U.S. patent application number 13/371654 was filed with the patent office on 2012-08-09 for n4-acylcytosine nucleosides for treatment of viral infections.
This patent application is currently assigned to Pharmasset, Inc.. Invention is credited to Michael J. Otto, Junxing Shi, Kyoichi A. Watanabe.
Application Number | 20120202766 13/371654 |
Document ID | / |
Family ID | 23338072 |
Filed Date | 2012-08-09 |
United States Patent
Application |
20120202766 |
Kind Code |
A1 |
Otto; Michael J. ; et
al. |
August 9, 2012 |
N4-ACYLCYTOSINE NUCLEOSIDES FOR TREATMENT OF VIRAL INFECTIONS
Abstract
The present invention is directed to a 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-acyl-2',3'-dideoxy-5-fluorocytidine or
N.sup.4-acyl-2',3'-didehyd-ro-2',3'-dideoxy-5-fluorocytidine, and
pharmaceutically acceptable salts, prodrugs, and other derivatives
thereof.
Inventors: |
Otto; Michael J.; (Lilburn,
GA) ; Shi; Junxing; (Duluth, GA) ; Watanabe;
Kyoichi A.; (Stone Mountain, GA) |
Assignee: |
Pharmasset, Inc.
Princeton
NJ
|
Family ID: |
23338072 |
Appl. No.: |
13/371654 |
Filed: |
February 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11969427 |
Jan 4, 2008 |
8114997 |
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13371654 |
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11461338 |
Jul 31, 2006 |
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11969427 |
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10318511 |
Dec 13, 2002 |
7105527 |
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11461338 |
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60341555 |
Dec 14, 2001 |
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Current U.S.
Class: |
514/49 ;
536/28.2 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 409/14 20130101; A61P 31/12 20180101; C07D 405/04 20130101;
A61P 1/16 20180101; A61P 31/20 20180101; A61P 31/22 20180101; A61P
31/18 20180101; C07H 19/06 20130101; C07H 19/16 20130101; A61P
31/14 20180101 |
Class at
Publication: |
514/49 ;
536/28.2 |
International
Class: |
A61K 31/7068 20060101
A61K031/7068; A61P 31/18 20060101 A61P031/18; A61P 31/20 20060101
A61P031/20; C07H 19/06 20060101 C07H019/06 |
Claims
1-17. (canceled)
18. A compound of formula (I): ##STR00030## or a pharmaceutically
acceptable salt thereof, wherein i) X is O, S, NR.sup.5, CH.sub.2,
CHF or CF.sub.2; ii) Y is CH.sub.2, CHF or CF.sub.2; iii) R.sup.1
is chosen from hydrogen, halogen, alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF.sub.3,
N.sub.3, NO.sub.2, aryl, heteroaryl and acyl; iv) 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; v) R.sup.3 and R.sup.3' are chosen independently
from H, halogen, CN, CF.sub.3, N.sub.3, NO.sub.2, alkyl, alkenyl,
and alkynyl; and vi) R.sup.4 is H, phosphate, 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, a lipid, an amino acid, a peptide,
or cholesterol. vii) R.sup.5 is H, acyl, alkyl, alkenyl, alkynyl,
or cycloalkyl.
19. A pharmaceutical composition that includes an effective HIV or
HBV treatment amount of a compound of claim 18 in a
pharmaceutically acceptable carrier or diluent.
20. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound of claim
18 in a pharmaceutically acceptable carrier.
21. A method for the treatment of a host infected with HBV that
includes administering an effective amount of a compound of claim
18 in a pharmaceutically acceptable carrier.
22. A method for the treatment of a host infected with HIV that
includes administering an effective amount of a compound of claim
18 in a pharmaceutically acceptable carrier in combination with
another anti-HIV agent.
23. A method for the treatment of a host infected with HBV that
includes administering an effective amount of a compound of claim
18 in a pharmaceutically acceptable carrier in combination with
another anti-HBV agent.
24. A compound of claim 18 for use in the treatment of host
infected with HIV.
25. A compound of claim 18 for use in the treatment of a host
infected with HBV infection.
Description
[0001] The present application claims priority to U.S. patent
application Ser. No. 10/318,511 filed on Dec. 13, 2002, which
claimed priority to U.S. Patent Application Ser. No. 60/341,555
filed on Dec. 14, 2001.
FIELD OF THE INVENTION
[0002] 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
[0003] 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).
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] The success 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) in
inhibiting the replication of HIV in vivo or in vitro 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).
[0012] .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.
[0013] 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'-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). 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]cyto-
sine. 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).
[0014] Therefore, it is an object of the present invention to
provide a method and composition for the treatment or prevention of
HIV infection in human patients.
[0015] It is another object of the present invention to provide a
method and composition for the treatment or prevention of HBV
infection in human patients or other host animals.
[0016] It is still another object of the present invention to
provide a method and composition for the treatment or prevention of
HIV and HBV infection in human patients or other host animals.
SUMMARY OF THE INVENTION
[0017] It has been found that certain N.sup.4-acyl-cytosine
nucleosides, and in particular,
N.sup.4-acyl-2',3'-dideoxy-5-fluorocytidine and
N.sup.4-acyl-2',3'-didehydro-2',3'-dideoxy-5-fluoro-cytidine, 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.
[0018] In one embodiment of the invention, the active compound is
of formula (I) or (II):
##STR00001##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
[0019] i) X is O, S, NR.sup.5, CH.sub.2, CHF or CF.sub.2; [0020]
ii) Y is CH.sub.2, CHF or CF.sub.2; [0021] iii) R.sup.1 is chosen
from hydrogen, halogen (F, Cl, Br, I), alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), cycloalkyl (including but not limited to C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8), CN, CF.sub.3,
N.sub.3, NO.sub.2, aryl (including but not limited to C.sub.6,
C.sub.7, C.sub.8, C.sub.9, and C.sub.10), heteroaryl (including but
not limited to C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and acyl (including but
not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6);
[0022] iv) R.sup.2 is chosen from alkyl (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), alkynyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), cycloalkyl (including but not limited to
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8),
aminoalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), hydroxyalkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), heteroaryl (including but not
limited to C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9,
C.sub.10, C.sub.11, and C.sub.12), 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 (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), aminoalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkoxy
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and aryl (including but
not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10);
[0023] v) 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6); [0024] vi) R.sup.4 is H, phosphate (including but not
limited to monophosphate, diphosphate, triphosphate, or a
stabilized phosphate prodrug), carbonyl substituted with alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), 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
[0025] vii) R.sup.5 is H, acyl, alkyl, alkenyl, alkynyl, or
cycloalkyl.
[0026] In one embodiment of the present invention, if the active
compound is of formula (II), and X is O, S, CH.sub.2, CHF or
CF.sub.2, R.sup.1 is F, and R.sup.3 and R.sup.3' are H or F, then
R.sup.2 cannot be an alkyl, alkoxyalkyl (such as methoxymethyl),
aralkyl (such as benzyl or substituted benzyl), aryloxyalkyl (such
as phenoxymethyl) or aryl (including but not limited to a 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)).
[0027] 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, Y is CH.sub.2 and both R.sup.3 and R.sup.3' groups are
hydrogen, forming a d2 nucleoside (i.e., a 2',3'-dideoxy
nucleoside).
[0028] In one embodiment, the active compound is
.beta.-D-N.sup.4-p-iodobenzoyl-2',3'-dideoxy-5-fluorocytidine.
Other specific examples of active compounds include
.beta.-D-N.sup.4-p-fluoro-benzoyl-2',3'-dideoxy-5-fluorocytidine,
.beta.-D-N.sup.4-p-chlorobenzoyl-2',3'-dideoxy-5-fluoro-cytidine,
.beta.-D-N.sup.4-p-bromobenzoyl-2',3'-dideoxy-5-fluorocytidine,
.beta.-D-N.sup.4-p-ethylbenzoyl-2',3'-dideoxy-5-fluorocytidine, and
.beta.-D-N.sup.4-p-t-butylbenzoyl-2',3'-dideoxy-5-fluoro-cytidine.
[0029] In another embodiment, the active compound is
.beta.-D-N.sup.4-p-bromobenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocyt-
idine. Other specific examples of active compounds include
.beta.-D-N.sup.4-p-fluorobenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocy-
tidine,
.beta.-D-N.sup.4-p-chlorobenzoyl-2',3'-didehydro-2',3'-dideoxy-5-f-
luorocytidine,
.beta.-D-N.sup.4-p-iodobenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocyti-
dine,
.beta.-D-N.sup.4-p-ethylbenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluo-
rocytidine, and
.beta.-D-N.sup.4-p-t-butylbenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluoroc-
ytidine.
[0030] In addition, the
2',3'-dideoxy-N.sup.4-acyl-cytosinenucleosides and
2',3'-didehydro-2',3'-dideoxy-N.sup.4-acyl-cytosinenucleosides are
inhibitors of HBV. Therefore, these compounds can also be used to
treat patients that are co-infected with both HIV and HBV.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
BRIEF DESCRIPTION OF THE FIGURES
[0038] FIG. 1 is a non-limiting example of the synthesis of active
compounds of the present invention, and in particular, the
synthesis of .beta.-D-N.sup.4-acyl-2',3'-dideoxy-5-fluorocytidine
and
.beta.-D-N.sup.4-acyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
nucleosides.
[0039] FIG. 2 is a graphic representation of the anti-HBV activity
of selected N.sup.4-acyl-substituted .beta.-D-2',3'-dideoxy- and
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
analogues.
DETAILED DESCRIPTION OF THE INVENTION
[0040] It has been found that N.sup.4-acyl-cytosine nucleosides,
and in particular, N.sup.4-acyl-2',3'-dideoxy-5-fluorocytidine and
N.sup.4-acyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, 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 nucleosides.
[0041] The present invention also provides a 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.
[0042] The present invention provides a 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.
[0043] The present invention provides a 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.
[0044] The present invention provides a 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.
[0045] In another aspect, there is provided a pharmaceutical
formulation comprising a compound of the invention in combination
with a pharmaceutically acceptable carrier or excipient.
[0046] 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.
[0047] 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
[0048] In one embodiment of the invention, the active compound is
of formula (I) or (II):
##STR00002##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
[0049] i) X is O, S, NR.sup.5, CH.sub.2, CHF or CF.sub.2; [0050]
ii) Y is CH.sub.2, CHF or CF.sub.2; [0051] iii) R.sup.1 is chosen
from hydrogen, halogen (F, Cl, Br, I), alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), cycloalkyl (including but not limited to C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8), CN, CF.sub.3,
N.sub.3, NO.sub.2, aryl (including but not limited to C.sub.6,
C.sub.7, C.sub.8, C.sub.9, and C.sub.10), heteroaryl (including but
not limited to C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and acyl (including but
not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6);
[0052] iv) R.sup.2 is chosen from alkyl (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), alkynyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, and C.sub.22), cycloalkyl (including but not limited to
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8),
aminoalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), hydroxyalkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), heteroaryl (including but not
limited to C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9,
C.sub.10 C.sub.11, and C.sub.12), 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 (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), aminoalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkoxy
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and aryl (including but
not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10);
[0053] v) 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6); [0054] vi) R.sup.4 is H, phosphate (including but not
limited to monophosphate, diphosphate, triphosphate, or a
stabilized phosphate prodrug), carbonyl substituted with alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), 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
[0055] vii) R.sup.5 is H, acyl, alkyl, alkenyl, alkynyl, or
cycloalkyl.
[0056] The compound of the present invention can be in the form of
the .beta.-L- or .beta.-D-configuration, or a racemic mixture.
[0057] In one embodiment of the present invention, if the active
compound is of formula (II), and X is O, S, CH.sub.2, CHF or
CF.sub.2, R.sup.1 is F, and R.sup.3 and R.sup.3' are H or F, then
R.sup.2 cannot be an alkyl, alkoxyalkyl (such as methoxymethyl),
aralkyl (such as benzyl or substituted benzyl), aryloxyalkyl (such
as phenoxymethyl) or aryl (including but not limited to a 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)).
[0058] In another particular sub-embodiment of the present
invention, the active compound is of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0059]
i) X is O; [0060] ii) Y is CH.sub.2, CHF or CF.sub.2; [0061] iii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), CN, CF.sub.3, N.sub.3, NO.sub.2, aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and
acyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6); [0062] iv) R.sup.2 is chosen from alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11,
C.sub.12, C.sub.13, C.sub.14, C.sub.15, C.sub.16, C.sub.17,
C.sub.18, C.sub.19, C.sub.20, C.sub.21, and C.sub.22), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12,
C.sub.13, C.sub.14, C.sub.15, C.sub.16, C.sub.17, C.sub.18,
C.sub.19, C.sub.20, C.sub.21, and C.sub.22), alkynyl (including but
not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13,
C.sub.14, C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19,
C.sub.20, C.sub.21, and C.sub.22), cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), aminoalkyl (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), hydroxyalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
thioalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), aryl (including but not limited to
C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10), heteroaryl
(including but not limited to C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12), 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 (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aminoalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkoxy (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10); [0063] v) 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 (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), and alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and [0064] vi) R.sup.4 is
H, phosphate (including but not limited to monophosphate,
diphosphate, triphosphate, or a stabilized phosphate prodrug),
carbonyl substituted with alkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10, 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 subtituents 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.
[0065] In another particular sub-embodiment of the present
invention, the active compound is of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0066]
i) X is O; [0067] ii) Y is CH.sub.2, CHF or CF.sub.2; [0068] iii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), CN, CF.sub.3, N.sub.3, or NO.sub.2;
[0069] iv) R.sup.2 is chosen from cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), aminoalkyl (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12), 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 (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aminoalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkoxy (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10); [0070] v) 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 (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), and alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and [0071] vi) R.sup.4 is
H, phosphate (including but not limited to monophosphate,
diphosphate, triphosphate, or a stabilized phosphate prodrug),
carbonyl substituted with alkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10), 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.
[0072] In another particular sub-embodiment of the present
invention, the active compound is of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0073]
i) X is O; [0074] ii) Y is CH.sub.2, CHF or CF.sub.2; [0075] iii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), CN, CF.sub.3, N.sub.3, or NO.sub.2;
[0076] iv) R.sup.2 is chosen from cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), aminoalkyl (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12);
[0077] v) 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6); and [0078] vi) R.sup.4 is H, phosphate (including but
not limited to monophosphate, diphosphate, triphosphate, or a
stabilized phosphate prodrug), carbonyl substituted with alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), 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.
[0079] In another particular sub-embodiment of the present
invention, the active compound is of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0080]
i) X is O; [0081] ii) Y is CH.sub.2, CHF or CF.sub.2; [0082] iii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), CN, CF.sub.3, N.sub.3, or NO.sub.2;
[0083] iv) R.sup.2 is C.sub.6H.sub.4R.sup.6 where R.sup.6 is chosen
from CN, CF.sub.3, N.sub.3, NO.sub.2, haloalkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), aminoalkyl (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), and aryl (including but not limited to C.sub.6,
C.sub.7, C.sub.8, C.sub.9, and C.sub.10); [0084] v) 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 (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
alkenyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), and alkynyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and [0085] vi)
R.sup.4 is H, phosphate (including but not limited to
monophosphate, diphosphate, triphosphate, or a stabilized phosphate
prodrug), carbonyl substituted with alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10), 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.
[0086] In another particular sub-embodiment of the present
invention, the active compound is of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0087]
i) X is O; [0088] ii) Y is CH.sub.2, CHF or CF.sub.2; [0089] iii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), CN, CF.sub.3, N.sub.3, or NO.sub.2;
[0090] iv) R.sup.2 is 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
aminoalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkoxy (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
thioalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkenyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), and aryl (including but not limited to C.sub.6,
C.sub.7, C.sub.8, C.sub.9, and C.sub.10); [0091] v) 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 (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
alkenyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), and alkynyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and [0092] vi)
R.sup.4 is H, phosphate (including but not limited to
monophosphate, diphosphate, triphosphate, or a stabilized phosphate
prodrug), carbonyl substituted with alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10), 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.
[0093] In a particular sub-embodiment of the present invention, the
active compound is of formula (II) or a pharmaceutically acceptable
salt or prodrug thereof, wherein [0094] i) X is O; [0095] ii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), CN, CF.sub.3, N.sub.3, NO.sub.2, aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and
acyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6); [0096] iii) R.sup.2 is chosen from
cycloalkyl (including but not limited to C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.7, and C.sub.8), aminoalkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), haloalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), thioalkyl (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), heteroaryl (including but not limited to C.sub.4,
C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11,
and C.sub.12), 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
aminoalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkoxy (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
thioalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkenyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), and aryl (including but not limited to C.sub.6,
C.sub.7, C.sub.8, C.sub.9, and C.sub.10); [0097] iv) 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 (including but not limited
to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
alkenyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), and alkynyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and [0098] v)
R.sup.4 is H, phosphate (including but not limited to
monophosphate, diphosphate, triphosphate, or a stabilized phosphate
prodrug), carbonyl substituted with alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10), 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.
