1-ethyl-3-methylbenzene
(m-ethyltoluene), 1-ethyl-4-methylbenzene (p-ethyltoluene),
1,3,5-trimethylbenzene (mesitylene), 1-ethyl-2-methylbenzene
(o-ethyltoluene), tert-butylbenzene, 1,2,4-trimethylbenzene
(pseudodocumene), isobutylbenzene, sec-butylbenzene,
3-isopropylmethylbenzene (3-isopropyltoluene; m-cymene),
1,2,3-trimethylbenzene (hemimellitene), trans-propenylbenzene,
indane, 4-isopropyl-1-methylbenzene (4-isopropyltoluene; 4-cymene),
2-isopropyl-methylbenzene (2-isopropyltoluene; 2-cymene),
1,3-diethbenzene, 1 methyl-3-proplybenzene (m-propyltoluene),
indene, n-butylbenzene, 1-methyl-4-propylbenzene (p-propyltoluene),
1,2-diethylbenzene, 1,4-diethylbenzene,
1,3-dimethyl-5-ethylbenzene, 1-methyl-2-propylbenzene
(o-propyltoluene), 2,2-dimethyl-1-phenylpropane (neopentylbenzene),
1,4-dimethyl-2-ethylbenzene, 2-methylindane,
3-methyl-2-phenylbutane, 1-methylindane,
1,3-dimethyl-4-ethylbenzene, 3-tert-butyl-menthylbenzene,
(3-tert-butyltoluene), 1,2-dimethyl-4-ethylbenzene,
1,3-dimethyl-2-ethylbenzene, 3-phenylpentane,
1-ethyl-3-isopropylbenzene, 2-methyl-2-phenylbutane,
4-tert-butyl1-methylbenzene (4-tert-butyltoluene),
1-ethyl-2-isopropylbenzene, 2-phenylpentane,
1,2-dimethyl-3-ethybenzene, 3-sec-butyl-1-methylbenzene,
(3-sec-butylotoluene), 3-isobutyl-1-methylbenzene,
(3-isobutyltoluene), d-2-methyl-1-phenylbutane,
1,3-dimethyl-5-isopropyl-benzene, 2-phenyl-cis-2-butene,
4-isobutyl-methylblenzene (p-isobulyltoluene),
2-sec-butyl-1-methylbenzene (2-sec-butyltoluene),
2-isobutyl-1-methylblenzene (o-isobutyltoluene),
1,4-dimethyl-2-isopropyl-benzene, 1-ethyl-4-isopropylbenzene,
d,l-2-methyl-1-phenylbutane, 1,2,3,5-tetramethylbenzene
(isodurene), 3-methyl-1-phenylbutane (isopentylbenzene),
1,3-dimethyl-2-isopropylbenzene, 1,3-dimethyl-4-isopropylbenzene),
3-methylindene, 4-sec-butyl-1-methylbenzene (p-sec-butyltoluene),
2-tert-butyl-1-methylbenzene (2-tert-butyltoluene),
3,5-diethyl-1-methylbenzene (3,5-diethyltoluene),
2-butyl-1-methylbenzene (2 butyltoluene), 1-ethyl-3-propylbenzene,
1,2-dimethyl-4-isopropylbenzene, 1,2-dimethyl-3-isopropylbenzene,
1-ethyl-2-propylbenzene, 1,3-di-isopropyllbenzene,
1,2-diethyl-4-methylbenzene, 1,2-di-isopropylbenzene,
1,4-dimethyl-2-proplybenzene, 1,2,3,4-tetramethylbenzene
(prehnitene), 1-ethyl-4-propylbenzene, 3-butyl-1-methlybenzene
(m-butyltoluene), 2,4-diethyl-1-methylbenzene (2,4-diethyltoluene),
n-pentylbenzene, 3-methyl-3-phenylpentane,
1,3-dimethyl-5-tert-butylbenzene, 1,3-dimethyl-4-propylbenzene,
1,2-diethyl-3-methylbenzene, 4-butyl-1-methylbenzene,
4-butyl-1-methylbenzene, 1,2,3,4-tetrahydronaphthalene,
1,3-diethyl-2-propylbenzene, 2,6-diethyl-1-methylbenzene,
1,2-dimethyl-4-propylbenzene, 1,3-dimethyl-5-propylbenzene,
2-methyl-3-phenylpentane, 4-tert-butyl-1,3-dimethylbenzene,
1,4-di-isopropylbenzene, 1,2-dimethyl-3-propylbenzene,
1-teri-butyl-4-ethylbenzene, d,l-3-phenylhexane,
2-ethyly-1,3,5-trimethyl-benzene,
3-ethyly-4-isopropyl-1-methylbenzene,
5-ethyl-1,2,4-trimethylbenzene, 6-ethyl-1-2,4-trimethylbenzene,
2-phenylhexane, 2-methyl-1-phenylpentane,
4-isopropyl-1-propylbenzene, 1,3-dipropylbenzene,
5-ethyl-1,2,3-trimethylbenzene, 1,2,4-triethylbenzene,
1,3,5-triethylbenzene, 2-methyl-1,2,3,4-tetrahydronaphthalene,
1-methyl-1,2,3,4-tetrahydronaphthalene,
4-ethyl-1,2,3-trimethylbenzene, 1,4-dipropylbenzene,
3-methyl-1-phenylpentane, 2-propyl-1,3,5-trimethylbenzene,
1,1-dimeihyl-1,2,3,4-tetrahydronaphthalene,
3-tert-butyl-1-isopropylbenzene, 1-methyl-3-pentylbenzene,
4-tert-butyl-1-isopropylbenzene, 2-methyl-2-phenylhexane,
2,4-di-isopropyl-1-methylbenzene, 3-methyl-3-phenylhexane,
n-hexylbenzene, 3-phenylheptane, 2,6-di-isopropyl-1-methylbenzene,
5-propyl-1,2,4-trimethylbenzene,
6-methyl-1,2,3,4-tetrahydronaphthalene,
2,2-dimethyl-1,2,3,4-tetrahydronaphthalene, 2-phenylheptane,
5-methyl-1,2,3,4-tetrahydronaphthalene,
2-ethyl-1,2,3,4-tetrahydronaphthalene, cyclohexylbenzene,
1-ethyl-1,2,3,4-tetrahydronaphthalene,
2,5-dimethyl-1,2,3,4-tetrahydronaphthalene,
2,8-dimethyl-1,2,3,4-tetrahydronaphthalene,
2,7-dimethyl-1,2,3,4-tetrahydronaphthalene,
2,6-dimethyl-1,2,3,4-tetrahydronaphthalene,
1,4-di-sec-butylbenzene,
1,5-dimethyl-1,2,3,4-tetrahydronaphthalene, 3-ethyl-3-phenylhexane,
6-ethyl-1,2,3,4-tetrahydronaphthalene, 2-methyl-1-phenyl-1-butene,
5-ethyl-1,2,3,4-tetrahydronaphthalene, n-heptylbenzene,
1-methylnaphthalene, 5,6-dimethyl-1,2,3,4-tetrahydronaphthalene,
6,7-dimethyl-1,2,3,4-tetrahydronaphthalene,
5,7-dimethyl-1,2,3,4-tetrahydronaphthalene, 2-ethylnaphthalene,
1-7-dimethylnaphthalene, 1,6-dimethylnaphthalene,
1,3-dimethylnaphthalene, n-octylbenzene, 1-allylnaphthalene,
1-isopropylnaphthalene, 1,4-dimethylnaphthalene,
1,1-diphenylethane, 2-isopropylnaphthalene, 2-propylnaphthalene,
1-propylnaphthalene, 1,3,7-trimethylnaphthalene,
1-isopropyl-7-methylnaphthalene, n-nonylbenzene,