[0099] In a particular sub-embodiment of the present invention, the
active compound is of formula (II) or a pharmaceutically acceptable
salt or prodrug thereof, wherein [0100] i) X is O; [0101] ii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including, but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), CN, CF.sub.3, N.sub.3, and
NO.sub.2; [0102] iii) R.sup.2 is chosen from cycloalkyl (including
but not limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), aminoalkyl (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12);
[0103] iv) 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6); and [0104] v) R.sup.4 is H, phosphate (including but
not limited to monophosphate, diphosphate, triphosphate, or a
stabilized phosphate prodrug), carbonyl substituted with alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), 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.
[0105] In a particular sub-embodiment of the present invention, the
active compound is of formula (II) or a pharmaceutically acceptable
salt or prodrug thereof, wherein [0106] i) X is O; [0107] ii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), CN, CF.sub.3, N.sub.3, NO.sub.2, aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and
acyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6); [0108] iii) R.sup.2 is 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 (including but not limited to C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), haloalkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), aminoalkyl (including but, not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkoxy
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), thioalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), alkynyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and aryl (including but
not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10);
[0109] iv) 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
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), and alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6); and [0110] v) R.sup.4 is H, phosphate (including but
not limited to monophosphate, diphosphate, triphosphate, or a
stabilized phosphate prodrug), carbonyl substituted with alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), alkenyl (including but not limited to
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), aryl (including but not limited to C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10), 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.
[0111] In a particular sub-embodiment of the present invention, the
active compound is of formula (II) or a pharmaceutically acceptable
salt or prodrug thereof, wherein [0112] i) X is O; [0113] ii)
R.sup.1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl
(including but not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), haloalkyl (including but not limited to
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl
(including but not limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6), haloalkenyl (including but not limited to C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
haloalkynyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), cycloalkyl (including but not
limited to C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8), CN, CF.sub.3, N.sub.3, NO.sub.2, aryl (including but not
limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10),
heteroaryl (including but not limited to C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, and C.sub.12) and
acyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6); [0114] iii) R.sup.2 is C.sub.6H.sub.4R.sup.6
where R.sup.6 is chosen from CN, CF.sub.3, N.sub.3, NO.sub.2,
haloalkyl (including but not limited to C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), aminoalkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), thioalkyl (including but not limited to C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6), alkenyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6),
alkynyl (including but not limited to C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6), and aryl (including but not limited to
C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10); [0115] iv)
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 (including but
not limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), and alkynyl (including but not
limited to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6); and
[0116] v) R.sup.4 is H, phosphate (including but not limited to
monophosphate, diphosphate, triphosphate, or a stabilized phosphate
prodrug), carbonyl substituted with alkyl (including but not
limited to C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6), alkenyl (including but not limited to C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6), alkynyl (including but not limited
to C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6), aryl
(including but not limited to C.sub.6, C.sub.7, C.sub.8, C.sub.9,
and C.sub.10), 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.
[0117] In one embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0118] i) X is O; Y is CH.sub.2; [0119]
ii) R.sup.1 is fluorine or hydrogen; [0120] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0121] 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.
[0122] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0123] i) X is O; Y is CH.sub.2; [0124]
ii) R.sup.1 is fluorine or hydrogen; [0125] iii) R.sup.3 and
R.sup.3' ate independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0126] iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the ortho position.
[0127] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0128] i) X is O; Y is CH.sub.2;
[0129] ii) R.sup.1 is fluorine or hydrogen; [0130] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0131] iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the ortho position.
[0132] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0133] i) X is O; Y is CH.sub.2;
[0134] ii) R.sup.1 is fluorine or hydrogen; [0135] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0136] iv) R.sup.2 is a phenyl moiety optionally
substituted with I in the ortho position.
[0137] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0138] i) X is O; Y is CH.sub.2;
[0139] ii) R.sup.1 is fluorine or hydrogen; [0140] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0141] iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the ortho position.
[0142] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0143] i) X is O; Y is CH.sub.2;
[0144] ii) R.sup.1 is fluorine or hydrogen; [0145] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0146] iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the ortho position.
[0147] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0148] i) X is O; Y is CH.sub.2;
[0149] ii) R.sup.1 is fluorine or hydrogen; [0150] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0151] iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the ortho position.
[0152] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0153] i) X is O; Y is
CH.sub.2; [0154] ii) R.sup.1 is fluorine or hydrogen; [0155] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0156] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkyl in the ortho position.
[0157] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0158] i) X is O; Y is
CH.sub.2; [0159] ii) R.sup.1 is fluorine or hydrogen; [0160] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0161] iv) R.sup.2 is a phenyl moiety
optionally substituted with methyl in the ortho position.
[0162] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0163] i) X is O; Y is
CH.sub.2; [0164] ii) R.sup.1 is fluorine or hydrogen; [0165] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0166] iv) R.sup.2 is a phenyl moiety
optionally substituted with ethyl in the ortho position.
[0167] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0168] i) X is O; Y is
CH.sub.2; [0169] ii) R.sup.1 is fluorine or hydrogen; [0170] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0171] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-propyl in the ortho position.
[0172] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0173] i) X is O; Y is
CH.sub.2; [0174] ii) R.sup.1 is fluorine or hydrogen; [0175] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0176] iv) R.sup.2 is a phenyl moiety
optionally substituted with iso-propyl in the ortho position.
[0177] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0178] i) X is O; Y is
CH.sub.2; [0179] ii) R.sup.1 is fluorine or hydrogen; [0180] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0181] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-butyl in the ortho position.
[0182] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0183] i) X is O; Y is
CH.sub.2; [0184] ii) R.sup.1 is fluorine or hydrogen; [0185] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0186] iv) R.sup.2 is a phenyl moiety
optionally substituted with sec-butyl in the ortho position.
[0187] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0188] i) X is O; Y is
CH.sub.2; [0189] ii) R.sup.1 is fluorine or hydrogen; [0190] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0191] iv) R.sup.2 is a phenyl moiety
optionally substituted with tert-butyl in the ortho position.
[0192] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0193] i) X is O; Y is
CH.sub.2; [0194] ii) R.sup.1 is fluorine or hydrogen; [0195] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0196] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-pentyl in the ortho position.
[0197] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0198] i) X is O; Y is
CH.sub.2; [0199] ii) R.sup.1 is fluorine or hydrogen; [0200] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0201] iv) R.sup.2 is a phenyl moiety
optionally substituted with isopentyl in the ortho position.
[0202] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0203] i) X is O; Y is
CH.sub.2; [0204] ii) R.sup.1 is fluorine or hydrogen; [0205] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0206] iv) R.sup.2 is a phenyl moiety
optionally substituted with neopentyl in the ortho position.
[0207] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0208] i) X is O; Y is
CH.sub.2; [0209] ii) R.sup.1 is fluorine or hydrogen; [0210] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0211] iv) R.sup.2 is a phenyl moiety
optionally substituted with cyclopentyl in the ortho position.
[0212] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0213] i) X is O; Y is
CH.sub.2; [0214] ii) R.sup.1 fluorine or hydrogen; [0215] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0216] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-hexyl in the ortho position.
[0217] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0218] i) X is O; Y is
CH.sub.2; [0219] ii) R.sup.1 is fluorine or hydrogen; [0220] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0221] iv) R.sup.2 is a phenyl moiety
optionally substituted with a cyclohexyl in the ortho position.
[0222] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0223] i) X is O; Y is
CH.sub.2; [0224] ii) R.sup.1 is fluorine or hydrogen; [0225] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0226] iv) R.sup.2 is a phenyl moiety
optionally substituted with CN in the ortho position.
[0227] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0228] i) X is O; Y is
CH.sub.2; [0229] ii) R.sup.1 is fluorine or hydrogen; [0230] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0231] iv) R.sup.2 is a phenyl moiety
optionally substituted with CF.sub.3 in the ortho position.
[0232] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0233] i) X is O; Y is
CH.sub.2; [0234] ii) R.sup.1 is fluorine or hydrogen; [0235] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0236] iv) R.sup.2 is a phenyl moiety
optionally substituted with N.sub.3 in the ortho position.
[0237] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0238] i) X is O; Y is
CH.sub.2; [0239] ii) R.sup.1 is fluorine or hydrogen; [0240] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0241] iv) R.sup.2 is a phenyl moiety
optionally substituted with haloalkyl in the ortho position.
[0242] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0243] i) X is O; Y is
CH.sub.2; [0244] ii) R.sup.1 is fluorine or hydrogen; [0245] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0246] iv) R.sup.2 is a phenyl moiety
optionally substituted with aminoalkyl in the ortho position.
[0247] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0248] i) X is O; Y is
CH.sub.2; [0249] ii) R.sup.1 is fluorine or hydrogen; [0250] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0251] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkoxy in the ortho position.
[0252] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0253] i) X is O; Y is
CH.sub.2; [0254] ii) R.sup.1 is fluorine or hydrogen; [0255] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0256] iv) R.sup.2 is a phenyl moiety
optionally substituted with thioalkyl in the ortho position.
[0257] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0258] i) X is O; Y is
CH.sub.2; [0259] ii) R.sup.1 is fluorine or hydrogen; [0260] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0261] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkenyl in the ortho position.
[0262] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0263] i) X is O; Y is
CH.sub.2; [0264] ii) R.sup.1 is fluorine or hydrogen; [0265] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0266] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkynyl in the ortho position.
[0267] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0268] i) X is O; Y is
CH.sub.2; [0269] ii) R.sup.1 is fluorine or hydrogen; [0270] iii)
R3 and R3' are independently hydrogen or fluorine; R4 is hydrogen;
and [0271] iv) R.sup.2 is a phenyl moiety optionally substituted
with aryl in the ortho position.
[0272] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0273] i) X is O; Y is
CH.sub.2; [0274] ii) R.sup.1 is fluorine or hydrogen; [0275] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0276] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzyl in the ortho position.
[0277] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0278] i) X is O; Y is
CH.sub.2; [0279] ii) R.sup.1 is fluorine or hydrogen; [0280] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0281] iv) R.sup.2 is a phenyl moiety
optionally substituted with thiophenyl in the ortho position.
[0282] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0283] i) X is O; Y is
CH.sub.2; [0284] ii) R.sup.1 is fluorine or hydrogen; [0285] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0286] iv) R.sup.2 is a phenyl moiety
optionally substituted with furanyl in the ortho position.
[0287] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0288] i) X is O; Y is
CH.sub.2; [0289] ii) R.sup.1 is fluorine or hydrogen; [0290] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0291] iv) R.sup.2 is a phenyl moiety
optionally substituted with naphthyl in the ortho position.
[0292] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0293] i) X is O; Y is
CH.sub.2; [0294] ii) R.sup.1 is fluorine or hydrogen; [0295] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0296] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzoyl in the ortho position.
[0297] In one embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0298] i) X is O; Y is CH.sub.2; [0299]
ii) R.sup.1 is fluorine or hydrogen; [0300] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0301] 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.
[0302] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0303] i) X is O; Y is CH.sub.2; [0304]
ii) R.sup.1 is fluorine or hydrogen; [0305] iii) R.sup.3 and
R.sup.3' independently independently hydrogen or fluorine; R.sup.4
is hydrogen; and [0306] iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the meta position.
[0307] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0308] i) X is O; Y is CH.sub.2;
[0309] ii) R.sup.1 is fluorine or hydrogen; [0310] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0311] iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the meta position.
[0312] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0313] i) X is O; Y is CH.sub.2;
[0314] ii) R.sup.1 is fluorine or hydrogen; [0315] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0316] iv) R.sup.2 is a phenyl moiety optionally
substituted with I in the meta position.
[0317] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0318] i) X is O; Y is CH.sub.2;
[0319] ii) R.sup.1 is fluorine or hydrogen; [0320] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0321] iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the meta position.
[0322] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0323] i) X is O; Y is CH.sub.2;
[0324] ii) R.sup.1 is fluorine or hydrogen; [0325] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0326] iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the meta position.
[0327] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0328] i) X is O; Y is CH.sub.2;
[0329] ii) R.sup.1 is fluorine or hydrogen; [0330] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0331] iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the meta position.
[0332] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0333] i) X is O; Y is
CH.sub.2; [0334] ii) R.sup.1 is fluorine or hydrogen; [0335] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0336] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkyl in the meta position.
[0337] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0338] i) X is O; Y is
CH.sub.2; [0339] ii) R.sup.1 is fluorine or hydrogen; [0340] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0341] iv) R.sup.2 is a phenyl moiety
optionally substituted with methyl in the meta position.
[0342] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0343] i) X is O; Y is
CH.sub.2; [0344] ii) R.sup.1 is fluorine or hydrogen; [0345] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0346] iv) R.sup.2 is a phenyl moiety
optionally substituted with ethyl in the meta position.
[0347] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0348] i) X is O; Y is
CH.sub.2; [0349] ii) R.sup.1 is fluorine or hydrogen; [0350] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0351] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-propyl in the meta position.
[0352] In yet another embodiment of the present invention, the
active compound is of formula, its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0353] i) X is O; Y is
CH.sub.2; [0354] ii) R.sup.1 is fluorine or hydrogen; [0355] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0356] iv) R.sup.2 is a phenyl moiety
optionally substituted with iso-propyl in the meta position.
[0357] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0358] i) X is O; Y is
CH.sub.2; [0359] ii) R.sup.1 is fluorine or hydrogen; [0360] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0361] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-butyl in the meta position.
[0362] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0363] i) X is O; Y is
CH.sub.2; [0364] ii) R.sup.1 is fluorine or hydrogen; [0365] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0366] iv) R.sup.2 is a phenyl moiety
optionally substituted with sec-butyl in the meta position.
[0367] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0368] i) X is O; Y is
CH.sub.2; [0369] ii) R.sup.1 is fluorine or hydrogen; [0370] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0371] iv) R.sup.2 is a phenyl moiety
optionally substituted with tert-butyl in the meta position.
[0372] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0373] i) X is O; Y is
CH.sub.2; [0374] ii) R.sup.1 is fluorine or hydrogen; [0375] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0376] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-pentyl in the meta position.
[0377] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0378] i) X is O; Y is
CH.sub.2; [0379] ii) R.sup.1 is fluorine or hydrogen; [0380] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0381] iv) R.sup.2 is a phenyl moiety
optionally substituted with isopentyl in the meta position.
[0382] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0383] i) X is O; Y is
CH.sub.2; [0384] ii) R.sup.1 is fluorine or hydrogen; [0385] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0386] iv) R.sup.2 is a phenyl moiety
optionally substituted with neopentyl in the meta position.
[0387] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0388] i) X is O; Y is
CH.sub.2; [0389] ii) R.sup.1 is fluorine or hydrogen; [0390] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0391] iv) R.sup.2 is a phenyl moiety
optionally substituted with cyclopentyl in the meta position.
[0392] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0393] i) X is O; Y is
CH.sub.2; [0394] ii) R.sup.1 is fluorine or hydrogen; [0395] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0396] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-hexyl in the meta position.
[0397] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0398] i) X is O; Y is
CH.sub.2; [0399] ii) R.sup.1 is fluorine or hydrogen; [0400] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0401] iv) R.sup.2 is a phenyl moiety
optionally substituted with a cyclohexyl in the meta position.
[0402] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0403] i) X is O; Y is
CH.sub.2; [0404] ii) R.sup.1 is fluorine or hydrogen; [0405] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0406] iv) R.sup.2 is a phenyl moiety
optionally substituted with CN in the meta position.
[0407] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0408] i) X is O; Y is
CH.sub.2; [0409] ii) R.sup.1 is fluorine or hydrogen; [0410] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0411] iv) R.sup.2 is a phenyl moiety
optionally substituted with CF.sub.3 in the meta position.
[0412] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0413] i) X is O; Y is
CH.sub.2; [0414] ii) R.sup.1 is fluorine or hydrogen; [0415] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0416] iv) R.sup.2 is a phenyl moiety
optionally substituted with N.sub.3 in the meta position.
[0417] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0418] i) X is O; Y is
CH.sub.2; [0419] ii) R.sup.1 is fluorine or hydrogen; [0420] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0421] iv) R.sup.2 is a phenyl moiety
optionally substituted with haloalkyl in the meta position.
[0422] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0423] i) X is O; Y is
CH.sub.2; [0424] ii) R.sup.1 is fluorine or hydrogen; [0425] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0426] iv) R.sup.2 is a phenyl moiety
optionally substituted with aminoalkyl in the meta position.
[0427] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0428] i) X is O; Y is
CH.sub.2; [0429] ii) R.sup.1 is fluorine or hydrogen; [0430] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0431] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkoxy in the meta position.
[0432] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0433] i) X is O; Y is
CH.sub.2; [0434] ii) R.sup.1 is fluorine or hydrogen; [0435] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0436] iv) R.sup.2 is a phenyl moiety
optionally substituted with thioalkyl in the meta position.
[0437] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0438] i) X is O; Y is
CH.sub.2; [0439] ii) R.sup.1 is fluorine or hydrogen; [0440] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0441] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkenyl in the meta position.
[0442] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0443] i) X is O; Y is
CH.sub.2; [0444] ii) R.sup.1 is fluorine or hydrogen; [0445] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0446] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkynyl in the meta position.
[0447] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0448] i) X is O; Y is
CH.sub.2; [0449] ii) R.sup.1 is fluorine or hydrogen; [0450] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0451] iv) R.sup.2 is a phenyl moiety
optionally substituted with aryl in the meta position.
[0452] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0453] i) X is O; Y is
CH.sub.2; [0454] ii) R.sup.1 is fluorine or hydrogen; [0455] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0456] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzyl in the meta position.
[0457] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0458] i) X is O; Y is
CH.sub.2; [0459] ii) R.sup.1 is fluorine or hydrogen; [0460] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0461] iv) R.sup.2 is a phenyl moiety
optionally substituted with thiophenyl in the meta position.
[0462] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0463] i) X is O; Y is
CH.sub.2; [0464] ii) R.sup.1 is fluorine or hydrogen; [0465] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0466] iv) R.sup.2 is a phenyl moiety
optionally substituted with furanyl in the meta position.
[0467] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0468] i) X is O; Y is
CH.sub.2; [0469] ii) R.sup.1 is fluorine or hydrogen; [0470] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0471] iv) R.sup.2 is a phenyl moiety
optionally substituted with naphthyl in the meta position.
[0472] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0473] i) X is O; Y is
CH.sub.2; [0474] ii) R.sup.1 is fluorine or hydrogen; [0475] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0476] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzoyl in the meta position.
[0477] In one embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0478] i) X is O; Y is CH.sub.2; [0479]
ii) R.sup.1 is fluorine or hydrogen; [0480] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0481] 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.
[0482] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [0483] i) X is O; Y is CH.sub.2; [0484]
ii) R.sup.1 is fluorine or hydrogen; [0485] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0486] iv) R.sup.2 is a phenyl moiety optionally
substituted with halogen (F, Cl, Br, I) in the para position.
[0487] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0488] i) X is O; Y is CH.sub.2;
[0489] ii) R.sup.1 is fluorine or hydrogen; [0490] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0491] iv) R.sup.2 is a phenyl moiety optionally
substituted with Br in the para position.
[0492] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0493] i) X is O; Y is CH.sub.2;
[0494] ii) R.sup.1 is fluorine or hydrogen; [0495] iii) R3 and R3'
are independently hydrogen or fluorine; R4 is hydrogen; and [0496]
iv) R.sup.2 is a phenyl moiety optionally substituted with I in the
para position.
[0497] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0498] i) X is O; Y is CH.sub.2;
[0499] ii) R.sup.1 is fluorine or hydrogen; [0500] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0501] iv) R.sup.2 is a phenyl moiety optionally
substituted with F in the para position.
[0502] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0503] i) X is O; Y is CH.sub.2;
[0504] ii) R.sup.1 is fluorine or hydrogen; [0505] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0506] iv) R.sup.2 is a phenyl moiety optionally
substituted with Cl in the para position.
[0507] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0508] i) X is O; Y is CH.sub.2;
[0509] ii) R.sup.1 is fluorine or hydrogen; [0510] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [0511] iv) R.sup.2 is a phenyl moiety optionally
substituted with NO.sub.2 in the para position.
[0512] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0513] i) X is O; Y is
CH.sub.2; [0514] ii) R.sup.1 is fluorine or hydrogen; [0515] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0516] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkyl in the para position.
[0517] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0518] i) X is O; Y is
CH.sub.2; [0519] ii) R.sup.1 is fluorine or hydrogen; [0520] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0521] iv) R.sup.2 is a phenyl moiety
optionally substituted with methyl in the para position.
[0522] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0523] i) X is O; Y is
CH.sub.2; [0524] ii) R.sup.1 is fluorine or hydrogen; [0525] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0526] iv) R.sup.2 is a phenyl moiety
optionally substituted with ethyl in the para position.
[0527] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0528] i) X is O; Y is
CH.sub.2; [0529] ii) R.sup.1 is fluorine or hydrogen; [0530] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0531] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-propyl in the para position.
[0532] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0533] i) X is O; Y is
CH.sub.2; [0534] ii) R.sup.1 is fluorine or hydrogen; [0535] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0536] iv) R.sup.2 is a phenyl moiety
optionally substituted with iso-propyl in the para position.
[0537] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0538] i) X is O; Y is
CH.sub.2; [0539] ii) R.sup.1 is fluorine or hydrogen; [0540] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0541] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-butyl in the para position.
[0542] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0543] i) X is O; Y is
CH.sub.2; [0544] ii) R.sup.1 is fluorine or hydrogen; [0545] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0546] iv) R.sup.2 is a phenyl moiety
optionally substituted with sec-butyl in the para position.
[0547] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0548] i) X is O; Y is
CH.sub.2; [0549] ii) R.sup.1 is fluorine or hydrogen; [0550] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0551] iv) R.sup.2 is a phenyl moiety
optionally substituted with tert-butyl in the para position.
[0552] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0553] i) X is O; Y is
CH.sub.2; [0554] ii) R.sup.1 is fluorine or hydrogen; [0555] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0556] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-pentyl in the para position.
[0557] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0558] i) X is O; Y is
CH.sub.2; [0559] ii) R.sup.1 is fluorine or hydrogen; [0560] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0561] iv) R.sup.2 is a phenyl moiety
optionally substituted with isopentyl in the para position.
[0562] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0563] i) X is O; Y is
CH.sub.2; [0564] ii) R.sup.1 is fluorine or hydrogen; [0565] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0566] iv) R.sup.2 is a phenyl moiety
optionally substituted with neopentyl in the para position.
[0567] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0568] i) X is O; Y is
CH.sub.2; [0569] ii) R.sup.1 is fluorine or hydrogen; [0570] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0571] iv) R.sup.2 is a phenyl moiety
optionally substituted with cyclopentyl in the para position.
[0572] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0573] i) X is O; Y is
CH.sub.2; [0574] ii) R.sup.1 is fluorine or hydrogen; [0575] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0576] iv) R.sup.2 is a phenyl moiety
optionally substituted with n-hexyl in the para position.
[0577] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0578] i) X is O; Y is
CH.sub.2; [0579] ii) R.sup.1 is fluorine or hydrogen; [0580] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0581] iv) R.sup.2 is a phenyl moiety
optionally substituted with a cyclohexyl in the para position.
[0582] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0583] i) X is O; Y is
CH.sub.2; [0584] ii) R.sup.1 fluorine or hydrogen; [0585] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0586] iv) R.sup.2 is a phenyl moiety
optionally substituted with CN in the para position.
[0587] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0588] i) X is O; Y is
CH.sub.2; [0589] ii) R.sup.1 is fluorine or hydrogen; [0590] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0591] iv) R.sup.2 is a phenyl moiety
optionally substituted with CF.sub.3 in the para position.
[0592] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0593] i) X is O; Y is
CH.sub.2; [0594] ii) R.sup.1 is fluorine or hydrogen; [0595] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0596] iv) R.sup.2 is a phenyl moiety
optionally substituted with N.sub.3 in the para position.
[0597] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0598] i) X is O; Y is
CH.sub.2; [0599] ii) R.sup.1 is fluorine or hydrogen; [0600] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0601] iv) R.sup.2 is a phenyl moiety
optionally substituted with haloalkyl in the para position.
[0602] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0603] i) X is O; Y is
CH.sub.2; [0604] ii) R.sup.1 is fluorine or hydrogen; [0605] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0606] iv) R.sup.2 is a phenyl moiety
optionally substituted with aminoalkyl in the para position.
[0607] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0608] i) X is O; Y is
CH.sub.2; [0609] ii) R.sup.1 is fluorine or hydrogen; [0610] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0611] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkoxy in the para position.
[0612] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0613] i) X is O; Y is
CH.sub.2; [0614] ii) R.sup.1 is fluorine or hydrogen; [0615] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0616] iv) R.sup.2 is a phenyl moiety
optionally substituted with thioalkyl in the para position.
[0617] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0618] i) X is O; Y is
CH.sub.2; [0619] ii) R.sup.1 is fluorine or hydrogen; [0620] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0621] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkenyl in the para position.
[0622] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0623] i) X is O; Y is
CH.sub.2; [0624] ii) R.sup.1 is fluorine or hydrogen; [0625] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0626] iv) R.sup.2 is a phenyl moiety
optionally substituted with alkynyl in the para position.
[0627] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0628] i) X is O; Y is
CH.sub.2; [0629] ii) R.sup.1 is fluorine or hydrogen; [0630] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0631] iv) R.sup.2 is a phenyl moiety
optionally substituted with aryl in the para position.
[0632] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0633] i) X is O; Y is
CH.sub.2; [0634] ii) R.sup.1 is fluorine or hydrogen; [0635] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0636] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzyl in the para position.
[0637] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0638] i) X is O; Y is
CH.sub.2; [0639] ii) R.sup.1 is fluorine or hydrogen; [0640] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0641] iv) R.sup.2 is a phenyl moiety
optionally substituted with thiophenyl in the para position.
[0642] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0643] i) X is O; Y is
CH.sub.2; [0644] ii) R.sup.1 is fluorine or hydrogen; [0645] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0646] iv) R.sup.2 is a phenyl moiety
optionally substituted with furanyl in the para position.
[0647] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0648] i) X is O; Y is
CH.sub.2; [0649] ii) R.sup.1 is fluorine or hydrogen; [0650] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0651] iv) R.sup.2 is a phenyl moiety
optionally substituted with naphthyl in the para position.
[0652] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0653] i) X is O; Y is
CH.sub.2; [0654] ii) R.sup.1 is fluorine or hydrogen; [0655] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0656] iv) R.sup.2 is a phenyl moiety
optionally substituted with benzoyl in the para position.
[0657] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0658] i) X is O; Y is
CH.sub.2; [0659] ii) R.sup.1 is fluorine or hydrogen; [0660] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0661] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3-dihalo.
[0662] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0663] i) X is O; Y is
CH.sub.2; [0664] ii) R.sup.1 is fluorine or hydrogen; [0665] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0666] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4-dihalo.
[0667] n yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0668] i) X is O; Y is
CH.sub.2; [0669] ii) R.sup.1 is fluorine or hydrogen; [0670] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0671] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5-dihalo.
[0672] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0673] i) X is O; Y is
CH.sub.2; [0674] ii) R.sup.1 is fluorine or hydrogen; [0675] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0676] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,6-dihalo.
[0677] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0678] i) X is O; Y is
CH.sub.2; [0679] ii) R.sup.1 is fluorine or hydrogen; [0680] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0681] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4-dihalo.
[0682] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0683] i) X is O; Y is
CH.sub.2; [0684] ii) R.sup.1 is fluorine or hydrogen; [0685] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0686] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,5-dihalo.
[0687] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0688] i) X is O; Y is
CH.sub.2; [0689] ii) R.sup.1 is fluorine or hydrogen; [0690] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0691] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4-trihalo.
[0692] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0693] i) X is O; Y is
CH.sub.2; [0694] ii) R.sup.1 is fluorine or hydrogen; [0695] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0696] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,5-trihalo.
[0697] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0698] i) X is O; Y is
CH.sub.2; [0699] ii) R.sup.1 is fluorine or hydrogen; [0700] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0701] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,5-trihalo.
[0702] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0703] i) X is O; Y is
CH.sub.2; [0704] ii) R.sup.1 is fluorine or hydrogen; [0705] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0706] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,6-trihalo.
[0707] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0708] i) X is O; Y is
CH.sub.2; [0709] ii) R.sup.1 is fluorine or hydrogen; [0710] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0711] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5,6-trihalo.
[0712] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0713] i) X is O; Y is
CH.sub.2; [0714] ii) R.sup.1 is fluorine or hydrogen; [0715] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0716] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4,5-trihalo.
[0717] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0718] i) X is O; Y is
CH.sub.2; [0719] ii) R.sup.1 is fluorine or hydrogen; [0720] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0721] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4,5-tetrahalo.
[0722] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0723] i) X is O; Y is
CH.sub.2; [0724] ii) R.sup.1 is fluorine or hydrogen; [0725] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0726] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4,5,6-pentahalo.
[0727] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0728] i) X is O; Y is
CH.sub.2; [0729] ii) R.sup.1 is fluorine or hydrogen; [0730] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0731] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3-dialkyl.
[0732] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0733] i) X is O; Y is
CH.sub.2; [0734] ii) R.sup.1 is fluorine or hydrogen; [0735] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0736] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4-dialkyl.
[0737] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0738] i) X is O; Y is
CH.sub.2; [0739] ii) R.sup.1 is fluorine or hydrogen; [0740] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0741] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5-dialkyl.
[0742] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0743] i) X is O; Y is
CH.sub.2; [0744] ii) R.sup.1 is fluorine or hydrogen; [0745] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0746] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,6-dialkyl.
[0747] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0748] i) X is O; Y is
CH.sub.2; [0749] iv) R.sup.1 is fluorine or hydrogen; [0750] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0751] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4-dialkyl.
[0752] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0753] i) X is O; Y is
CH.sub.2; [0754] ii) R.sup.1 is fluorine or hydrogen; [0755] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0756] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,5-dialkyl.
[0757] In yet another embodiment of the present invention, the
active compound is of formula (I), its Pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0758] i) X is O; Y is
CH.sub.2; [0759] ii) R.sup.1 is fluorine or hydrogen; [0760] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0761] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4-trialkyl.
[0762] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0763] i) X is O; Y is
CH.sub.2; [0764] ii) R.sup.1 is fluorine or hydrogen; [0765] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0766] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,5-trialkyl.
[0767] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0768] i) X is O; Y is
CH.sub.2; [0769] ii) R.sup.1 is fluorine or hydrogen; [0770] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0771] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,5-trialkyl.
[0772] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0773] i) X is O; Y is
CH.sub.2; [0774] ii) R.sup.1 is fluorine or hydrogen; [0775] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0776] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,6-trialkyl.
[0777] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0778] i) X is O; Y is
CH.sub.2; [0779] ii) R.sup.1 is fluorine or hydrogen; [0780] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0781] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5,6-trialkyl.
[0782] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0783] i) X is O; Y is
CH.sub.2; [0784] ii) R.sup.1 is fluorine or hydrogen; [0785] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0786] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4,5-trialkyl.
[0787] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0788] i) X is O; Y is
CH.sub.2; [0789] ii) R.sup.1 is fluorine or hydrogen; [0790] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0791] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4,5-tetraalkyl.
[0792] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0793] i) X is O; Y is
CH.sub.2; [0794] ii) R.sup.1 is fluorine or hydrogen; [0795] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0796] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4,5,6-pentaalkyl.
[0797] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0798] i) X is O; Y is
CH.sub.2; [0799] ii) R.sup.1 is fluorine or hydrogen; [0800] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0801] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3-di-NO.sub.2.
[0802] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0803] i) X is O; Y is
CH.sub.2; [0804] ii) R.sup.1 is fluorine or hydrogen; [0805] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0806] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4-di-NO.sub.2.
[0807] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0808] i) X is O; Y is
CH.sub.2; [0809] ii) R.sup.1 is fluorine or hydrogen; [0810] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0811] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5-di-NO.sub.2.
[0812] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0813] i) X is O; Y is
CH.sub.2; [0814] ii) R.sup.1 is fluorine or hydrogen; [0815] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0816] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,6-di-NO.sub.2.
[0817] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0818] i) X is O; Y is
CH.sub.2; [0819] ii) R.sup.1 is fluorine or hydrogen; [0820] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0821] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4-di-NO.sub.2.
[0822] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0823] i) X is O; Y is
CH.sub.2; [0824] ii) R.sup.1 is fluorine or hydrogen; [0825] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0826] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,5-di-NO.sub.2.
[0827] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0828] i) X is O; Y is
CH.sub.2; [0829] ii) R.sup.1 is fluorine or hydrogen; [0830] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0831] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,4-tri-NO.sub.2.
[0832] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0833] i) X is O; Y is
CH.sub.2; [0834] ii) R.sup.1 is fluorine or hydrogen; [0835] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0836] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,3,5-tri-NO.sub.2.
[0837] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0838] i) X is O; Y is
CH.sub.2; [0839] ii) R.sup.1 is fluorine or hydrogen; [0840] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0841] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,5-tri-NO.sub.2.
[0842] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0843] i) X is O; Y is
CH.sub.2; [0844] ii) R.sup.1 is fluorine or hydrogen; [0845] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0846] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,4,6-tri-NO.sub.2.
[0847] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0848] i) X is O; Y is
CH.sub.2; [0849] ii) R.sup.1 is fluorine or hydrogen; [0850] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0851] iv) R.sup.2 is a phenyl moiety
optionally substituted with 2,5,6-tri-NO.sub.2.