2-butylnaphthalene, 2-tert-butylnaphthalene,
1-tert-butylnaphthalene, 1-butylnaphthalene, 4,5-benzindane,
n-decylbenzene, 1-pentylnaphthalene, 2-pentylnaphthalene,
n-undecylbenzene, 1-hexylnaphthalene, 2-hexylnaphthalene,
n-dodecylbenzene, 1-heptylnaphthalene, 2-heptylnaphthalene,
tridecylbenzene, 1-octylnaphthalene, 2-octylnaphthalene,
1-nonylnaphthalene, 2-nonylnaphthalene, 1-decylnaphthalene,
1,2,6-trimethylnaphthalene, diphenylmethane,
1,2,3-trimethylnaphthalene, 1,6,7-trimethylnaphthalene,
2-isopropylazulene, 1,4-dimethyl-7-isopropylazulene,
2,6-dimethylphenanthrene, 1,2,5-trimethylnaphthalene,
1-propylphenanthrene, 5-isopropylazulene, 5-isopropylazulene,
2-propylphenanthrene, 2-methylnaphthalene,
1-ethyl-5-methylnaphthalene, 9-isopropylnaphthalene,
6-isopropylazulene, 2-ethyl-6-methylnaphthalene,
2-isopropylphenanthrene, 6-isopropyl-1-methylphenanthrene,
2-ethylazulene, 2,5,-dimethylphenanthrene,
1,3,5-trimethylnaphthalene, 3-ethyl-6-methylphenanthrene,
2-methylazulene, 1,3,8-trimethylnaphthalene; 4-methylphenanthrene,
1,4-dimethylphenanthrene, bibenzyl, methylenefluorene,
3,5-dimethylphenanthrene, 1,3-dimethylazulene,
7-methyl-3,4-benzphenanthrene, pentamethylbenzene,
1,2,4-trimethylnaphthalene, 3,3-dimethylstilbene,
1,4,5,7-tetramethylnaphthalene, 1,2,4,8-tetramethylnaphthalene,
2,9-dimethylphenanthrene, 1,5-dimethylphenanthrene,
2-benzylnaphthalene, 1-benzylnaphthalene, 1-benzylnaphthalene,
1,2-dimethylazulene, 9-propylphenanthrene,
1,7-dimethyl-4-isopropylnaphthalene, 3-methylphenanthrene,
3,4-dimethylphenanthrene, 1-ethylphenanthrene,
symdiphenylacetylene, 9-ethylphenanthrene,
1,4,5-trimethylnaphthalene, 4-methylfluorene,
1,4,6,7-tretramethylnaphthalene, 1,2,3-trimethylphenanthrene,
1,8-dimethylnaphthalene, 8-methyl-3,4-benzphenanthrene,
2-ethylphenanthrene, 3,4-benzphenanthrene,
1,3,7-trimethylphenanthrene, 4-isopropyl-1-methylphenanthrene,
4,8-dimethylazulene, biphenyl, 2-methyl-3,4-benzphenanthrene,
3-methylpyrene, 1,4,7-trimethylphenanthrene,
1,4-dimethylanthracene, 4,9-dimethyl-1,2-benzanthracene,
benzalfluorene, 1,3-dimethylphenanthrene,
1-methyl-3,4-benzphenanthrene, 3-isopropyl-1-methylphenanthrene,
1,2-binaphthyl, 2,3-dimethylphenanthrene,
1-ethyl-2-methylphenanthrene, 1,5-dimethylnaphthalene,
6-methyl-3,4-benzphenanthrene, naphthalene,
1,3,6,8-tetramethylnaphthalene, 1-ethyl-7methylphenanthrene,
9-methylanthracene, 1-isopropyl-7-methylphenanthrene,
6-methylazulene, 1,3-dimethylanthracene, 2,2-dimethylstilbene,
1-methylanthracene, 1,7-dimethylphenanthrene,
1,6-diphenylnaphthalene, 1,6-dimethylphenanthrene,
1,9-dimethylphenanthrene, 9-methylphenanthrene,
1,2,10-trimethylanthracene, 7-ethyl-1-methylphenanthrene,
triphenylmethane, 5-isopropylnaphthanthracene,
3,9-dimethyl-1,2-benzanthracene, 5,6-benzindane,
12-isopropylnaphthanthracene, acenaphthene,
2,7-dimethylnaphthalene, 7-isopropyl-1-methylfluorene, azulene,
retene, phenanthrene, 2,7-dimethfylphenanthrene,
2,3,6-trimethfylnaphthalene, 2-phenylnaphthalene,
1,2,3,4-tetrahydroanthracene, 2,3-dimethylnaphthalene,
ethylidenefluorene, 1,7-dimethylfuorene, 1,1-dinaphthylmethane,
fluoranthrene, 2,6-dimethylnaphthalene, 2,4-dimethylphenanthrene,
fluorene, 4,10-dimethyl-1,2-benzanthracene, 4h-cyclopenta(def)
phenanthrene, 1,3,8-trimethylphenanthrene,
11-methylnaphthanthracene, 5-methylchrysene,
1,2,5,6-tetramethylnaphthalene, cyclohept(fg)acenaphthene,
1,2,7-trimethylphenanthrene, 1,10-dimethyl-1,2-dibenzanthracene,
9,10-dimethyl-1-benzanthracene, benz(bc)aceanthrylene,
1-methylphenanthrene, 1,6,7-trimethylphenanthrene,
1,1-diacenaphthene, trans-stilbene, 3,4-benzflurorene,
9-isopropylnaphthanthracene, 6-methylnaphthanthracene,
5,8-dimethyl-1,2-bezanthracene, 8-isopropylnaphthanthracene,
1,4,5,8-tetramethylnaphthalene, 12-methylnaphthanthracene,
2-methyl-1,2-benzpyrene, 1,5-dimethylanthracene,
7-methylnaphthanthracene, 3,6-dimethylphenanthrene,
5-methyl-3,4-benzphenanthrene, 1,4-dimethylchrysene,
1,2-dimethylphenanthrene, 8,10-dimethyl-1,2-benzanthracene,
1,2,8-trimethylphenanthrene, 3-methyl-1,2-benzpyrene,
9-methyl-1,2-benzpyrene, 9-phenylfluorene,
2-methylnaphthanthracene, pyrene, 9-methylnaphthanthracene,
4-methylchrysene, trans-trans-1,4-diphenyl-1,3-butadiene,
cinnamalfluorene, 5-methylnaphthanthracene, 1,2-benzanthracene,
8-methylnaphthanthracene, 1,1-binaphthyl, di-1-naphthastibene,
6-methylchrysene, 3-methylnaphthanthracene,
2,6-dimethyl-1,2-benzanthracene, cyclopentadienophenanthrene,
10,11-benzfluoranthene, hexamethylbenzene, 3-methylchrysene,
cholanthrene, 6-methyl-1,2-benzpyrene,
6,7-dimethyl-1,2-benzanthracene, 1,2-benzpyrene,
5,10-dimethyl-1,2-benzanthracene, 4,5-benzpyrene,
9,10-dimethylanthracene, 10-methylnaphthanthracene,
5,6-dimethyl-1,2-benzanthracene, 2,2-binaphthyl, 1,2-benfluorene,
1,8-dimethylphenanthrene, 8-methyl-1,2-benzpyrene,