[0852] In yet another embodiment of the present invention, the
active compound is of formula (I), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0853] i) X is O; Y is
CH.sub.2; [0854] ii) R.sup.1 is fluorine or hydrogen; [0855] iii)
R.sup.3 and R.sup.3' are independently hydrogen or fluorine;
R.sup.4 is hydrogen; and [0856] iv) R.sup.2 is a phenyl moiety
optionally substituted with 3,4,5-tri-NO.sub.2.
[0857] In one embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [0858] i) X is O; [0859] ii) R.sup.1
is fluorine or hydrogen; [0860] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [0861]
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.
[0862] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [0863] i) X is O; [0864] ii) R.sup.1
is fluorine or hydrogen; [0865] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [0866]
iv) R.sup.2 is a phenyl moiety optionally substituted with halogen
(F, Cl, Br, I) in the ortho position.
[0867] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0868] i) X is O; [0869] ii)
R.sup.1 is fluorine or hydrogen; [0870] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0871] iv) R.sup.2 is a phenyl moiety optionally substituted with
Br in the ortho position.
[0872] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0873] i) X is O; [0874] ii)
R.sup.1 is fluorine or hydrogen; [0875] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0876] iv) R.sup.2 is a phenyl moiety optionally substituted with I
in the ortho position.
[0877] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0878] i) X is O; [0879] ii)
R.sup.1 is fluorine or hydrogen; [0880] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0881] iv) R.sup.2 is a phenyl moiety optionally substituted with F
in the ortho position.
[0882] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0883] i) X is O; [0884] ii)
R.sup.1 is fluorine or hydrogen; [0885] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0886] iv) R.sup.2 is a phenyl moiety optionally substituted with
Cl in the ortho position.
[0887] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [0888] i) X is O; [0889] ii)
R.sup.1 is fluorine or hydrogen; [0890] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0891] iv) R.sup.2 is a phenyl moiety optionally substituted with
NO.sub.2 in the ortho position.
[0892] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0893] i) X is O; [0894] ii)
R.sup.1 is fluorine or hydrogen; [0895] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0896] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkyl in the ortho position.
[0897] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0898] i) X is O; [0899] ii)
R.sup.1 is fluorine or hydrogen; [0900] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0901] iv) R.sup.2 is a phenyl moiety optionally substituted with
methyl in the ortho position.
[0902] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0903] i) X is O; [0904] ii)
R.sup.1 is fluorine or hydrogen; [0905] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0906] iv) R.sup.2 is a phenyl moiety optionally substituted with
ethyl in the ortho position.
[0907] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0908] i) X is O; [0909] ii)
R.sup.1 is fluorine or hydrogen; [0910] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0911] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-propyl in the ortho position.
[0912] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0913] i) X is O; [0914] ii)
R.sup.1 is fluorine or hydrogen; [0915] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0916] iv) R.sup.2 is a phenyl moiety optionally substituted with
iso-propyl in the ortho position.
[0917] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0918] i) X is O; [0919] ii)
R.sup.1 is fluorine or hydrogen; [0920] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0921] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-butyl in the ortho position.
[0922] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0923] i) X is O; [0924] ii)
R.sup.1 is fluorine or hydrogen; [0925] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0926] iv) R.sup.2 is a phenyl moiety optionally substituted with
sec-butyl in the ortho position.
[0927] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0928] i) X is O; [0929] ii)
R.sup.1 is fluorine or hydrogen; [0930] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0931] iv) R.sup.2 is a phenyl moiety optionally substituted with
tert-butyl in the ortho position.
[0932] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0933] i) X is O; [0934] ii)
R.sup.1 is fluorine or hydrogen; [0935] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0936] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-pentyl in the ortho position.
[0937] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0938] i) X is O; [0939] ii)
R.sup.1 is fluorine or hydrogen; [0940] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0941] iv) R.sup.2 is a phenyl moiety optionally substituted with
isopentyl in the ortho position.
[0942] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0943] i) X is O; [0944] ii)
R.sup.1 is fluorine or hydrogen; [0945] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0946] iv) R.sup.2 is a phenyl moiety optionally substituted with
neopentyl in the ortho position.
[0947] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0948] i) X is O; [0949] ii)
R.sup.1 is fluorine or hydrogen; [0950] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0951] iv) R.sup.2 is a phenyl moiety optionally substituted with
cyclopentyl in the ortho position.
[0952] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0953] i) X is O; [0954] ii)
R.sup.1 is fluorine or hydrogen; [0955] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0956] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-hexyl in the ortho position.
[0957] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0958] i) X is O; [0959] ii)
R.sup.1 is fluorine or hydrogen; [0960] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0961] iv) R.sup.2 is a phenyl moiety optionally substituted with a
cyclohexyl in the ortho position.
[0962] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0963] i) X is O; [0964] ii)
R.sup.1 is fluorine or hydrogen; [0965] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0966] iv) R.sup.2 is a phenyl moiety optionally substituted with
CN in the ortho position.
[0967] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0968] i) X is O; [0969] ii)
R.sup.1 is fluorine or hydrogen; [0970] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0971] iv) R.sup.2 is a phenyl moiety optionally substituted with
CF.sub.3 in the ortho position.
[0972] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0973] i) X is O; [0974] ii)
R.sup.1 is fluorine or hydrogen; [0975] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0976] iv) R.sup.2 is a phenyl moiety optionally substituted with
N.sub.3 in the ortho position.
[0977] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0978] i) X is O; [0979] ii)
R.sup.1 is fluorine or hydrogen; [0980] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0981] iv) R.sup.2 is a phenyl moiety optionally substituted with
haloalkyl in the ortho position.
[0982] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0983] i) X is O; [0984] ii)
R.sup.1 is fluorine or hydrogen; [0985] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0986] iv) R.sup.2 is a phenyl moiety optionally substituted with
aminoalkyl in the ortho position.
[0987] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0988] i) X is O; [0989] ii)
R.sup.1 is fluorine or hydrogen; [0990] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0991] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkoxy in the ortho position.
[0992] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0993] i) X is O; [0994] ii)
R.sup.1 is fluorine or hydrogen; [0995] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[0996] iv) R.sup.2 is a phenyl moiety optionally substituted with
thioalkyl in the ortho position.
[0997] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [0998] i) X is O; [0999] ii)
R.sup.1 is fluorine or hydrogen; [1000] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1001] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkenyl in the ortho position.
[1002] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1003] i) X is O; [1004] ii)
R.sup.1 is fluorine or hydrogen; [1005] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1006] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkynyl in the ortho position.
[1007] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1008] i) X is O; [1009] ii)
R.sup.1 is fluorine or hydrogen; [1010] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1011] iv) R.sup.2 is a phenyl moiety optionally substituted with
aryl in the ortho position.
[1012] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1013] i) X is O; [1014] ii)
R.sup.1 is fluorine or hydrogen; [1015] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1016] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzyl in the ortho position.
[1017] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1018] i) X is O; [1019] ii)
R.sup.1 is fluorine or hydrogen; [1020] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1021] iv) R.sup.2 is a phenyl moiety optionally substituted with
thiophenyl in the ortho position.
[1022] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1023] i) X is O; [1024] ii)
R.sup.1 is fluorine or hydrogen; [1025] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1026] iv) R.sup.2 is a phenyl moiety optionally substituted with
furanyl in the ortho position.
[1027] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1028] i) X is O; [1029] ii)
R.sup.1 is fluorine or hydrogen; [1030] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1031] iv) R.sup.2 is a phenyl moiety optionally substituted with
naphthyl in the ortho position.
[1032] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1033] i) X is O; [1034] ii)
R.sup.1 is fluorine or hydrogen; [1035] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1036] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzoyl in the ortho position.
[1037] In one embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1038] i) X is O; [1039] ii) R.sup.1
is fluorine or hydrogen; [1040] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1041]
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.
[1042] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1043] i) X is O; [1044] ii) R.sup.1
is fluorine or hydrogen; [1045] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1046]
iv) R.sup.2 is a phenyl moiety optionally substituted with halogen
(F, Cl, Br, I) in the meta position.
[1047] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1048] i) X is O; [1049] ii)
R.sup.1 is fluorine or hydrogen; [1050] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1051] iv) R.sup.2 is a phenyl moiety optionally substituted with
Br in the meta position.
[1052] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1053] i) X is O; [1054] ii)
R.sup.1 is fluorine or hydrogen; [1055] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1056] iv) R.sup.2 is a phenyl moiety optionally substituted with I
in the meta position.
[1057] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1058] i) X is O; [1059] ii)
R.sup.1 is fluorine or hydrogen; [1060] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1061] iv) R.sup.2 is a phenyl moiety optionally substituted with F
in the meta position.
[1062] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1063] i) X is O; [1064] ii)
R.sup.1 is fluorine or hydrogen; [1065] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1066] iv) R.sup.2 is a phenyl moiety optionally substituted with
Cl in the meta position.
[1067] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1068] i) X is O; [1069] ii)
R.sup.1 is fluorine or hydrogen; [1070] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1071] iv) R.sup.2 is a phenyl moiety optionally substituted with
NO.sub.2 in the meta position.
[1072] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1073] i) X is O; [1074] ii)
R.sup.1 is fluorine or hydrogen; [1075] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1076] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkyl in the meta position.
[1077] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1078] i) X is O; [1079] ii)
R.sup.1 is fluorine or hydrogen; [1080] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1081] iv) R.sup.2 is a phenyl moiety optionally substituted with
methyl in the meta position.
[1082] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1083] i) X is O; [1084] ii)
R.sup.1 is fluorine or hydrogen; [1085] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1086] iv) R.sup.2 is a phenyl moiety optionally substituted with
ethyl in the meta position.
[1087] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1088] i) X is O; [1089] ii)
R.sup.1 is fluorine or hydrogen; [1090] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1091] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-propyl in the meta position.
[1092] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1093] i) X is O; [1094] ii)
R.sup.1 is fluorine or hydrogen; [1095] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1096] iv) R.sup.2 is a phenyl moiety optionally substituted with
iso-propyl in the meta position.
[1097] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1098] i) X is O; [1099] ii)
R.sup.1 is fluorine or hydrogen; [1100] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1101] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-butyl in the meta position.
[1102] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1103] i) X is O; [1104] ii)
R.sup.1 is fluorine or hydrogen; [1105] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1106] iv) R.sup.2 is a phenyl moiety optionally substituted with
sec-butyl in the meta position.
[1107] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1108] i) X is O; [1109] ii)
R.sup.1 is fluorine or hydrogen; [1110] iii) R.sup.3 and R.sup.3
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1111] iv) R.sup.2 is a phenyl moiety optionally substituted with
tert-butyl in the meta position.
[1112] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1113] i) X is O; [1114] ii)
R.sup.1 is fluorine or hydrogen; [1115] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1116] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-pentyl in the meta position.
[1117] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1118] i) X is O; [1119] ii)
R.sup.1 is fluorine or hydrogen; [1120] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1121] iv) R.sup.2 is a phenyl moiety optionally substituted with
isopentyl in the meta position.
[1122] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1123] i) X is O; [1124] ii)
R.sup.1 is fluorine or hydrogen; [1125] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1126] iv) R.sup.2 is a phenyl moiety optionally substituted with
neopentyl in the meta position.
[1127] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1128] i) X is O; [1129] ii)
R.sup.1 is fluorine or hydrogen; [1130] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1131] iv) R.sup.2 is a phenyl moiety optionally substituted with
cyclopentyl in the meta position.
[1132] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1133] i) X is O; [1134] ii)
R.sup.1 is fluorine or hydrogen; [1135] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1136] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-hexyl in the meta position.
[1137] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1138] i) X is O; [1139] ii)
R.sup.1 is fluorine or hydrogen; [1140] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1141] iv) R.sup.2 is a phenyl moiety optionally substituted with a
cyclohexyl in the meta position.
[1142] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1143] i) X is O; [1144] ii)
R.sup.1 is fluorine or hydrogen; [1145] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1146] iv) R.sup.2 is a phenyl moiety optionally substituted with
CN in the meta position.
[1147] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1148] i) X is O; [1149] ii)
R.sup.1 is fluorine or hydrogen; [1150] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1151] iv) R.sup.2 is a phenyl moiety optionally substituted with
CF.sub.3 in the meta position.
[1152] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1153] i) X is O; [1154] ii)
R.sup.1 is fluorine or hydrogen; [1155] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1156] iv) R.sup.2 is a phenyl moiety optionally substituted with
N.sub.3 in the meta position.
[1157] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1158] i) X is O; [1159] ii)
R.sup.1 is fluorine or hydrogen; [1160] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1161] iv) R.sup.2 is a phenyl moiety optionally substituted with
haloalkyl in the meta position.
[1162] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1163] i) X is O; [1164] ii)
R.sup.1 is fluorine or hydrogen; [1165] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1166] iv) R.sup.2 is a phenyl moiety optionally substituted with
aminoalkyl in the meta position.
[1167] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1168] i) X is O; [1169] ii)
R.sup.1 is fluorine or hydrogen; [1170] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1171] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkoxy in the meta position.
[1172] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1173] i) X is O; [1174] ii)
R.sup.1 is fluorine or hydrogen; [1175] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1176] iv) R.sup.2 is a phenyl moiety optionally substituted with
thioalkyl in the meta position.
[1177] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1178] i) X is O; [1179] ii)
R.sup.1 is fluorine or hydrogen; [1180] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1181] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkenyl in the meta position.
[1182] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1183] i) X is O; [1184] ii)
R.sup.1 is fluorine or hydrogen; [1185] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1186] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkynyl in the meta position.
[1187] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1188] i) X is O; [1189] ii)
R.sup.1 is fluorine or hydrogen; [1190] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1191] iv) R.sup.2 is a phenyl moiety optionally substituted with
aryl in the meta position.
[1192] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1193] i) X is O; [1194] ii)
R.sup.1 is fluorine or hydrogen; [1195] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1196] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzyl in the meta position.
[1197] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1198] i) X is O; [1199] ii)
R.sup.1 is fluorine or hydrogen; [1200] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1201] iv) R.sup.2 is a phenyl moiety optionally substituted with
thiophenyl in the meta position.
[1202] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1203] i) X is O; [1204] ii)
R.sup.1 is fluorine or hydrogen; [1205] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1206] iv) R.sup.2 is a phenyl moiety optionally substituted with
furanyl in the meta position.
[1207] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1208] i) X is O; [1209] ii)
R.sup.1 is fluorine or hydrogen; [1210] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1211] iv) R.sup.2 is a phenyl moiety optionally substituted with
naphthyl in the meta position.
[1212] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1213] i) X is O; [1214] ii)
R.sup.1 is fluorine or hydrogen; [1215] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1216] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzoyl in the meta position.
[1217] In one embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1218] i) X is O; [1219] ii) R.sup.1
is fluorine or hydrogen; [1220] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1221]
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.
[1222] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1223] i) X is O; [1224] ii) R.sup.1
is fluorine pr hydrogen; [1225] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1226]
iv) R.sup.2 is a phenyl moiety optionally substituted with halogen
(F, Cl, Br, I) in the para position.
[1227] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1228] i) X is O; [1229] ii)
R.sup.1 is fluorine or hydrogen; [1230] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1231] iv) R.sup.2 is a phenyl moiety optionally substituted with
Br in the para position.
[1232] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1233] i) X is O; [1234] ii)
R.sup.1 is fluorine or hydrogen; [1235] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1236] iv) R.sup.2 is a phenyl moiety optionally substituted with I
in the para position.
[1237] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1238] i) X is O; [1239] ii)
R.sup.1 is fluorine or hydrogen; [1240] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1241] iv) R.sup.2 is a phenyl moiety optionally substituted with F
in the para position.
[1242] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1243] i) X is O; [1244] ii)
R.sup.1 is fluorine or hydrogen; [1245] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1246] iv) R.sup.2 is a phenyl moiety optionally substituted with
Cl in the para position.
[1247] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salt or prodrugs thereof, wherein: [1248] i) X is O; [1249] ii)
R.sup.1 is fluorine or hydrogen; [1250] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1251] iv) R.sup.2 is a phenyl moiety optionally substituted with
NO.sub.2 in the para position.
[1252] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1253] i) X is O; [1254] ii)
R.sup.1 is fluorine or hydrogen; [1255] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1256] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkyl in the para position.
[1257] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1258] X is O; [1259] ii)
R.sup.1 is fluorine or hydrogen; [1260] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1261] iv) R.sup.2 is a phenyl moiety optionally substituted with
methyl in the para position.
[1262] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1263] i) X is O; [1264] ii)
R.sup.1 is fluorine or hydrogen; [1265] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1266] iv) R.sup.2 is a phenyl moiety optionally substituted with
ethyl in the para position.
[1267] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1268] i) X is O; [1269] ii)
R.sup.1 is fluorine or hydrogen; [1270] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1271] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-propyl in the para position.
[1272] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1273] i) X is O; [1274] ii)
R.sup.1 is fluorine or hydrogen; [1275] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1276] iv) R.sup.2 is a phenyl moiety optionally substituted with
iso-propyl in the para position.
[1277] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1278] i) X is O; [1279] ii)
R.sup.1 is fluorine or hydrogen; [1280] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1281] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-butyl in the para position.