bifluorenylidene, 1,2,7,8-dibenzanthracene,
4-methylnaphthanthracene, 1,2,3,4-dibenzanthracene,
di-2-fluorenylmethane, 2,3-benzfluorene, 5-methyl-1,2-benzpyrene,
anthracene, 11,12-benzfluoranthene, 4-methyl-1,2-benzpyrene,
2,8-dimethylchrysene, 2-methylchrysene, 6,12-dimethylchrysene,
1,2-benzphenanthrene, di-2-naphthastilbene, 1-methylchrysene,
2,3,6,7-dibenzphenanthrene, 2,3,5,6-dibenzphenanthrene,
1,2,5,6-dibenzanthracene, perylene, picene,
1,2,3,4,5,6,7,8-tetrabenzanthracene, and coronene. The term aryl
includes both substituted and unsubstituted moieties. The aryl
group may be optionally substituted with any moiety that does not
adversely affect the process, including but not limited to but not
limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy,
amino, amido, carboxyl derivatives, alkylamino, dialkylamino,
arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol,
imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic
acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine,
thioester, thioether, acid halide, anhydride, oxime, hydrazine,
carbamate, phosphonic acid, phosphonate, or any other viable
functional group that does not inhibit the pharmacological activity
of this compound, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in Greene
et al., Protective Groups in Organic Synthesis, John Wiley &
Sons, Second Edition, 1991, hereby incorporated by reference.
Non-limiting examples of substituted aryl include heteroarylamino,
N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino,
heteroaralkoxy, arylamino, aralkylamino, arylthio,
monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl,
monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl,
aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyl,
haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl,
saturated heterocyclyl, partially saturated heterocyclyl,
heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,
heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, carboaralkoxy.
The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an
aryl substituent. The terms "aralkyl" or "arylalkyl" refer to an
aryl group with an alkyl substituent.
The term "halo," as used herein, includes chloro, bromo, iodo and
fluoro.
The term "acyl" refers to a carboxylic acid ester in which the
non-carbonyl moiety of the ester group is selected from straight,
branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but
not limited to methoxymethyl, aralkyl including but not limited to
benzyl, aryloxyalkyl such as phenoxymethyl, aryl including but not
limited to phenyl optionally substituted with halogen (F, Cl, Br,
I), alkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
and C.sub.4) or alkoxy (including but not limited to C.sub.1,
C.sub.2, C.sub.3, and C.sub.4), sulfonate esters such as alkyl or
aralkyl sulphonyl including but not limited to methanesulfonyl, the
mono, di or triphosphate ester, trityl or monomethoxytrityl,
substituted benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or
diphenylmethylsilyl. Aryl groups in the esters optimally comprise a
phenyl group. The term "lower acyl" refers to an acyl group in
which the non-carbonyl moiety is lower alkyl.
The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched
oxy-containing radicals having alkyl moieties, such as methoxy
radical. The term "alkoxyalkyl" also embraces alkyl radicals having
one or more alkoxy radicals attached to the alkyl radical, that is,
to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
Examples of such radicals include fluoromethoxy, chloromethoxy,
trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy,
tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
The term "alkylamino" denotes "monoalkylamino" and "dialkylamino"
containing one or two alkyl radicals, respectively, attached to an
amino radical. The terms arylamino denotes "monoarylamino" and
"diarylamino" containing one or two aryl radicals, respectively,
attached to an amino radical. The term "aralkylamino", embraces
aralkyl radicals attached to an amino radical. The term
aralkylamino denotes "monoaralkylamino" and "diaralkylamino"
containing one or two aralkyl radicals, respectively, attached to
an amino radical. The term aralkylamino further denotes
"monoaralkyl monoalkylamino" containing one aralkyl radical and one
alkyl radical attached to an amino radical.
The term "heteroatom," as used herein, refers to oxygen, sulfur,
nitrogen and phosphorus.
The terms "heteroaryl" or "heteroaromatic," as used herein, refer
to an aromatic that includes at least one sulfur, oxygen, nitrogen
or phosphorus in the aromatic ring.
The term "heterocyclic" refers to a nonaromatic cyclic group
wherein there is at least one heteroatom, such as oxygen, sulfur,
nitrogen, or phosphorus in the ring.