[1282] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1283] i) X is O; [1284] ii)
R.sup.1 is fluorine or hydrogen; [1285] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1286] iv) R.sup.2 is a phenyl moiety optionally substituted with
sec-butyl in the para position.
[1287] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1288] i) X is O; [1289] ii)
R.sup.1 is fluorine or hydrogen; [1290] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1291] iv) R.sup.2 is a phenyl moiety optionally substituted with
tert-butyl in the para position.
[1292] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1293] i) X is O; [1294] ii)
R.sup.1 is fluorine or hydrogen; [1295] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1296] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-pentyl in the para position.
[1297] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1298] i) X is O; [1299] ii)
R.sup.1 is fluorine or hydrogen; [1300] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1301] iv) R.sup.2 is a phenyl moiety optionally substituted with
isopentyl in the para position.
[1302] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1303] i) X is O; [1304] ii)
R.sup.1 is fluorine or hydrogen; [1305] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1306] iv) R.sup.2 is a phenyl moiety optionally substituted with
neopentyl in the para position.
[1307] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1308] i) X is O; [1309] ii)
R.sup.1 is fluorine or hydrogen; [1310] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1311] iv) R.sup.2 is a phenyl moiety optionally substituted with
cyclopentyl in the para position.
[1312] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1313] i) X is O; [1314] ii)
R.sup.1 is fluorine or hydrogen; [1315] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1316] iv) R.sup.2 is a phenyl moiety optionally substituted with
n-hexyl in the para position.
[1317] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1318] i) X is O; [1319] ii)
R.sup.1 is fluorine or hydrogen; [1320] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1321] iv) R.sup.2 is a phenyl moiety optionally substituted with a
cyclohexyl in the para position.
[1322] In yet another embodiment of the present invention, the
active compound is of formula (H), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1323] i) X is O; [1324] ii)
R.sup.1 is fluorine or hydrogen; [1325] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1326] iv) R.sup.2 is a phenyl moiety optionally substituted with
CN in the para position.
[1327] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1328] i) X is O; [1329] ii)
R.sup.1 is fluorine or hydrogen; [1330] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1331] iv) R.sup.2 is a phenyl moiety optionally substituted with
CF.sub.3 in the para position.
[1332] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1333] i) X is O; [1334] ii)
R.sup.1 is fluorine or hydrogen; [1335] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1336] iv) R.sup.2 is a phenyl moiety optionally substituted with
N.sub.3 in the para position.
[1337] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1338] i) X is O; [1339] ii)
R.sup.1 is fluorine or hydrogen; [1340] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1341] iv) R.sup.2 is a phenyl moiety optionally substituted with
haloalkyl in the para position.
[1342] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1343] i) X is O; [1344] ii)
R.sup.1 is fluorine or hydrogen; [1345] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1346] iv) R.sup.2 is a phenyl moiety optionally substituted with
aminoalkyl in the para position.
[1347] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1348] i) X is O; [1349] ii)
R.sup.1 is fluorine or hydrogen; [1350] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1351] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkoxy in the para position.
[1352] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1353] i) X is O; [1354] ii)
R.sup.1 is fluorine or hydrogen; [1355] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1356] iv) R.sup.2 is a phenyl moiety optionally substituted with
thioalkyl in the para position.
[1357] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1358] i) X is O; [1359] ii)
R.sup.1 is fluorine or hydrogen; [1360] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1361] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkenyl in the para position.
[1362] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1363] i) X is O; [1364] ii)
R.sup.1 is fluorine or hydrogen; [1365] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1366] iv) R.sup.2 is a phenyl moiety optionally substituted with
alkynyl in the para position.
[1367] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1368] i) X is O; [1369] ii)
R.sup.1 is fluorine or hydrogen; [1370] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1371] iv) R.sup.2 is a phenyl, moiety optionally substituted with
aryl in the para position.
[1372] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1373] i) X is O; [1374] ii)
R.sup.1 is fluorine or hydrogen; [1375] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1376] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzyl in the para position.
[1377] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1378] i) X is O; [1379] ii)
R.sup.1 is fluorine or hydrogen; [1380] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1381] iv) R.sup.2 is a phenyl moiety optionally substituted with
thiophenyl in the para position.
[1382] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1383] i) X is O; [1384] ii)
R.sup.1 is fluorine or hydrogen; [1385] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1386] iv) R.sup.2 is a phenyl moiety optionally substituted with
furanyl in the para position.
[1387] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1388] i) X is O; [1389] ii)
R.sup.1 is fluorine or hydrogen; [1390] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1391] iv) R.sup.2 is a phenyl moiety optionally substituted with
naphthyl in the para position.
[1392] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1393] i) X is O; [1394] ii)
R.sup.1 is fluorine or hydrogen; [1395] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1396] iv) R.sup.2 is a phenyl moiety optionally substituted with
benzoyl in the para position.
[1397] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1398] i) X is O; [1399] ii)
R.sup.1 is fluorine or hydrogen; [1400] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1401] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3-dihalo.
[1402] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1403] i) X is O; [1404] ii)
R.sup.1 is fluorine or hydrogen; [1405] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1406] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4-dihalo.
[1407] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1408] i) X is O; [1409] ii)
R.sup.1 is fluorine or hydrogen; [1410] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1411] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5-dihalo.
[1412] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1413] i) X is O; [1414] ii)
R.sup.1 is fluorine or hydrogen; [1415] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1416] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,6-dihalo.
[1417] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1418] i) X is O; [1419] ii)
R.sup.1 is fluorine or hydrogen; [1420] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1421] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4-dihalo.
[1422] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1423] i) X is O; [1424] ii)
R.sup.1 is fluorine or hydrogen; [1425] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1426] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,5-dihalo.
[1427] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1428] i) X is O; [1429] ii)
R.sup.1 is fluorine or hydrogen; [1430] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1431] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4-trihalo.
[1432] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1433] i) X is O; [1434] ii)
R.sup.1 is fluorine or hydrogen; [1435] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1436] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,5-trihalo.
[1437] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1438] i) X is O; [1439] ii)
R.sup.1 is fluorine or hydrogen; [1440] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1441] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4,5-trihalo.
[1442] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1443] i) X is O; [1444] ii)
R.sup.1 is fluorine or hydrogen; [1445] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1446] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4,6-trihalo.
[1447] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1448] i) X is O; [1449] ii)
R.sup.1 is fluorine or hydrogen; [1450] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1451] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5,6-trihalo.
[1452] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1453] i) X is O; [1454] ii)
R.sup.1 is fluorine or hydrogen; [1455] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1456] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4,5-trihalo.
[1457] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1458] i) X is O; [1459] ii)
R.sup.1 is fluorine or hydrogen; [1460] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1461] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4,5-tetrahalo.
[1462] In yet another embodiment of the present invention, the
active compound is of formula (H), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1463] i) X is O; [1464] ii)
R.sup.1 is fluorine or hydrogen; [1465] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1466] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4,5,6-pentahalo.
[1467] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1468] i) X is O; [1469] ii)
R.sup.1 is fluorine or hydrogen; [1470] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1471] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3-dialkyl.
[1472] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1473] i) X is O; [1474] ii)
R.sup.1 is fluorine or hydrogen; [1475] iii) R.sup.3 and R.sup.3
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1476] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4- dialkyl.
[1477] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1478] i) X is O; [1479] ii)
R.sup.1 is fluorine or hydrogen; [1480] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1481] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5- dialkyl.
[1482] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1483] i) X is O; [1484] ii)
R.sup.1 is fluorine or hydrogen; [1485] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen;
and
[1486] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,6- dialkyl.
[1487] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1488] i) X is O; [1489] ii)
R.sup.1 is fluorine or hydrogen; [1490] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1491] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4- dialkyl.
[1492] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1493] i) X is O; [1494] ii)
R.sup.1 is fluorine or hydrogen; [1495] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1496] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,5- dialkyl.
[1497] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1498] i) X is O; [1499] ii)
R.sup.1 is fluorine or hydrogen; [1500] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1501] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4-trialkyl.
[1502] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1503] i) X is O; [1504] ii)
R.sup.1 is fluorine or hydrogen; [1505] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1506] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,5-trialkyl.
[1507] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1508] i) X is O; [1509] ii)
R.sup.1 is fluorine or hydrogen; [1510] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1511] iv) R.sup.2 is a phenyl, moiety optionally substituted with
2,4,5-trialkyl.
[1512] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1513] i) X is O; [1514] ii)
R.sup.1 is fluorine or hydrogen; [1515] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1516] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4,6-trialkyl.
[1517] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1518] i) X is O; [1519] ii)
R.sup.1 is fluorine or hydrogen; [1520] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1521] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5,6-trialkyl.
[1522] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1523] i) X is O; [1524] ii)
R.sup.1 is fluorine or hydrogen; [1525] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1526] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4,5-trialkyl.
[1527] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1528] i) X is O; [1529] ii)
R.sup.1 is fluorine or hydrogen; [1530] iii) R.sup.3 and
R.sup.3'are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1531] iv) R.sup.2 is a phenyl moiety optionally
substituted with 2,3,4,5-tetraalkyl.
[1532] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1533] i) X is O; [1534] ii)
R.sup.1 is fluorine or hydrogen; [1535] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1536] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4,5,6-pentaalkyl.
[1537] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1538] i) X is O; [1539] ii)
R.sup.1 is fluorine or hydrogen; [1540] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1541] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3-di-NO.sub.2.
[1542] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1543] i) X is O; [1544] ii)
R.sup.1 is fluorine or hydrogen; [1545] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1546] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4- di-NO.sub.2.
[1547] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1548] i) X is O; [1549] ii)
R.sup.1 is fluorine or hydrogen; [1550] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1551] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5- di-NO.sub.2.
[1552] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1553] i) X is O; [1554] ii)
R.sup.1 is fluorine or hydrogen; [1555] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1556] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,6- di-NO.sub.2.
[1557] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1558] i) X is O; [1559] ii)
R.sup.1 is fluorine or hydrogen; [1560] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1561] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4- di-NO.sub.2.
[1562] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1563] i) X is O; [1564] ii)
R.sup.1 is fluorine or hydrogen; [1565] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1566] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,5- di-NO.sub.2.
[1567] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1568] i) X is O; [1569] ii)
R.sup.1 is fluorine or hydrogen; [1570] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1571] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,4-tri-NO.sub.2.
[1572] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1573] i) X is O; [1574] ii)
R.sup.1 is fluorine or hydrogen; [1575] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1576] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,3,5-tri-NO.sub.2.
[1577] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1578] i) X is O; [1579] ii)
R.sup.1 is fluorine or hydrogen; [1580] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and d
[1581] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4,5-tri-NO.sub.2.
[1582] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1583] i) X is O; [1584] ii)
R.sup.1 is fluorine or hydrogen; [1585] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1586] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,4,6-tri-NO.sub.2.
[1587] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1588] i) X is O; [1589] ii)
R.sup.1 is fluorine or hydrogen; [1590] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1591] iv) R.sup.2 is a phenyl moiety optionally substituted with
2,5,6-tri-NO.sub.2.
[1592] In yet another embodiment of the present invention, the
active compound is of formula (II), its pharmaceutically acceptable
salts or prodrugs thereof, wherein: [1593] i) X is O; [1594] ii)
R.sup.1 is fluorine or hydrogen; [1595] iii) R.sup.3 and R.sup.3'
are independently hydrogen or fluorine; R.sup.4 is hydrogen; and
[1596] iv) R.sup.2 is a phenyl moiety optionally substituted with
3,4,5-tri-NO.sub.2.
[1597] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1598] i) X is O; Y is CH.sub.2; [1599]
ii) R.sup.1 is fluorine or hydrogen; [1600] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1601] 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.
[1602] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1603] i) X is O; Y is CH.sub.2; [1604]
ii) R.sup.1 is fluorine or hydrogen; [1605] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1606] 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.
[1607] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1608] i) X is O; Y is CH.sub.2; [1609]
ii) R.sup.1 is fluorine or hydrogen; [1610] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1611] 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.
[1612] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1613] i) X is O; Y is CH.sub.2; [1614]
ii) R.sup.1 is fluorine or hydrogen; [1615] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1616] 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.
[1617] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1618] i) X is O; Y is CH.sub.2; [1619]
ii) R.sup.1 is fluorine or hydrogen; [1620] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1621] 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.
[1622] In another embodiment of the present invention, the active
compound is of formula (I), its pharmaceutically acceptable salt or
prodrugs thereof, wherein: [1623] i) X is O; Y is CH.sub.2; [1624]
ii) R.sup.1 is fluorine or hydrogen; [1625] iii) R.sup.3 and
R.sup.3' are independently hydrogen or fluorine; R.sup.4 is
hydrogen; and [1626] 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.
[1627] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1628] i) X is O; [1629] ii) R.sup.1
is fluorine or hydrogen; [1630] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1631]
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 or 3
position.
[1632] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1633] i) X is O; [1634] ii) R.sup.1
is fluorine or hydrogen; [1635] iii) R.sup.3 and R.sup.3'
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1636]
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 4-position.
[1637] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1638] i) X is O; [1639] ii) R.sup.1
is fluorine or hydrogen; [1640] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1641]
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.
[1642] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1643] i) X is O; [1644] ii) R.sup.1
is fluorine or hydrogen; [1645] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1646]
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.
[1647] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1648] i) X is O; [1649] ii) R.sup.1
is fluorine or hydrogen; [1650] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1651]
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.
[1652] In another embodiment of the present invention, the active
compound is of formula (II), its pharmaceutically acceptable salt
or prodrugs thereof, wherein: [1653] i) X is O; [1654] ii) R.sup.1
is fluorine or hydrogen; [1655] iii) R.sup.3 and R.sup.3' are
independently hydrogen or fluorine; R.sup.4 is hydrogen; and [1656]
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.
[1657] In one preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(4-iodobenzoyl)cytidine of
the structure:
##STR00003##
or a pharmaceutically acceptable salt or prodrug thereof.
[1658] In another preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine
of the structure:
##STR00004##
or a pharmaceutically acceptable salt or prodrug thereof.
[1659] In still another preferred embodiment, the active compound
is
.beta.-D-N.sup.4-(4-chlorobenzoyl)-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00005##
or a pharmaceutically acceptable salt or prodrug thereof.
[1660] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-bromobenzoyl)-2',3'-dideoxy-5-fluorocytidine of
the structure:
##STR00006##
or a pharmaceutically acceptable salt or prodrug thereof.
[1661] In another preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(3-fluorobenzoyl)cytidine
of the structure:
##STR00007##
or a pharmaceutically acceptable salt or prodrug thereof.
[1662] In still another preferred embodiment, the active compound
is
.beta.-D-N.sup.4-(3-chlorobenzoyl)-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00008##
or a pharmaceutically acceptable salt or prodrug thereof.
[1663] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(3-bromobenzoyl)-2',3'-dideoxy-5-fluorocytidine of
the structure:
##STR00009##
or a pharmaceutically acceptable salt or prodrug thereof.
[1664] In another preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(4-nitrobenzoyl)cytidine of
the structure:
##STR00010##
or a pharmaceutically acceptable salt or prodrug thereof.
[1665] In still another preferred embodiment, the active compound
is .beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-p-toluoylcytidine of the
structure:
##STR00011##
or a pharmaceutically acceptable salt or prodrug thereof.
[1666] In one preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(m-toluoyl)cytidine of the
structure:
##STR00012##
or a pharmaceutically acceptable salt or prodrug thereof.
[1667] In another preferred embodiment, the active compound is
.beta.-D-2',3'-dideoxy-N.sup.4-(4-ethylbenzoyl)-5-fluorocytidine of
the structure:
##STR00013##
or a pharmaceutically acceptable salt or prodrug thereof.
[1668] In still another preferred embodiment, the active compound
is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(4-propylbenzoyl)cytidine
of the structure:
##STR00014##
or a pharmaceutically acceptable salt or prodrug thereof.
[1669] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-tert-butylbenzoyl)-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00015##
or a pharmaceutically acceptable salt or prodrug thereof.
[1670] In still another preferred embodiment, the active compound
is
.beta.-D-2',3'-dideoxy-5-fluoro-N.sup.4-(2-thiophenecarbonyl)cytidine
of the structure:
##STR00016##
or a pharmaceutically acceptable salt or prodrug thereof.
[1671] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(benzo-[b]-thiophene-2-carbonyl)-2'3'-dideoxy-5-fluorocy-
tidine of the structure:
##STR00017##
or a pharmaceutically acceptable salt or prodrug thereof.
[1672] In another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(cyclohexane-carbonyl)-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00018##
or a pharmaceutically acceptable salt or prodrug thereof.
[1673] In still another preferred embodiment, the active compound
is
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(4-iodobenzoyl)cy-
tidine of the structure:
##STR00019##
or a pharmaceutically acceptable salt or prodrug thereof.
[1674] In one preferred embodiment, the active compound is
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(4-fluorobenzoyl)-
cytidine of the structure:
##STR00020##
or a pharmaceutically acceptable salt or prodrug thereof.