Nonlimiting examples of heteroaryl and heterocyclic groups include
furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl,
imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl,
quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,
thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole,
1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole,
isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines,
thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine,
pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine,
phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl,
quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,
5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine,
N.sup.6-alkylpurines, N.sup.6-benzylpurine, N.sup.6-halopurine,
N.sup.6-vinypurine, N.sup.6-acetylenic purine, N.sup.6-acyl
purine,N.sup.6-hydroxyalkyl purine, N.sup.6-thioalkyl purine,
thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidine, uracil,
N.sup.5-alkylpyrimidines; N.sup.5-benzylpyrimidines,
N.sup.5-halopyrimidines, N.sup.5-vinylpyrimidine,
N.sup.5-acetylenic pyrimidine, N.sup.5-acyl pyrimidine,
N.sup.5-hydroxyalkyl purine, and N.sup.6-thioalkyl purine, and
isoxazolyl. The heteroaromatic group can be optionally substituted
as described above for aryl. The heterocyclic or heteroaromatic
group can be optionally substituted with one or more substituent
selected from halogen (F, Cl, Br, I), haloalkyl, alkyl, alkoxy,
hydroxy, carboxyl derivatives, amido, amino, alkylamino,
dialkylamino. The heteroaromatic can be partially or totally
hydrogenated as desired. As a nonlimiting example, dihydropyridine
can be used in place of pyridine. Functional oxygen and nitrogen
groups on the heterocyclic or heteroaryl group can be protected as
necessary or desired. Suitable protecting groups are well known to
those skilled in the art, and include trimethylsilyl,
dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl,
trityl or substituted trityl, alkyl groups, acyl groups such as
acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl. The
heterocyclic or heteroaromatic group can be substituted with any
moiety that does not adversely affect the reaction, including but
not limited to but not limited to those described above for
aryl.
The term "host," as used herein, refers to a unicellular or
multicellular organism in which the virus can replicate, including
but not limited to cell lines and animals, and preferably a human.
Alternatively, the host can be carrying a part of the viral genome,
whose replication or function can be altered by the compounds of
the present invention. The term host specifically refers to
infected cells, cells transfected with all or part of the viral
genome and animals, in particular, primates (including but not
limited to chimpanzees) and humans. In most animal applications of
the present invention, the host is a human patient. Veterinary
applications, in certain indications, however, are clearly
anticipated by the present invention (such as chimpanzees).
The term "pharmaceutically acceptable salt or prodrug" is used
throughout the specification to describe any pharmaceutically
acceptable form (such as an ester, phosphate ester, salt of an
ester or a related group) of a nucleoside compound which, upon
administration to a patient, provides the nucleoside compound.
Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic or organic bases and acids.
Suitable salts include those derived from alkali metals such as
potassium and sodium, alkaline earth metals such as calcium and
magnesium, among numerous other acids well known in the
pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a
compound that is metabolized, for example hydrolyzed or oxidized,
in the host to form the compound of the present invention. Typical
examples of prodrugs include compounds that have biologically
labile protecting groups on a functional moiety of the active
compound. Prodrugs include compounds that can be oxidized, reduced,
aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed,
dehydrolyzed, alkylated, dealkylated, acylated, deacylated,
phosphorylated, dephosphorylated to produce the active compound.
The compounds of this invention possess antiviral activity against
Flaviviridae, or are metabolized to a compound that exhibits such
activity.
Prodrugs also include natural or unnatural amino acid esters of the
disclosed nucleosides (see, e.g., European Patent Specification No.
99493, the text of which is incorporated by reference, which
describes amino acid esters of acyclovir, specifically the glycine
and alanine esters which show improved water-solubility compared
with acyclovir itself, and U.S. Pat. No. 4,957,924 (Beauchamp),
which discloses the valine ester of acyclovir, characterized by
side-chain branching adjacent to the a-carbon atom, which showed
improved bioavailability after oral administration compared with
the alanine and glycine esters). A process for preparing such amino
acid esters is disclosed in U.S. Pat. No. 4,957,924 (Beauchamp),
the text of which is incorporated by reference. As an alternative
to the use of valine itself, a functional equivalent of the amino
acid may be used (e.g., an acid halide such as the acid chloride,
or an acid anhydride). In such a case, to avoid undesirable
side-reactions, it may be is advantageous to use an amino-protected
derivative.
IV. Nucleotide Salt or Prodrug Formulations
In cases where compounds are sufficiently basic or acidic to form
stable nontoxic acid or base salts, administration of the compound
as a pharmaceutically acceptable salt may be appropriate. Examples
of pharmaceutically acceptable salts are organic acid addition
salts formed with acids, which form a physiological acceptable
anion, for example, tosylate, methanesulfonate, acetate, citrate,
malonate, tartarate, succinate, benzoate, ascorbate,
.alpha.-ketoglutarate and .alpha.-glycerophosphate. Suitable
inorganic salts may also be formed, including but not limited to,
sulfate, nitrate, bicarbonate and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard
procedures well known in the art, for example by reacting a
sufficiently basic compound such as an amine with a suitable acid,
affording a physiologically acceptable anion. Alkali metal (e.g.,
sodium, potassium or lithium) or alkaline earth metal (e.g.,
calcium) salts of carboxylic acids can also be made.
Any of the nucleosides described herein can be administered as a
nucleotide prodrug to increase the activity, bioavailability,
stability or otherwise alter the properties of the nucleoside. A
number of nucleotide prodrug ligands are known. In general,
alkylation, acylation or other lipophilic modification of the mono,
di or triphosphate of the nucleoside will increase the stability of
the nucleotide. Examples of substituent groups that can replace one
or more hydrogens on the phosphate moiety are alkyl, aryl,
steroids, carbohydrates, including but not limited to sugars,
1,2-diacylglycerol and alcohols. Many are described in R. Jones
& N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of
these can be used in combination with the disclosed nucleosides to
achieve a desired effect.
The active nucleoside can also be provided as a 5'-phosphoether
lipid or a 5'-ether lipid, as disclosed in the following
references, which are incorporated by reference: Kucera, L. S., N.
Iyer, E. Leake, A. Raben, Modest E. K., D. L. W., and C.
Piantadosi, "Novel membrane-interactive ether lipid analogs that
inhibit infectious HIV-1 production and induce defective virus
formation," AIDS Res. Hum. Retroviruses, 1990, 6, 491-501;
Piantadosi, C., J. Marasco C. J., S. L. Morris-Naischke, K. L.
Meyer, F. Gumus, J. R. Surles, K. S. Ishaq, L. S. Kucera, N. Iyer,
C. A. Wallen, S. Piantadosi, and E. J. Modest, "Synthesis and
evaluation of novel ether lipid nucleoside conjugates for anti-HIV
activity," J. Med. Chem., 1991, 34, 1408-1414; Hosteller, K. Y., D.
D. Richman, D. A. Carson, L. M. Stuhmiller, G. M. T. van Wijk, and
H. van den Bosch, "Greatly enhanced inhibition of human
immunodeficiency virus type 1 replication in CEM and HT4-6C cells
by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid
prodrug of 3, -deoxythymidine," Antimicrob. Agents Chemother.,
1992, 36, 2025-2029; Hostetler, K. Y., L. M. Stuhmiller, H. B.
Lenting, H. van den Bosch, and D. D. Ricbman, "Synthesis and
antiretroviral activity of phospholipid analogs of azidothymidine
and other antiviral nucleosides." J. Biol. Chem., 1990, 265,
61127.
Nonlimiting examples of U.S. patents that disclose suitable
lipophilic substituents that can be covalently incorporated into
the nucleoside, preferably at the 5'-OH position of the nucleoside
or lipophilic preparations, include U.S. Pat. No. 5,149,794 (Yatvin
et al.); U.S. Pat. No. 5,194,654 (Hostetler et al.), U.S. Pat. No.
5,223,263 (Hostetler et al.); U.S. Pat. No. 5,256,641 (Yatvin et
al.); U.S. Pat. No. 5,411,947 (Hostetler et al.); U.S. Pat. No.
5,463,092 (Hostetler et al.); U.S. Pat. No. 5,543,389 (Yatvin et
al.); U.S. Pat. No. 5,543,390 (Yatvin et al.); U.S. Pat. No.
5,543,391 (Yatvin et al.); and U.S. Pat. No. 5,554,728 (Basava et
al.), all of which are incorporated by reference. Foreign patent
applications that disclose lipophilic substituents that can be
attached to nucleosides of the present invention, or lipophilic
preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO
91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP
93917054.4, and WO 91/19721.
V. Combination or Alternation Therapy
In another embodiment for the treatment of HIV or HBV infection,
the active compound or its prodrug or salt can be administered in
combination or alternation with another antiviral agent, such as
another active anti-HIV or anti-HBV agent, including but not
limited to those of the formulae above, others listed below or
known in the art. In general, in combination therapy, effective
dosages of two or more agents are administered together, whereas
during alternation therapy, an effective dosage of each agent is
administered serially. The dosage will depend on absorption,
inactivation and excretion rates of the drug as well as other
factors known to those of skill in the art. It is to be noted that
dosage values will also vary with the severity of the condition to
be alleviated. It is to be further understood that for any
particular subject, specific dosage regimens and schedules should
be adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the compositions.
Nonlimiting examples of antiviral agents that can be used in
combination with the compounds disclosed herein include those in
the tables below.
TABLE-US-00001 Hepatitis B Therapies Drug Name Drug Class Company
Intron A (interferon alfa- interferon Schering-Plough 2b)
Epivir-HBV (lamivudine; nucleoside analogue GlaxoSmithKline 3TC)
Hepsera (Adefovir nucleoside analogue Gilead Sciences Dipivoxi)''
Coviracil (emtricitabine; nucleoside analogue Triangle FTC)
Pharmaceuticals Entecavir nucleoside analogue Bristol-Myers Squibb
Clevudine (L-FMAU) nucleoside analogue Triangle Pharmaceuticals ACH
126, 443 (L-Fd4C) nucleoside analogue Achillion Pharmaceuticals AM
365 nucleoside analogue Amrad Amdoxovir (formerly nucleoside
analogue Triangle DAPD) Pharmaceuticals LdT (telbivudine)
nucleoside analogue Idenix XTL 001 monoclonal XTL Biopharm antibody
Theradigm Immune stimulant Epimmune Zadaxin (thymosin) Immune
stimulant SciClone EHT 899 viral protein Enzo Biochem HBV DNA
vaccine Immune stimulant PowderJect (UK) MCC 478 nucleoside
analogue Eli Lilly valLdC (valtorcitabine) nucleoside analogue
Idenix ICN 2001 nucleoside analogue ICN Fluro L and D nucleosides
nucleoside analogue Pharmasset Racivir nucleoside analogue
Pharmasset Robustaflavone nucleoside analogue Advanced Life
Sciences Penciclovir DXG HDP-P-acyclovir LM-019c CS-109 PS-019
PS-018 ara-AMP prodrugs HBV/MF59 Hammerhead ribozymes Glycosidase
Inhibitors Pegylated Interferon Human Monoclonal Antibodies
Famciclovir
TABLE-US-00002 HIV Therapies: Protease Inhibitors (PIs) Brand
Pharmaceutical Name Generic Name Abbreviation Company Invirase
.RTM. saquinavir (Hard SQV (HGC) Hoffman-La Roche Gel Cap)
Fortovase .RTM. saquinavir (Soft Gel SQV (SGC) Hoffman-La Roche
Cap) Norvir .RTM. ritonavir RTV Abbott Laboratories Crixivan .RTM.
indinavir IDV Merck & Co. Viracept .RTM. nelfinavir NFV Pfizer
Agenerase .RTM. amprenavir APV GlaxoSmithKline Kaletra .RTM.
lopinavir + ritonavir LPV Abbott Laboratories fosamprenavir
GlaxoSmithKline tipranavir TBV Boehringer Ingelheim atazanavir
Bristol-Myers Squibb
TABLE-US-00003 HIV Therapies: Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTIs) Brand Pharmaceutical Name Generic
Name Abbreviation Company Retrovir .RTM. zidovudine AZT or ZDV
GlaxoSmithKline Epivir .RTM. lamivudine 3TC GlaxoSmithKline
Combivir .RTM. zidovudine + AZT + 3TC GlaxoSmithKline lamivudine
Trizivir .RTM. abacavir + ABC + GlaxoSmithKline zidovudine + AZT +
3TC lamivudine Ziagen .RTM. abacavir ABC GlaxoSmithKline Hivid
.RTM. zalcitabine ddC Hoffman-La Roche Videx .RTM. didanosine:
buffered ddI Bristol-Myers versions Squibb Videx .RTM. EC
didanosine: delayed- ddI Bristol-Myers release capsules Squibb
Zerit .RTM. stavudine d4T Bristol-Myers Squibb Viread .TM.
tenofovir disoproxil TDF or Gilead Sciences fumarate (DF) Bis(POC)
PMPA Coviracil .TM. emtricitabine FTC Triangle Pharmaceuticals
amdoxovir DAPD Triangle Pharmaceuticals
TABLE-US-00004 HIV Therapies: Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs) Brand Name Generic Name Abbreviation
Pharmaceutical Company Viramune .RTM. nevirapine NVP Boehringer
Ingelheim Rescriptor .RTM. delavirdine DLV Pfizer Sustiva .RTM.
efavirenz EFV Bristol-Myers Squibb (+)-calanolide A Sarawak
Medichem capravirine CPV Pfizer Bristol-Myers Squibb Tibotec-Virco
Group Tibotec-Virco Group
TABLE-US-00005 Pharmaceutical Brand Name Generic Name Abbreviation
Company HIV Therapies: Other Classes of Drugs Viread .TM. tenofovir
disoproxil TDF or Bis(POC) Gilead Sciences fumarate (DF) PMPA
Cellular Inhibitors Droxia .RTM. hydroxyurea HU Bristol-Myers
Squibb Entry Inhibitors (including Fusion Inhibitors) Fuzeon .TM.