[1675] In another preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-chlorobenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluoro-
cytidine of the structure:
##STR00021##
or a pharmaceutically acceptable salt or prodrug thereof.
[1676] In still another preferred embodiment, the active compound
is
.beta.-D-N.sup.4-(4-bromobenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluoroc-
ytidine of the structure:
##STR00022##
or a pharmaceutically acceptable salt or prodrug thereof.
[1677] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-p-anisoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00023##
or a pharmaceutically acceptable salt or prodrug thereof.
[1678] In still another preferred embodiment, the active compound
is
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(3-nitrobenzoyl)c-
ytidine of the structure:
##STR00024##
or a pharmaceutically acceptable salt or prodrug thereof.
[1679] In one preferred embodiment, the active compound is
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-p-toluoylcytidine
of the structure:
##STR00025##
or a pharmaceutically acceptable salt or prodrug thereof.
[1680] In another preferred embodiment, the active compound is
.beta.-D-2',3'-didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-m-toluoylcytidine
of the structure:
##STR00026##
or a pharmaceutically acceptable salt or prodrug thereof.
[1681] In one preferred embodiment, the active compound is
.beta.-D-N.sup.4-(4-t-butylbenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluor-
ocytidine of the structure:
##STR00027##
or a pharmaceutically acceptable salt or prodrug thereof.
[1682] In still another preferred embodiment, the active compound
is
.beta.-D-N.sup.4-cyclopentanecarbonyl-2',3'-didehydro-2',3'-dideoxy-5-flu-
orocytidine of the structure:
##STR00028##
or a pharmaceutically acceptable salt or prodrug thereof.
[1683] In one preferred embodiment, the active compound is
(cyclohexanecarbonyl)-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
of the structure:
##STR00029##
or a pharmaceutically acceptable salt or prodrug thereof.
II. Stereoisomerism and Polymorphism
[1684] 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.
[1685] Examples of methods to obtain optically active materials
include at least the following. [1686] 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;
[1687] 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; [1688] 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;
[1689] 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; [1690] 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; [1691] 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; [1692] 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; [1693]
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; [1694] 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; [1695] 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; [1696] 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; [1697] 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; [1698] 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.
[1699] 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
[1700] 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.
[1701] 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.
[1702] 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.
[1703] 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
[1704] In the text, whenever the term C(alkyl range) is used, the
term independently includes each member of that class as if
specifically and separately set out. As a nonlimiting example, the
term "C.sub.1-22" independently represents each species that falls
within the scope. 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
dimethylcyclopropane, 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.2.6,0.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-sopropyl-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,1-cis-1-ethyl-3-methylcyclohexane, d,1-2,5-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(.alpha.-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,1-pinane,
2,3,3,4-tetramethylhexane, 3,3-dimethyl-4-ethylhexane,
5-methylnonane, 4-methylnonane, 3-ethyl-2-methylheptane,
3,4-dimethyloctane, d-.alpha.-pinane,
d,1-1-isopropyl-3-methylcyclohexane(d,1-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, pentadecycicyclopentane,
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,1-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,
norbomane(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".
[1705] 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.
[1706] 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.
[1707] The term "alkylamino" or "arylamino" refers to an amino
group that has one or two alkyl or aryl substituents,
respectively.
[1708] 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.
[1709] 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-isopropyl-methylbenzene(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-isobutyltoluene),
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,1-2-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-tent-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-teri-butyl-1,3-dimethylbenzene, 1,4-di-isopropylbenzene,
1,2-dimethyl-3-propylbenzene, 1-tert-butyl-4-ethylbenzene,
d,I-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-dimethyl-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-d
imethyl-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 -diphenyl
ethane, 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-butyl naphthalene, 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-isopropyiphenanthrene, 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,
1,4,5,74etramethylnaphthalene, 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,
sym-diphenylacetylene, 9-ethylphenanthrene,
1,4,5-trimethylnaphthalene, 4-methyl fluorene,
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, ethyl idenefluorene, 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-1,2-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-methyl naphthanthracene,
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-dimethylehrysene,
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-tertrabenzanthracene, 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, hydrozine,
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.
[1710] The term "halo," as used herein, includes chloro, bromo,
iodo and fluoro.
[1711] 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.
[1712] 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.
[1713] 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.
[1714] The term "heteroatom," as used herein, refers to oxygen,
sulfur, nitrogen and phosphorus.
[1715] 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.
[1716] 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.
[1717] 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.
[1718] 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).
[1719] 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.
[1720] 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
.alpha.-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
[1721] 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.
[1722] 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.
[1723] 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.
[1724] 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-Natschke, 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. Richman, "Synthesis and antiretroviral
activity of phospholipid analogs of azidothymidine and other
antiviral nucleosides." J. Biol. Chem., 1990, 265, 61127.
[1725] Nonlimiting examples of US 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
[1726] 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.
[1727] 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-2b) interferon Schering-Plough Epivir-HBV
(lamivudine; 3TC) nucleoside analogue GlaxoSmithKline Hepsera
(Adefovir Dipivoxi)'' nucleotide analogue Gilead Sciences Coviracil
(emtricitabine; FTC) nucleoside analogue Triangle 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 DAPD) nucleoside
analogue Triangle Pharmaceuticals LdT (telbivudine) nucleoside
analogue Idenix XTL 001 monoclonal antibody XTL Biopharm 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) Hoffmann-La Roche Gel Cap)
Fortovase .RTM. saquinavir (Soft SQV (SGC) Hoffmann-La Roche Gel
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 + LPV Abbott Laboratories ritonavir fosamprenavir
GlaxoSmithKline tipranavir TPV 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 + AZT + GlaxoSmithKline zidovudine +
3TC lamivudine Ziagen .RTM. abacavir ABC GlaxoSmithKline Hivid
.RTM. zalcitabine ddC Hoffmann-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 HIV Therapies: Other Classes of Drugs Pharmaceutical
Brand Name Generic Name Abbreviation Company Viread .TM. tenofovir
disoproxil TDF or Bis(POC) Gilead Sciences fumarate (DF) PMPA
TABLE-US-00006 Cellular Inhibitors Brand Pharmaceutical Name
Generic Name Abbreviation Company Droxia .RTM. hydroxyurea HU
Bristol-Myers Squibb
TABLE-US-00007 Entry Inhibitors (including Fusion Inhibitors) Brand
Generic Pharmaceutical Name Name Abbreviation Company Fuzeon .TM.
enfuvirtide Trimeris Trimeris AnorMED, Inc. Progenics
Pharmaceuticals
TABLE-US-00008 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-00009 HIV Therapies: Treatments for Side Effects
Pharmaceutical Brand Name Generic Name Side Effect Company Procrit
.RTM. epoetin alfa Anemia Ortho Biotech (erythropoietin) Serostim
.RTM. somatropin, or Lipodystrophy Serono human growth Laboratories
hormone
[1728] 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.
[1729] 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
[1730] 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.
[1731] 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.
[1732] 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.
[1733] 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.
[1734] 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.
[1735] 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.
[1736] 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.
[1737] 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.
[1738] 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 bisulfate; 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.
[1739] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[1740] 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.
[1741] 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 Compounds
[1742] A method for the facile preparation of
N.sup.4-acyl-substituted 2',3'-dideoxy-5-fluorocytidine and
2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine nucleosides is also
provided. The method includes condensation of a 5'-O-silyl
protected 2',3'-dideoxy-5-fluorocytidine or a 5'-O-silyl protected
2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, 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.
[1743] The N.sup.4-acyl-substituted 2',3'-dideoxy-5-fluorocytidine
and 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine nucleosides
disclosed herein can be prepared as described in detail below, or
by other assays known to those skilled in the art.
[1744] 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
[1745] 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
(S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid (2)
[1746] To a mixture of L-glutamic acid (1, 25 g, 170 mmol) in water
(67 mL) and conc. HCl (35 mL) at 0.degree. C. with stirring was
added a solution of NaNO.sub.2 (17.5 g, 253.6 mmol) in water (37.5
mL) over a period of 4 h, and then the resulting clear solution was
stirred at room temperature overnight. After removal of the solvent
by evaporation in vacuo, the residue was treated with EtOAC (80 mL)
and filtered. The filtrate was dried over Na.sub.2SO.sub.4, and
concentrated. The residue, after crystallization from
EtOAc/benzene/hexane, afforded the title compound 2 as a white
crystalline solid (13.12 g, 59%). M.P. 71-73.degree. C.; .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.4.20 (m, 1H, CHO), 1.8-2.3 (m, 4H,
CH.sub.2CH.sub.2).
Example 2
(S)-(+)-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (3)
[1747] To a solution of 2 (10 g, 76.85 mmol) in anhydrous THF (200
mL) at 0.degree. C. was slowly added BH.sub.3--SMe.sub.2 (2 M
solution in THF, 46.1 mL, 92.2 mmol) over a period of 10 min. The
reaction solution was stirred at 0.degree. C. for 3 h under
nitrogen, followed by the slow addition of anhydrous MeOH (20 mL).
After removal of the solvent, the residue was purified by flash
chromatography on silica gel eluting with CH.sub.2Cl.sub.2/MeOH
(95:5) to give the title compound 3 as a colorless oil (8.41 g,
94%). .sup.1H NMR (CDCl.sub.3) .delta.4.66-4.65 (m, 1H, H-5),
3.95-3.91 (m, 1H, CH.sub.2OH), 3.72-3.65 (m, 1H, CH.sub.2OH),
2.65-2.57 (m, 2H, H-3), 2.30-2.17 (m, 3H, H-4, OH).
Example 3
(S)-5-[(tert-Butyldiphenylsilyl)hydroxymethyl]-dihydro-2(3H)-furanone
(4)
[1748] To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g,
135 mmol) in anhydrous DMF (70 mL) was added
tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and
the solution was stirred at room temperature under a nitrogen
atmosphere for 1 h. After removal of the solvent by evaporation,
the residue was dissolved in CHCl.sub.3, washed with water and
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated. After
crystallization from hexane, the oily residue gave the title
compound 4 as a white crystalline solid (20.6 g, 97%). M.P.
76.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.7.68-7.65 (m, 4H,
arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5), 3.90-3.87
(dd, J=3 & 11 Hz, 1H, CH.sub.2OH), 3.70-3.67 (dd, J=3 & 11
Hz, 1H, CH.sub.2OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H,
H-3), 2.32-2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).
Example 4
(5S,3R)-5-[(tert-Butyldiphenylsilyl)hydroxymethyl]-dihydro-3-(phenylselene-
nyl)-2(3H)-furanone (5)
[1749] To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL)
at -78.degree. C. was added lithium bis(trimethylsilyl)amide (1 M
solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After
stirring at -78.degree. C. for 1 h, Me.sub.3SiCl (1.918 g, 17.65
mmol) was added dropwise, and the reaction mixture was allowed to
warm to room temperature. After being stirred at room temperature
for 30 min, the mixture was cooled to -78.degree. C., and a
solution of PhSeBr (5,g, 21.19 mmol) in anhydrous THF 25 mL) was
added rapidly. The mixture was diluted with ether (50 mL), washed
with water until the color of organic layer changed from dark brown
to light yellow, dried (Na.sub.2SO.sub.4), filtered, and
evaporated. The resulting oily residue [containing 3R(.alpha., 5)
and 3S(.beta.) isomers; TLC: hexane/EtOAc, 10:1; R.sub.f=0.42 and
0.28, respectively] was purified by flash chromatography on silica
gel eluting with hexane/EtOAc (99:1 to 95:5) to give the title
compound 5 as a light yellow oil (4.22 g, 59%). .sup.1H NMR
(CDCl.sub.3) .delta.7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H,
arom.), 4.37-4,34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82
(dd, J=3 & 11 Hz, 1H, CH.sub.2OH), 3.62-3.59 (dd, J=3 & 11
Hz, 1H, CH.sub.2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H,
H-4), 1.02 (s, 9H, t-Bu).
Example 5
1-O-Acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-(phenylselenenyl)-.-
alpha./.beta.-D-erythro-pentofuranose (6)
[1750] To a stirred solution of 5 (13.68 g, 26.88 mmol) in
anhydrous toluene (120 mL) at -78.degree. C. was added
diisobutylaluminum hydride (1 M solution in toluene, 43 mL, 43
mmol), and the solution was stirred at -78.degree. C. for 2 h under
an argon atmosphere. The reaction was quenched by addition of
anhydrous MeOH (10 mL), and the mixture was allowed to warm to room
temperature. After stirring at room temperature for 30 min, EtOAc
(50 mL) and water (50 mL) were added. The resulting white
precipitate was filtered, and the aqueous layer was extracted with
EtOAc. The combined organic phase was washed with water and brine,
dried (Na.sub.2SO4), filtered, and evaporated. The resulting oily
residue was dissolved in anhydrous CH.sub.2Cl.sub.2 (60 mL), and
cooled to 0.degree. C. 4-Dimethylaminopyridine (DMAP, 5 mg) and
pyridine (15 mL) were added, followed by Ac.sub.2O (8.22 g, 80.64
mmol). The mixture was stirred at 0.degree. C. for 30 min, then at
room temperature overnight. Evaporation of the solvent in vacuo
afforded the title compound 6 as a clear yellow oil (13.45 g, 90%).
This crude product was used directly without further purification.
.sup.1H NMR (CDCl.sub.3) .delta. 7.69-7.55 (m, 6H, arom.),
7.44-7.25 (m, 9H, arom.), 6.47-6.46 (d, H-1), 6.28 (s, H-1),
4.47-4,34 (m, 1H, H-4), 3.82-3.54 (m, 3H, H-5, H-2), 2.50-1.99 (m,
2H, H-3), 2.12, 1.86 (2s, 3H, CH.sub.3CO), 1.05, 1.96 (2s, 9H,
t-Bu).
Example 6
.beta.-D-5'-O-(tert-Butyldiphenylsilyl)-2',3'-dideoxy-5-fluoro-2'-(phenyls-
elenenyl)-cytidine (7)
[1751] A suspension of 5-fluorocytosine (1.61 g, 12.5 mmol) and
(NH.sub.4).sub.2SO.sub.4 (165 mg, 1.25 mmol) in
hexamethyldisilazane (20 mL) was heated at reflux for 2 h under an
argon atmosphere, and then evaporated to dryness in vacuo. To the
residue was added a solution of 6 (5.53 g, 10.0 mmol) in anhydrous
1,2-dichloroethane (25 mL), and the mixture was cooled to 5.degree.
C. TMSOTf (2.0 mL, 11 mmol) was added, and the resulting solution
was stirred at 5.degree. C. for 15 min under an argon atmosphere,
then at room temperature for another 30 min. The solution was
poured into a mixture of EtOAc and saturated aqueous NaHCO.sub.3
with stirring. The organic layer was separated, washed with
saturated NaHCO.sub.3 solution, water, and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by flash chromatography on silica gel eluting with
CH.sub.2Cl.sub.2/MeOH (99:1 to 96:4) to give 7 (5.36 g, 86%) as a
white solid. M.P. 163-164.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta.7.95 (d, J=6.4 Hz, 1H, H-6), 7.67-7.62 (m, 6H, arom.),
7.47-7.25 (m, 9H, arom.), 6.90 (bs, 1H, NH), 6.15-6.14 (m, 1H,
H-1'), 5.40 (bs, 1H, NH), 4.32-4.30 (m, 1H, H-4'), 4.12-4.08 (m,
1H, H-5'a), 3.84-3.83 (m, 1H, H-2'), 3.65 (dd, J=2.4 & 11.2 Hz,
1H, H-5'b), 2.45-2.42, 2.01-1.98 (2m, 2H, H-3'), 1.08 (s, 9H,
t-Bu); .sup.13C NMR (CDCl.sub.3) .delta.157.0, 156.8, 153.3, 137.3,
135.6, 135.5, 135.4, 134.9, 132.6, 132.3, 130.1, 130.0, 129.2,
128.3, 127.9, 127.4, 125.5, 125.2, 91.0, 80.2, 64.8, 45.4, 32.3,
26.9, 19.2.
Example 7
.beta.-D-5'-O-(tert-Butyldiphenylsilyl)-2',3'-dideoxy-5-fluorocytidine
(8)
[1752] A suspension of 7 (4.976 g, 8 mmol), Et.sub.3B (1 M solution
in hexane, 8.8 mL, 8.8 mmol), and n-Bu.sub.3SnH (3.23 mL, 12 mmol)
in anhydrous benzene (40 mL) was stirred at room temperature under
an argon atmosphere for 5 h. After evaporation of the solvent, the
residue was purified by flash chromatography on silica gel eluting
with CH.sub.2Cl.sub.2/MeOH (99:1 to 96:4) to give the title
compound 8 as a pale yellow foam (3.45 g, 92%). .sup.1H NMR
(CDCl.sub.3) .delta.8.14 (d, J=6.4 Hz, 1H, H-6), 7.71-7.66 (m 4H,
arom.), 7.49-7.38 (m, 6H, arom.), 6.04 (m, 1H, H-1'), 4.17-4.12 (m,
1H, H-4'), 4.12-4.08 (m, 1H, H-5'a), 3.73-3.69 (m, 1H, H-5'b),
2.54-2.44, 2.18-2.09 (2m, 2H, H-2'), 2.05-1.95, 1.89-1.82 (2m, 2H,
H-3'), 1.10 (s, 9H, t-Bu).