enfuvirtide Trimeris Trimeris AnorMED, Inc. Progenics
Pharmaceuticals
TABLE-US-00006 HIV Therapies: Immune-Based Therapies Brand
Pharmaceutical Name Generic Name Abbreviation Company Proleukin
.RTM. aldesleukin, or IL-2 Chiron Corporation Interleukin-2 Remune
.RTM. HIV-1 The Immune Immunogen, or Response Salk vaccine
Corporation HollisEden Pharmaceuticals
TABLE-US-00007 HIV Therapies: Treatments for Side Effects Brand
Pharmaceutical Name Generic Name Side Effect Company Procrit .RTM.
epoetin alfa Anemia Ortho Biotech (erythropoietin) Serostim .RTM.
somatropin, or Lipodystrophy Serono human growth Laboratories
hormone
In one embodiment, the compounds of the invention may be employed
together with at least one other antiviral agent chosen from
reverse transcriptase inhibitors, protease inhibitors, fusion
inhibitors, entry inhibitors and polymerase inhibitors.
In addition, compounds according to the present invention can be
administered in combination or alternation with one or more
anti-retrovirus, anti-HBV, anti-HCV or anti-herpetic agent or
interferon, anti-cancer or antibacterial agents, including but not
limited to other compounds of the present invention. Certain
compounds according to the present invention may be effective for
enhancing the biological activity of certain agents according to
the present invention by reducing the metabolism, catabolism or
inactivation of other compounds and as such, are co-administered
for this intended effect.
VI. Pharmaceutical Compositions
Host, including but not limited to humans, infected with a human
immunodeficiency virus, a hepatitis virus, or a gene fragment
thereof, can be treated by administering to the patient an
effective amount of the active compound or a pharmaceutically
acceptable prodrug or salt thereof in the presence of a
pharmaceutically acceptable carrier or diluent. The active
materials can be administered by any appropriate route, for
example, orally, parenterally, intravenously, intradermally,
subcutaneously, or topically, in liquid or solid form.
A preferred dose of the compound for an HIV or HBV infection will
be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg,
of body weight per day, more generally 0.1 to about 100 mg per
kilogram body weight of the recipient per day. The effective dosage
range of the pharmaceutically acceptable salts and prodrugs can be
calculated based on the weight of the parent nucleoside to be
delivered. If the salt or prodrug exhibits activity in itself, the
effective dosage can be estimated as above using the weight of the
salt or prodrug, or by other means known to those skilled in the
art.
The compound is conveniently administered in unit any suitable
dosage form, including but not limited to but not limited to one
containing 7 to 3000 mg, preferably 70 to 1400 mg of active
ingredient per unit dosage form. An oral dosage of 50-1000 mg is
usually convenient.
Ideally the active ingredient should be administered to achieve
peak plasma concentrations of the active compound of from about 0.2
to 70 .mu.M, preferably about 1.0 to 10 .mu.M. This may be
achieved, for example, by the intravenous injection of a 0.1 to 5%
solution of the active ingredient, optionally in saline, or
administered as a bolus of the active ingredient.
The concentration of active compound in the drug composition will
depend on absorption, inactivation and excretion rates of the drug
as well as other factors known to those of skill in the art. It is
to be noted that dosage values will also vary with the severity of
the condition to be alleviated. It is to be further understood that
for any particular subject, specific dosage regimens should be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the compositions, and that the concentration
ranges set forth herein are exemplary only and are not intended to
limit the scope or practice of the claimed composition. The active
ingredient may be administered at once, or may be divided into a
number of smaller doses to be administered at varying intervals of
time.
A preferred mode of administration of the active compound is oral.
Oral compositions will generally include an inert diluent or an
edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches or capsules.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition.
The tablets, pills, capsules, troches and the like can contain any
of the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring. When the dosage unit form is a capsule, it can
contain, in addition to material of the above type, a liquid
carrier such as a fatty oil. In addition, unit dosage forms can
contain various other materials that modify the physical form of
the dosage unit, for example, coatings of sugar, shellac, or other
enteric agents.
The compound can be administered as a component of an elixir,
suspension, syrup, wafer, chewing gum or the like. A syrup may
contain, in addition to the active compound(s), sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
The compound or a pharmaceutically acceptable prodrug or salts
thereof can also be mixed with other active materials that do not
impair the desired action, or with materials that supplement the
desired action, such as antibiotics, antifungals,
anti-inflammatories or other antivirals, including but not limited
to other nucleoside compounds. Solutions or suspensions used for
parenteral, intradermal, subcutaneous, or topical application can
include the following components: a sterile diluent such as water
for injection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents, such as ethylenediaminetetraacetic acid; buffers, such as
acetates, citrates or phosphates, and agents for the adjustment of
tonicity, such as sodium chloride or dextrose. The parental
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
If administered intravenously, preferred carriers are physiological
saline or phosphate buffered saline (PBS).
In a preferred embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
but not limited to implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene
vinyl acetate, polyanhydrides, polyglycolic acid, collagen,
polyorthoesters and polylactic acid. For example, enterically
coated compounds can be used to protect cleavage by stomach acid.
Methods for preparation of such formulations will be apparent to
those skilled in the art. Suitable materials can also be obtained
commercially.
Liposomal suspensions (including but not limited to liposomes
targeted to infected cells with monoclonal antibodies to viral
antigens) are also preferred as pharmaceutically acceptable
carriers. These may be prepared according to methods known to those
skilled in the art, for example, as described in U.S. Pat. No.
4,522,811 (incorporated by reference). For example, liposome
formulations may be prepared by dissolving appropriate lipid(s)
(such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl
choline, arachadoyl phosphatidyl choline, and cholesterol) in an
inorganic solvent that is then evaporated, leaving behind a thin
film of dried lipid on the surface of the container. An aqueous
solution of the active compound or its monophosphate, diphosphate,
and/or triphosphate derivatives is then introduced into the
container. The container is then swirled by hand to free lipid
material from the sides of the container and to disperse lipid
aggregates, thereby forming the liposomal suspension.
VII. Processes for the Preparation of Active Compound
A process for the facile preparation of
N.sup.4-acyl-cytosine-1,3-dioxolane nucleosides is also provided.
The method includes condensation of a 5'-O-silyl protected
5-fluorocytidine-1,3-dioxolane, with either a carboxylic acid
chloride, or carboxylic acid anhydride, or a carboxylic acid,
followed by desilylation. The other N.sup.4-acyl-substituted
cytosine nucleosides can be synthesized using the similar
approaches.