Example 8
.beta.-D-5'-O-(tert-Butyldiphenylsilyl)-2',3'-didehydro-2',3'-dideoxy-5-fl-
uorocytidine (9)
[1753] To a solution,of 7 (15.47 g, 24.87 mmol) in CH.sub.2Cl.sub.2
(150 mL) containing 5 drops of pyridine at 0.degree. C. was added a
solution of H.sub.2O.sub.2 (15.5 mL of 30% solution) dropwise over
a period of 15 min. After stirring at 0.degree. C. for 20 min, and
at room temperature for 30 min, the reaction solution was diluted
with CHCl.sub.3 (200 mL), washed with H.sub.2O, saturated
NaHCO.sub.3 solution, and H.sub.2O, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue, after purification by
chromatography over silica gel eluted with CH.sub.2Cl.sub.2/MeOH
(96:4), gave 9 as a pale yellow foam (9.907 g, 86%). M.P.
150-152.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.7.88 (d, J=6.4
Hz, 1H, H-6), 7.66-7.65 (m, 4H, arom.), 7.47-7.37 (m, 6H, arom.),
7.00-6.99 (m, 1H, H-1'), 6.50 (bs, 1H, NH), 6.12 (d, J=6.0 Hz, 1H,
H-3'), 5.98 (d, J=4.8 Hz, 1H, H-2'), 5.35 (bs, 1H, NH), 4.89 (bs,
1H, H-4'), 4.00 (dd, J=3.2 & 11.6 Hz, 1H, H-5'a), 3.81 (dd,
J=3.6 & 12.4 Hz, 1H, H-5'b), 1.06 (s, 9H, t-Bu). .sup.13C NMR
(CDCl.sub.3) .delta.157.3, 157.1, 153.6, 137.5, 135.6, 135,4,
135.1, 133.3, 132.8, 132.6, 130.1, 130.0, 127.9, 127.8, 127.4,
126.1, 125.8, 91.3, 87.3, 65.1, 26.9, 19.2.
Example 9
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(4-iodobenzoyl)cytidine
(10)
[1754] To a solution of 8 (131 mg, 0.28 mmol) and DMAP (5 mg) in
anhydrous CH.sub.2Cl.sub.2 (2 mL) and Et.sub.3N (0.5 mL) at
0.degree. C. was added 4-iodobenzoyl chloride (85 mg, 0.31 mmol).
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 (3 mL), and TBAF (1
M solution in THF, 0.28 mL, 0.28 mmol) 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 10 as a yellow
powder (48 mg, 37%). .sup.1H NMR (DMSO-d.sub.6) .delta.8.9 (bs, 1H,
NH), 7.90-7.73 (m, 5H, H-6, arom.), 5.91 (bs, 1H, H-1'), 5.10 (m,
1H, OH), 4.14 (m, 1H, H-4'), 3.80, 3.57 (2m, 2H, H-5'), 2.35, 2.08
(2m, 2H, H-2'), 1.86 (m, 2H, H-3').
[1755] By following the same procedures as above but using the
corresponding carboxylic acid chloride starting materials, the
following compounds are also prepared:
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(4-fluorobenzoyl)cytidine
(11)
[1756] .sup.1H NMR (DMSO-d.sub.6) .delta.8.9 (bs, 1H, NH), 8.05,
7.34 (2m, 5H, H-6, arom.), 5.90 (d, 1H, H-1'), 5.25 (m, 1H, OH),
4.11 (m, 1H, H-4'), 3.79, 3.58 (2m, 2H, H-5'), 2.35, 2.08 (2m, 2H,
H-2'), 1.85 (m, 2H, H-3').
.beta.-D-N.sup.4-(4-chlororobenzoyl)-2',3'-dideoxy-5-fluorocytidine
(12)
[1757] .sup.1H NMR (DMSO-d6) .delta.8.9 (bs, 1H, NH), 7.99, 7.60
(2m, 5H, H-6, arom.), 5.90 (bs, 1H, H-1'), 5.38 (m, 1H, OH), 4.14
(m, 1H, H-4'), 3.82, 3.58 (2m, 2H, H-5'), 2.35, 2.08 (2m, 2H,
H-2'), 1.84 (m, 2H, H-3').
.beta.-D-N.sup.4-(4-bromobenzoyl)-2',3'-dideoxy-5-fluorocytidine
(13)
[1758] .sup.1H NMR (DMSO-d.sub.6) .delta.8.9 (bs, 1H, NH), 7.93,
7.72 (2m, 5H, H-6, arom.), 5.91 (d, 1H, H-1'), 5.25 (m, 1H, OH),
4.11 (m, 1H, H-4'), 3.79, 3.58 (2m, 2H, H-5'), 2.35, 2.07 (2m, 2H,
H-2'), 1.85 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(3-fluorobenzoyl)cytidine
(14)
[1759] .sup.1H NMR (CDCl.sub.3) .delta.8.37 (d, 1H, H-6), 8.09-7.24
(m, 4H, arom.), 6.08 (m, 1H, H-1'), 4.27 (m, 1H, H-4'), 4.13, 3.82
(2d, 2H, H-5'), 2.48, 2.20 (2m, 2H, H-2'), 2.02 (m, 2H, H-3').
.beta.-D-N.sup.4-(3-Chlorobenzoyl)-2',3'-dideoxy-5-fluorocytidine
(15)
[1760] .sup.1H NMR (DMSO-d.sub.6) .delta.8.8 (bs, 1H, NH),
8.01-7.53 (m, 5H, H-6, arom.), 5.91 (d, 1H, H-1'), 5.34 (t, 1H,
OH), 4.12 (m, 1H, H-4'), 3.81, 3.58 (2d, 2H, H-5'), 2.40, 2.10 (2m,
2H, H-2'), 1.85 (m, 2H, H-3').
.beta.-D-N.sup.4-(3-Bromobenzoyl)-2',3'-dideoxy-5-fluorocytidine
(16)
[1761] .sup.1H NMR (DMSO-d.sub.6) .delta.8.75 (bs, 1H, NH),
8.14-7.45 (m, 5H, H-6, arom.), 5.90 (d, 1H, H-1'), 5.29 (bs, 1H,
OH), 4.11 (m, 1H, H-4'), 3.80, 3.58 (2m, 2H, H-5'), 2.40, 2.08 (2m,
2H, H-2'), 1.85 (m, 2H, H-3').
.beta.-D-N.sup.4-p-Anisoyl-2',3'-dideoxy-5-fluorocytidine (17)
[1762] .sup.1H NMR (DMSO-d.sub.6) .delta.8.1 (bs, 1H, NH), 7.97,
7.04 (2m, 5H, H-6, arom.), 5.95 (m, 1H, H-1'), 4.50 (m, 1H, OH),
4.40 (m, 1H, H-4'), 3.82 (s, 3H, CH.sub.3), 3.80 (m, 2H, H-5'),
2.35, 2.05 (2m, 2H, H-2'), 1.90 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(4-nitrobenzoyl)cytidine
(18)
[1763] .sup.1H NMR (DMSO-d.sub.6) .delta.8.9 (bs, 1H, NH), 8.32,
8.23 (2m, 5H, H-6, arom.), 5.92 (d, 1H, H-1'), 5.30 (bs, 1H, OH),
4.11 (m, 1H, H-4'), 3.79, 3.59 (2m, 2H, H-5'), 2.35, 2.10 (2m, 2H,
H-2'), 1.86 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(3-nitrobenzoyl)cytidine
(19)
[1764] .sup.1H NMR (DMSO-d.sub.6) .delta.8.76 (d, 1H, H-6), 8.7
(bs, 1H, NH), 8.40, 7.80 (2m, 4H, arom.), 5.95 (d, 1H, H-1'), 5.30
(m, 1H, OH), 4.08 (m, 1H, H-4'), 3.79, 3.58 (2m, 2H, H-5'), 2.35,
2.08 (2m, 2H, H-2'), 1.85 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(2-nitrobenzoyl)cytidine
(20)
[1765] .sup.1H NMR (CDCl.sub.3) .delta.8.49 (d, 1H, H-6), 7.96-7.50
(m, 4H, arom.), 6.02 (d, 1H, H-1'), 4.22 (m, 1H, H-4'), 4.11, 3.81
(2d, 2H, H-5'), 2.45, 2.15 (2m, 2H, H-2'), 1.98 (m, 2H, H-3').
.beta.-D-N.sup.4-Benzoyl-2',3'-dideoxy-5-fluorocytidine (21)
[1766] .sup.1H NMR (DMSO-d.sub.6) .delta.8.2 (bs, 1H, NH), 7.98,
7.52 (2m, 5H, H-6, arom.), 5.95 (d, 1H, H-1'), 5.74 (bs, 1H, OH),
4.57, 4.40 (2m, 3H, H-4', H-5'), 2.35, 2.08 (2m, 2H, H-2'), 1.90
(m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-p-toluoylcytidine (22)
[1767] .sup.1H NMR (CDCl.sub.3) .delta.8.31 (d, 1H, H-6), 8.15,
7.24 (2m, 4H, arom.), 6.08 (m, 1H, H-1'), 4.25 (m, 1H, H-4'), 4.10,
3.82 (2m, 2H, H-5'), 2.42 (s, 3H, CH.sub.3), 2.47, 2.15 (2m, 2H,
H-2'), 2.00 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-m-toluoylcytidine (23)
[1768] .sup.1H NMR (CDCl.sub.3) .delta.8.31 (d, 1H, H-6), 8.07,
7.36 (2m, 4H, arom.), 6.09 (m, 1H, H-1'), 4.25 (m, 1H, H-4'), 4.11,
3.83 (2m, 2H, H-5'), 2.45, 2.18 (2m, 2H, H-2'), 2.42 (s, 3H,
CH.sub.3), 2.00 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-o-toluoylcytidine (24)
[1769] .sup.1H NMR (DMSO-d.sub.6) .delta.8.8 (bs, 1H, NH),
7.55-7.26 (m, 6H, H-6, arom.), 5.88 (d, 1H, H-1'), 5.30 (t, 1H,
OH), 4.12 (m, 1H, H-4'), 3.82, 3.58 (2m, 2H, H-5'), 2.41 (s, 3H,
CH.sub.3), 2.32, 2.07 (2m, 2H, H-2'), 1.83 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-N.sup.4-(4-ethylbenzoyI)-5-fluorocytidine
(25)
[1770] .sup.1H NMR (CDCl.sub.3) .delta.8.24 (d, 1H, H-6), 8.18,
7.29 (2m, 4H, l arom.), 6.10 (d, 1H, H-1'), 4.24 (m, 1H, H-4'),
4.10, 3.80 (2m, 2H, H-5'), 2.72 (q, 2H, CH.sub.2), 2.50, 2.20 (2m,
2H, H-2'), 2.00 (m, 2H, H-3'), 1.26 (t, 3H, CH.sub.3).
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(4-n-propylbenzoyl)cytidine
(26)
[1771] .sup.1H NMR (CDCl.sub.3) .delta.8.30 (d, 1H, H-6), 8.17,
7.25 (2m, 4H, arom.), 6.09 (m, 1H, H-1'), 4.24 (m, 1H, H-4'), 4.11,
3.80 (2m, 2H, H-5'), 2.65 (t, 2H, CH.sub.2), 2.45, 2.18 (2m, 2H,
H-2'), 2.02 (m, 2H, H-3'), 1.66 (m, 2H, CH.sub.2), 0.94 (t, 3H,
CH.sub.3).
.beta.-D-N.sup.4-(4-n-Butylbenzoyl)-2',3'-dideoxy-5-fluorocytidine
(27)
[1772] .sup.1H NMR (CDCl.sub.3) .delta.8.34 (d, 1H, H-6), 8.17,
7.25 (2m, 4H, arom.), 6.10 (m, 1H, H-1'), 4.25 (m, 1H, H-4'), 4.13,
3.82 (2m, 2H, H-5'), 2.68 (t, 2H, CH.sub.2), 2.50, 2.20 (2m, 2H,
H-2'), 2.02 (m, 2H, H-3'), 1.66 (m, 2H, CH.sub.2), 1.37 (m, 2H,
CH.sub.2), 0.93 (t, 3H, CH.sub.3).
.beta.-D-N.sup.4-(4-tert-Butylbenzoyl)-2',3'-dideoxy-5-fluorocytidine
(28)
[1773] .sup.1H NMR (CDCl.sub.3) .delta.8.31 (d, 1H, H-6), 8.17,
7.48 (2m, 4H, arom.), 6.08 (m, 1H, H-1'), 4.25 (m, 1H, H-4'), 4.10,
3.80 (2m, 2H, H-5'), 2.47, 2.15 (2m, 2H, H-2'), 2.00 (m, 2H, H-3'),
1.35 (s, 9H, t-Bu).
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(2-furoyl)cytidine (29)
[1774] .sup.1H NMR (CDCl.sub.3) .delta.8.37 (d, 1H, H-6), 7.62,
7.38, 6.52 (3m, 3H, furoyl), 6.07 (m, 1H, H-1'), 4.25 (m, 1H,
H-4'), 4.11, 3.80 (2m, 2H, H-5'), 2.47, 2.17 (2m, 2H, H-2'), 2.01
(m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(2-thiophenecarbonyl)cytidine
(30)
[1775] .sup.1H NMR (CDCl.sub.3) .delta.8.32 (d, 1H, H-6), 7.96 (d,
1H, thiophenyl), 7.60 (d, 1H, thiophenyl), 7.13 (t, 1H,
thiophenyl), 6.08 (m, 1H, H-1'), 4.25 (m, 1H, H-4'), 4.13, 3.82
(2m, 2H, H-5'), 2.47, 2.17 (2m, 2H, H-2'), 2.02 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(nicotinoyl)cytidine
(31)
[1776] .sup.1H NMR (CDCl.sub.3) .delta.9.11 (s, 1H, nicotinoyl),
8.53 (d, 1H, H-6), 8.75, 8.54, 7.40 (3m, 3H, nicotinoyl), 6.10 (m,
1H, H-1'), 4.27 (m, 1H, H-4'), 4.16, 3.83 (2m, 2H, H-5'), 2.48,
2.20 (2m, 2H, H-2'), 2.03 (m, 2H, H-3').
.beta.-D-2',3'-Dideoxy-5-fluoro-N.sup.4-(benzo[b]thiophene-2-carbonyl)cyti-
dine (32)
[1777] .sup.1H NMR (DMSO-d.sub.6) .delta.8.7 (bs, 1H, NH), 8.00,
7.45 (2m, 6H, H-6, arom.), 5.91 (d, 1H, H-1'), 5.32 (m, 1H, OH),
4.11 (m, 1H, H-4'), 3.80, 3.58 (2m, 2H, H-5'), 2.44, 2.08 (2m, 2H,
H-2'), 1.86 (m, 2H, H-3').
.beta.-D-N.sup.4-2',3'-dideoxy-5-fluorocytidine (33)
[1778] .sup.1H NMR (CDCl.sub.3) .delta.8.45 (d, 1H, H-6), 6.04 (d,
1H, H-1'), 4.25 (m, 1H, H-4'), 4.12, 3.81 (2m, 2H, H-5'), 2.50-1.20
(m, 15H, H-2', H-3', c-hexyl).
Example 10
.beta.-D-N.sup.4-Butyryl-2',3'-dideoxy-5-fluorocytidine (34)
[1779] To a solution of 8 (131 mg, 0.28 mmol) and DMAP (5 mg) in
anhydrous CH.sub.2Cl.sub.2 (2 mL) and Et.sub.3N (0.5 mL) at
0.degree. C. was added butyric anhydride (52 mg, 0.33 mmol). 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 (3 mL), and TBAF (1 M
solution in THF, 0.30 mL, 0.30 mmol) 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 34 as a white
solid (31 mg, 35%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.21 (d, 1H,
H-6), 5.92 (t, 1H, H-1'), 4.26 (m, 1H, H-4'), 4.22 (m, 2H, H-5'),
2.30 (t, 2H, CH.sub.2), 2.38, 2.04 (2m, 2H, H-2'), 1.90 (m, 2H,
H-3'), 1.58 (m, 2H, CH.sub.2), 0.85 (t, 3H, CH.sub.3).
Example 11
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(4-fluorobenzoyl)c-
ytidine (35)
[1780] To a solution of 9 (140 mg, 0.3 mmol) and DMAP (5 mg) in
anhydrous CH.sub.2Cl.sub.2 (2 mL) and Et.sub.3N (0.5 mL) at
0.degree. C. was added 4-fluorobenzoyl chloride (52 mg, 0.33 mmol).