The N.sup.4-acyl-substituted 5-fluorocytidine-1,3-dioxolane
disclosed herein can be prepared as described in detail below, or
by other assays known to those skilled in the art.
The present invention is further illustrated in the following
examples. It will be understood by one of ordinary skill in the art
that these examples are in no way limiting and that variations of
detail can be made without departing from the spirit and scope of
the present invention.
EXAMPLES
Anhydrous solvents were purchased from Aldrich Chemical Company,
Inc. (Milwaukee). Melting points (mp) were determined on an
Electrothermal digit melting point apparatus and are uncorrected.
.sup.1H and .sup.13C NMR spectra were taken on a Varian Unity Plus
400 spectrometer at room temperature and reported in ppm downfield
from internal tetramethylsilane. Deuterium exchange, decoupling
experiments or 2D-COSY were performed to confirm proton
assignments. Signal multiplicities are represented by s (singlet),
d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet),
br (broad), bs (broad singlet), m (multiplet). All J-values are in
Hz. Mass spectra were recorded on a JEOL JMS-SX/SX102A/E mass
spectrometer. Elemental analyses were performed by Atlantic
Microlab Inc. (Norcross, GA). Analytic TLC was performed on Whatman
LK6F silica gel plates, and preparative TLC on Whatman PK5F silica
gel plates. Column chromatography was carried out on Silica Gel
(Fisher, S733-1) at atmospheric pressure.
Example 1
General Process for the Preparation of
1,3-DioxolaneIntermediate(i)
The 1,3-dioxolane intermediate (i) of the present invention can be
synthesized according to U.S. Pat. No. 5,041,449, filed Jun. 29,
1990; U.S. Pat. No. 5,270,315, filed Mar. 7, 1991
("2-Substituted-4-substituted-1,3-dioxolanes, synthesis and use
thereof"); PCT application CA 92/00209, filed May 20, 1992; U.S.
Pat. No. 5,756,706, filed May 13, 1994; U.S. Pat. No. 5,744,596,
filed Jun. 5, 1995 ("Processes for diastereoselective synthesis of
nucleosides"); PCT Application CA 94/00311, filed Jun. 7, 1994;
U.S. Pat. No. 5,763,606, filed Feb. 2, 1995 ("Stereoselective
synthesis of nucleoside analogues using bicyclic intermediate");
U.S. Patent Application 60/119,756, filed Feb. 11, 1999; U.S.
Patent Application 60/119,885, filed Feb. 12, 1999; PCT Application
CA 00/00144, filed Feb. 11, 2000; U.S. patent application Ser. No.
09/890,283, filed Feb. 11, 2000 (Stereoselective Synthesis Of
Nucleoside Analogues); U.S. Patent Application 60/181,977, filed
Feb. 11, 2000; U.S. patent application Ser. No. 09/779,853, filed
Feb. 9, 2001; PCT Application CA 01/00117, filed Feb. 2, 2001
(Stereoselective Synthesis Of Nucleoside Analogues); U.S. Patent
Application 60/350968, filed Jan. 25, 2002 (Process for producing
dioxolane nucleoside analogues) or any manner known to those of
ordinary skills in the art.
Additionally, the 1,3-dioxolane intermediate can also be prepared
according to the process as set forth in U.S. Pat. No. 5,444,063,
filed Oct. 28, 1992; U.S. Pat. No. 5,684,010, filed Jun. 6, 1995;
U.S. Pat. No. 5,834,474, filed Apr. 15, 1997; U.S. Pat. No.
5,830,898, filed Apr. 15, 1997; PCT Application WO 94/09793, filed
Oct. 28, 1993 ("Enantiomerically .beta.-D-Dioxolane Nucleosides
with Selective Anti-Hepatitis B Virus Activity"); U.S. Pat. No.
5,179,104, filed Dec. 5, 1990; PCT Application WO 92/10497, filed
Dec. 5, 1990 ("Process for the preparation of enantiomerically pure
.beta.-D-(-)-dioxolane"); U.S. Pat. No. 5,767,122, filed Jun. 6,
1995 ("Enantiomerically pure .beta.-D-(-)-dioxolane-nucleosides");
U.S. Pat. No. 5,276,151, filed Dec. 6, 1991 ("Method of Synthesis
of 1,3-Dioxolane Nucleosides"); U.S. patent application Ser. No.
09/669,806, filed Sep. 26, 2000 ("Method of Manufacture of
1,3-Oxathiolane Nucleosides"); U.S. Patent Application No.
60/106,664, filed Nov. 2, 1998; U.S. patent application Ser. No.
09/432,247, filed Nov. 2, 1999; and PCT Application WO 00/25797,
filed Nov. 2, 1999 ("Combination Therapy to Treat Hepatitis B
Virus"); U.S. patent application Ser. No. 10/023,636, filed Dec.
17, 2001; PCT Application US 01/48817, filed Dec. 17, 2001 ("DAPD
Combination Therapy with Ribavirin or Mycophenolic Acid"); and U.S.
Patent Application No. 60/393,935, filed Jul. 3, 2002 ("Combination
Therapy with 1,3, -Dioxolanes and Inosine Monophosphate
Dehydrogenase Inhibitors"), all assigned to Emory University,
Atlanta, Ga., USA.
Example 2
General Process for Acylation of 1,3-Dioxolane
The 1,3-dioxolane intermediate (i) is protected at the 5'-hydroxyl
with any known method known in the art. The protected 1,3-dioxolane
(ii) is then acylated and deprotected to form the
N.sup.4-acylcytosine-1,3-dixolane nucleoside of formula (iv). See
Scheme 1. ##STR00022## Wherein are R.sup.1 is hydrogen or F; P is
an oxygen protecting group; and R.sup.2 is chosen from alkyl,
alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,
thioalkyl, aryl, heteroaryl, and C.sub.6H.sub.4R.sup.6 where
R.sup.6 is chosen from halogen (F, Cl, Br, I), CN, CF.sub.3,
N.sub.3, NO.sub.2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl,
alkenyl, alkynyl, and aryl.
Example 3
.beta.-D-5-fluoro-N.sup.4-(4-iodobenzoyl)cytidine-1',3'-dioxolane
(vi)
To a solution of (ii) and DMAP in anhydrous CH.sub.2Cl.sub.2 and
Et.sub.3N at 0.degree. C. was added 4-iodobenzoyl chloride. The
reaction mixture was stirred at 0.degree. C. for 30 min, then at
room temperature for another 3 h. After removal of the solvent by
evaporation, the residue was mixed with THF, and TBAF was added.
After stirring for 2 h at room temperature, the solvent was
evaporated, and the residue was purified by flash chromatography on
silica gel eluting with CH.sub.2Cl.sub.2/MeOH (96:4) to give, after
recrystallization from CH.sub.2Cl.sub.2/hexane, the title compound
vi as a yellow powder.
Example 4
.beta.D-N.sup.4-Butyryl-5-fluorocytidine-1,3-dixolane (vii)
To a solution of ii and DMAP in anhydrous CH.sub.2Cl.sub.2 and
Et.sub.3N at 0 C. was added butyric anhydride. The reaction mixture
was stirred at 0.degree. C. for 30 min, then at room temperature
for another 2 h. After removal of the solvent by evaporation, the
residue was mixed with THF, and TBAF was added. After stirring for
2 h at room temperature, the solvent was evaporated, and the
residue was purified by flash chromatography on silica gel eluting
with CH.sub.2Cl.sub.2/MeOH (96:4) to give, after recrystallization
from CH.sub.2Cl.sub.2/hexane, the title compound vii.
Example 5
.beta.-D-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine-1,3-dioxolane
(viii)
To a solution of ii and DMAP in anhydrous CH.sub.2Cl.sub.2 and
Et.sub.3N at 0.degree. C. was added 4-fluorobenzoyl chloride. The
reaction mixture was stirred at 0.degree. C. for 30 min, then at
room temperature for another 2 h. After removal of the solvent by
evaporation, the residue was mixed with THF, and TBAF was added.
After stirring for 2 h at room temperature, the solvent was
evaporated, and the residue was purified by flash chromatography on
silica gel eluting with CH.sub.2Cl.sub.2/MeOH (96:4) to give, after
recrystallization from CH.sub.2Cl.sub.2/hexane, the title
compound.
Example 6
Anti-HIV (in PBM Cells) Assay
Anti-HIV-1 activity of the compounds was determined in human
peripheral blood mononuclear (PBM) cells as described previously
(Schinazi R. F., McMillan A., Cannon D., Mathis R., Lloyd R. M.
Jr., Peck A., Sommadossi J.-P., St. Clair M., Wilson J., Furman P.
A., Painter G., Choi W.-B., Liotta D.C. Antimicrob. Agents
Chemother. 1992, 36, 2423; Schinazi R. F., Sommadossi J.-P.,
Saalmann V., Cannon D., Xie M.-Y., Hart G., Smith G., Hahn E.
Antimicrob. Agents Chemother. 1990, 34, 1061). Stock solutions
(20-40 mM) of the compounds were prepared in sterile DMSO and then
diluted to the desired concentration in growth medium. Cells were
infected with the prototype HIV-1.sub.LAI at a multiplicity of
infection of 0.01. Virus obtained from the cell supernatant was
quantified on day 6 after infection by a reverse transcriptase
assay using (rA).sub.n-(dT).sub.12-18 as template-primer. The DMSO
present in the diluted solution (<0.1%) had no effect on the
virus yield. AZT was included as positive control. The antiviral
EC.sub.50 and EC.sub.90 were obtained from the
concentration-response curve using the median effective method
described previously (Chou T.-C. & Talalay P. Adv. Enzyme
Regul. 1984, 22, 27-55; Belen'kii M. S. & Schinazi R. F.
Antiviral Res. 1994, 25, 1-11).
Example 7
Anti-HIV (in MT-2 Cells) Assay
In a second antiviral testing system, the potency of the compounds
was determined by measurement of viral RNA accumulation in
HIV-I.sub.RF infected MT-2 cells (Bacheler L T, Paul M, Otto M J,
Jadhav P K, Stone B A & Miller J A (1994) An assay for HIV RNIn
infected cell lysates, and its use for rapid evaluation of
antiviral efficacy. Antivir. Chem. Chemother. 5:111-121). The virus
titer was established to determine the dilution producing 15 to 30
ng/RNA per well of HIV RNIn 3 days of infection. HIV-1 RNA was
quantified using biotinylated capture and alkaline
phosphatase-derivatized reporter oligonucleotides as described
previously (Charvet A-S, Camplo M, Faury P, Graciet J C, Mourier N,
Chermann J C & Kraus J L (1994) Inhibition of human
immunodeficiency virus type 1 replication by phosphonoformate- and
phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates. J. Med.
Chem. 37:2216-2223). In a third system, the effect of analogs on
the replication of HIV-I.sub.NL4-3 was determined via the
InterCompany Consortium consensus p24 assay as previously described
(Jadhav P K & MacKay M F (1997) Cyclic urea amide: HIV-1
protease inhibitors with low nanomolar potency against both wild
types and protease inhibitor resistant mutants of HIV. J. Med.
Chem. 40:181-190). Recombinant viruses were recovered by
transfecting the appropriate NL4-3 plasmid by lipofection. Virus
stocks recovered 7 to 10 days post-transfection were titered on
MT-4 cells to determine if the dilution produced 1,000 to 3,000 ng
p24 in 4 days. This dilution was then used in drug susceptibility
assays, where drug was added 24 h post infection of cells, and
p2.sup.4 quantified by ELISA 3 days later.
Example 8
Anti-HBV Assay
The anti-HBV activity of the compounds was determined by treating
the AD-38 cell line carrying wild type HBV under the control of
tetracycline (Ladner S. K., Otto M. J., Barker C. S., Zaifert K.,
Wang G. H., Guo J. T., Seeger C. & King R. W. Antimicrob.
Agents Chemother. 1997, 41, 1715-1720). Removal of tetracycline
from the medium [Tet(-)] results in the production of HBV. The
levels of HBV in the culture supernatant fluids from cells treated
with the compounds were compared with that of the untreated
controls. Control cultures with tetracycline [Tet(+)] were also
maintained to determine the basal levels of HBV expression. 3TC was
included as positive control.
Example 9
Cytotoxicity Assay
The toxicity of the compounds was assessed in Vero, human PBM, CEM
(human lymphoblastoid), MT-2, and HepG2 cells, as described
previously (Schinazi R. F., Sommadossi J.-P., Saalmann V., Cannon
D. L., Xie M.-Y., Hart G. C., Smith G. A. & Hahn E. F.
Antimicrob Agents Chemother. 1990, 34, 1061-1067). Cycloheximide
was included as positive cytotoxic control, and untreated cells
exposed to solvent were included as negative controls. The
cytotoxicity IC.sub.50 was obtained from the concentration-response
curve using the median effective method described previously (Chou
T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27-55;
Belen'kii M. S. & Schinazi R. F. Antiviral Res. 1994, 25,
1-11).
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