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 (3 mL), and TBAF (1
M solution in THF, 0.30 mL, 0.30 mmol) 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 35 as a pale
yellow solid (33 mg, 32%). .sup.1H NMR (DMSO-d.sub.6) .delta.8.07,
7.35 (2m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'),
5.98 (m, 1H, H-3'), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m,
2H, H-5').
[1781] By following the same procedures as above but using the
corresponding carboxylic acid chloride starting materials, the
following compounds are also prepared:
.beta.-D-N.sup.4-(4-Chlorobenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluoroc-
ytidine (36)
[1782] .sup.1H NMR (DMSO-d.sub.6) .delta.8.00, 7.59 (2m, 5H, H-6,
arom.), 6.84 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-N.sup.4-(4-Bromobenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluorocy-
tidine (37)
[1783] .sup.1H NMR (DMSO-d.sub.6) .delta.7.86, 7.72 (2m, 5H, H-6,
arom.), 6.85 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 4.88 (m, 1H, H-4'), 3.90-3.65 (m, 2H, H-5').)
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(4-iodobenzoyl)cyt-
idine (38)
[1784] .sup.1H NMR (DMSO-d.sub.6) .delta.7.90-7.60 (2m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(3-fluorobenzoyl)c-
ytidine (39)
[1785] .sup.1H NMR (DMSO-d.sub.6) .delta.7.85-7.39 (m, 5H, H-6,
arom.), 6.84 (bs, 1B, H-1'), 6.42 (m, 1H, H-2'), 5.98 (m, 1H,
H-3'), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H, H-5').
.beta.-D-N.sup.4-(3-Chlorobenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluoro-
cytidine (40)
[1786] .sup.1H NMR (DMSO-d.sub.6) .delta.8.00-7.40 (2m, 5H, H-6,
arom.), 6.84 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-N.sup.4-(3-Bromobenzoyl)-2',3'-didehydro-2',3'-dideoxy)-5-fluoroc-
ytidine (41)
[1787] .sup.1H NMR (DMSO-d.sub.6) .delta.8.16-7.34 (m, 5H, H-6,
arom.), 6.84 (bs, 1H, H-1'), 6.46 (m, 1H, H-2'), 5.98 (m, 1H,
H-3'), 5.23 (t, 1H, OH), 4.88 (bs, 1H, H-4'), 3.68 (m, 2H,
H-5').
.beta.-D-N.sup.4-p-Anisoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
(42)
[1788] .sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6) .delta.7.72 (d, 2H,
arom.), 7.12 (d, J=7.2 Hz, 1H, H-6), 6.93 (m, 1H, H-1'), 6.48 (d,
2H, arom.), 6.45 (m, 1H, H-2'), 5.87 (m, 1H, H-3'), 5.78 (m, 1H,
H-4'), 4.03 (s, 3H, OCH.sub.3), 3.40 (m, 2H, H-5').
.beta.-D-N.sup.4-m-Anisoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
(43)
[1789] .sup.1H NMR (CDCl.sub.3) .delta.7.35-6.60 (m, 5H, H-6, H-1',
arom.), 6.60 (m, 1H, arom.), 6.58 (m, 1H, H-2'), 5.82 (m, 1H,
H-3'), 5.74 (m, 1H, H-4'), 3.99 (s, 3H, OCH.sub.3), 3.36 (m, 2H,
H-5').
.beta.-D-N.sup.4-o-Anisoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
(44)
[1790] .sup.1H NMR (DMSO-d.sub.6) .delta.10.75(bs, 1H, NH), 8.55
(d, 1H, H-6), 7.77-7.08 (m, 4H, arom.), 6.84 (bs, 1H, H-1'), 6.40
(m, 1H, H-2'), 5.99 (m, 1H, H-3'), 5.19 (t, 1H, OH), 4.89 (m, 1H,
H-4'), 3.91 (s, 3H, OCH.sub.3), 3.66 (m, 2H, H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(4-nitrobenzoyl)cy-
tidine (45)
[1791] .sup.1H NMR (DMSO-d.sub.6) .delta.8.34-8.20 (m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.95 (m, 1H,
H-3'), 5.18 (m, 1H, OH), 4.87 (bs, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(3-nitrobenzoyl)cy-
tidine (46)
[1792] .sup.1H NMR (DMSO-d.sub.6) .delta.8.74-7.38 (m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.18 (m, 1H, OH), 4.87 (bs, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(2-nitrobenzoyl)cy-
tidine (47)
[1793] .sup.1H NMR (DMSO-d.sub.6) .delta.8.14-7.71 (m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1`), 6.42 (m, 1H, H-2'), 5.95 (m, 1H,
H-3'), 5.18 (m, 1H, OH), 4.87 (bs, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-p-toluoylcytidine
(48)
[1794] .sup.1H NMR (DMSO-d.sub.6) .delta.7.87-7.31 (2m, 5H, H-6,
arom.), 6.83 (m, 1H, H-1'), 6.40 (m, 1H, H-2'), 5.95 (m, 1H, H-3'),
5.18 (m, 1H, OH), 4.85 (m, 1H, H-4'), 3.66 (m, 2H, H-5'), 2.37 (s,
3H, CH.sub.3).
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-m-toluoylcytidine
(49)
[1795] .sup.1H NMR (DMSO-d.sub.6) .delta.7.78, 7.42 (2m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1'), 6.41 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.17 (bs, 1H, OH), 4.87 (m, 1H, H-4'), 3.66 (m, 2H, H-5'),
2.36 (s, 3H, CH.sub.3).
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-o-toluoylcytidine
(50)
[1796] .sup.1H NMR (DMSO-d.sub.6) .delta.7.60-7.40 (m, 5H, H-6,
arom.), 6.83 (bs, 1H, H-1'), 6.40 (m, 1H, H-2'), 5.99 (m, 1H,
H-3'), 5.17 (bs, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H, H-5'),
2.42 (s, 3H, CH.sub.3).
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-N.sup.4-(4-ethyllbenzoyl)-5-fluoroc-
ytidine (51)
[1797] .sup.1H NMR (CDCl.sub.3) .delta.8.19 (m, 2H, arom.), 8.09
(d, 1H, H-6), 7.28 (m, 2H, arom.), 7.03 (m, 1H, H-1'), 6.39 (m, 1H,
H-2'), 5.91 (m, 1H, H-3'), 5.20 (m, 1H, OH), 4.97 (m, 1H, H-4'),
4.02-3.85 (m, 2H, H-5'), 2.71 (q, 2H, CH.sub.2), 1.26 (t, 3H,
CH.sub.3).
.beta.-D-N.sup.4-(4-n-Butylbenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-fluoro-
-.sup.4cytidine (52)
[1798] .sup.1H NMR (CDCl.sub.3) .delta.8.19 (m, 2H, arom.), 8.12
(d, 1H, H-6), 7.26 (m, 2H, arom.), 7.04 (m, 1H, H-1'), 6.37 (m, 1H,
H-2'), 5.92 (m, 1H, H-3'), 4.99 (m, 1H, H-4'), 4.03-3.87 (m, 2H,
H-5'), 2.68 (t, 2H, CH.sub.2), 1.66 (m, 2H, CH.sub.2), 1.36 (m, 2H,
CH.sub.2), 0.93 (t, 3H, CH.sub.3).
.beta.-D-N.sup.4-(4-tert-Butylbenzoyl)-2',3'-didehydro-2',3'-dideoxy-5-flu-
orocytidine (53)
[1799] .sup.1H NMR (CDCl.sub.3) 88.19 (m, 2H, arom.), 8.09 (d, 1H,
H-6), 7.48 (m, 2H, arom.), 7.04 (m, 1H, H-1'), 6.36 (m, 1H, H-2'),
5.91 (m, 1H, H-3'), 5.22 (m, 1H, OH), 4.98 (m, 1H, H-4'), 4.02-3.86
(m, 2H, H-5'), 1.34 (s, 9H, t-Bu).
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(2-thiophenecarbon-
yl)cytidine (54)
[1800] .sup.1H NMR (DMSO-d.sub.6) .delta.8.30-7.20 (m, 4H, H-6,
thiophene), 6.82 (m, 1H, H-1'), 6.42 (m, 1H, H-2'), 5.93 (m, 1H,
H-3'), 5.16 (m, 1H, OH), 4.85 (m, 1H, H-4'), 3.65 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-nicotinoylcytidine
(55)
[1801] .sup.1H NMR (DMSO-d.sub.6) .delta.9.11-7.53 (m, 5H, H-6,
nicotinoyl), 6.83 (bs, 1H, H-1'), 6.42 (d, 1H, H-2'), 5.95 (m, 1H,
H-3'), 5.18 (m, 1H, OH), 4.88 (m, 1H, H-4'), 3.66 (m, 2H,
H-5').
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-(benzo[b]thiophene-
-2-carbonyl)cytidine (56)
[1802] .sup.1H NMR (DMSO-d.sub.6) .delta.8.34-7.44 (m, 6H, arom.),
6.83 (bs, 1H, H-1`), 6.41 (d, 1H, H-2'), 5.94 (m, 1H, H-3'), 5.18
(m, 1H, OH), 4.85 (m, 1H, H-4'), 3.66 (m, 2H, H-5').
.beta.-D-N.sup.4-(Cyclopentanecarbonyl)-2',3'-didehydro-2',3'-dideoxy-5
-fluorocytidine (57)
[1803] .sup.1H NMR (DMSO-d.sub.6) .delta.10.60 (bs, 1H, NH), 8.48
(d, 1H, H-6), 6.81 (bs, 1H, H-1'), 6.38 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.16 (t, 1H, OH), 4.88 (bs, 1H, H-4'), 3.65 (m, 2H, H-5'),
3.06 (m, 1H, CH), 1.85-1.51 (m, 8H, 4 CH.sub.2).
.beta.-D-N.sup.4-(Cyclohexanecarbonyl)-2',3'-didehydro-2',3'-dideoxy-5-flu-
orocytidine (58)
[1804] .sup.1H NMR (DMSO-d.sub.6) .delta.10.50 (bs, 1H, NH), 8.47
(d, 1H, H-6), 6.81 (d, 1H, H-1'), 6.38 (m, 1H, H-2'), 5.97 (m, 1H,
H-3'), 5.16 (t, 1H, OH), 4.88 (bs, 1H, H-4'), 3.65 (m, 2H, H-5'),
2.60 (m, 1H, CH), 1.81-1.17 (m, 10H, 5 CH.sub.2).
.beta.-D-2',3'-Didehydro-2',3'-dideoxy-5-fluoro-N.sup.4-heptanoylcytidine
(59)
[1805] .sup.1H NMR (CDCl.sub.3) .delta.8.27 (d, 1H, H-6), 7.00 (bs,
1H, H-1'), 6.28 (m, 1H, H-2'), 5.99 (m, 1H, H-3'), 5.30 (bs, 1H,
OH), 5.01 (bs, 1H, H-4'), 4.03-3.86 (m, 2H, H-5'), 1.68, 1.30 (2m,
10H, 5 CH.sub.2), 0.88 (t, 3H, CH.sub.3).
Example 12
.beta.-D-N.sup.4-Butyryl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
(60)
[1806] To a solution of 9 (140 mg, 0.3 mmol) and DMAP (5 mg) in
anhydrous CH.sub.2Cl.sub.2 (2 mL) and Et.sub.3N (0.5 mL) at
0.degree. C. was added butyric anhydride (52 mg, 0.33 mmol). 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 (3 mL), and TBAF (1 M
solution in THF, 0.30 mL, 0.30 mmol) 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 60 as a white
solid (31 mg, 35%). .sup.1H NMR (DMSO-d.sub.6) .delta.8.47 (d, 1H,
H-6), 6.82 (t, 1H, H-1'), 6.39 (m, 1H, H-2'), 5.98 (m, 1H, H-3'),
5.20 (t, 1H, OH), 4.89 (m, 1H, H-4'), 3.66 (m, 2H, H-5'), 2.51 (t,
2H, CH.sub.2), 1.58 (m, 2H, CH.sub.2), 0.89 (t, 3H, CH.sub.3).
Example 13
Anti-HIV (in PBM Cells) Assay
[1807] 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).
Anti-HIV (in MT-2 Cells) Assay
[1808] In a second antiviral testing system, the potency of the
compounds was determined by measurement of viral RNA accumulation
in HIV-1.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-1.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 p24
quantified by ELISA 3 days later.
Example 14
Anti-HBV Assay
[1809] 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 (see Tables 1, 2).
Example 15
Cytotoxicity Assay
[1810] 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)
(see Tables 1, 2).
TABLE-US-00010 TABLE 1 Anti-HIV activity and cytotoxicity of
N.sup.4-acyl-2',3'-dideoxy-5-fluorocytidine Anti-HIV-1 activity in
different Cytotoxicity in different cells cells (EC.sub.90, .mu.M)
(IC.sub.50, .mu.M) Cmpd. No. N.sup.4-substituent PBM MT-2 MT-4 PBM
CEM Vero MT-2 HepG2 D-D2FC H 0.32 1.4 1.3 >100 >100 >100
>50 >100 10 p-IBz 0.019 0.025 0.17 >100 >100 >100
>50 >100 11 p-FBz 0.027 0.32 0.61 >100 45.7 >100 >50
>100 12 p-ClBz 0.02 0.22 0.37 >100 33.4 >100 >50 7.3 13
p-BrBz 0.03 0.14 0.30 >100 31.6 >100 >50 >100 14 m-FBz
0.106 0.46 0.43 >100 80.8 >100 >50 >100 15 m-ClBz 0.08
0.4 0.51 >100 68.1 91.6 >50 >100 16 m-BrBz 0.145 0.51 0.42
>100 40.6 80.6 >50 >100 17 p-MeOBz 8.31 6 69.2 31.6 5.3 16
4.5 18 p-NO.sub.2Bz 0.18 0.4 0.30 >100 >100 >100 >50
>100 19 m-NO.sub.2Bz 1.6 1.8 1.59 >100 >100 >100 >50
>100 20 o-NO.sub.2Bz 1.5 0.7 >100 >100 >100 >50
>100 21 Bz 1.29 1.2 67.0 38.5 5.8 19 15.3 22 p-MeBz 0.028 0.31
0.23 >100 >100 >100 >50 >100 23 m-MeBz 0.012 0.24
8.4 >100 61.1 >50 >100 24 o-MeBz 1.2 6.8 20.6 22.5 39.6
>50 >100 25 p-EtBz 0.03 0.12 0.22 >100 89.8 >100 50
>100 26 p-PrBz 0.017 0.1 0.22 >100 >100 >100 >50
>100 27 p-BuBz 0.31 ND 1.1 1.3 3.2 ND 1.9 28 p-t-BuBz 0.088 0.6
ND 12.5 6.0 25.9 50 21.3 29 o-furoyl 1.5 0.9 ND 16.9 5.7 29.6
>50 31.1 30 o- 0.052 0.4 ND 19.4 13.7 23.9 >50 37.9
thiophenecarbonyl 31 Nicotinoyl 0.17 5.9 ND 8.8 5.5 28.1 >50
19.4 32 benzo[b]thiophene- 0.19 0.3 ND 23.5 4.5 39.6 >50 1.3
2-carbonyl 33 c-hexanecarbonyl 0.086 0.3 ND 4.5 6.4 11.8 50 6.5 34
Butyryl 1.6 0.71 ND 17.1 31.6 5.8 7.2 7.6 ND = not determined
TABLE-US-00011 TABLE 2 Anti-HIV activity and cytotoxicity of
N.sup.4-acyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine
Anti-HIV-1 activity in different Cytotoxicity in different cells
Compd. cells (EC.sub.90, .mu.M) (IC.sub.50, .mu.M) No.
N.sup.4-substituent PBM MT-2 MT-4 PBM CEM Vero MT-2 HepG2 D-D4FC H
0.77 1.19 1.15 >100 >100 >100 >50 >100 35 p-FBz 1.08
0.88 7.2 53.1 51.3 83.1 >50 93.6 36 p-ClBz 0.48 0.23 1.9 11.9
16.8 72.2 >50 >100 37 p-BrBz 1.4 0.14 5.2 53 24 40.5 >50
>100 38 p-IBz 0.76 0.31 0.85 57 11.4 100 >50 >100 39 m-FBz
7.82 1.0 3.1 45.3 4.2 >100 >50 >100 40 m-ClBz 1.71 2.0 3.4
45.3 11.2 100 >50 32.4 41 m-BrBz 1.71 1.0 2.2 51.6 24.9 99.7
>50 >100 42 p-MeOBz 0.70 0.58 ND >100 ND ND >50 >100
43 m-MeOBz 2.1 0.34 ND 18.5 24.6 >100 >50 >100 44 o-MeOBz
14.6 >50 ND 13.1 3.9 5.6 >50 3.4 45 p-NO.sub.2Bz 1.7 0.29 ND
3.4 4.2 6.6 >50 5.6 46 m-NO.sub.2Bz 0.93 0.58 ND 11.9 54.5
>100 >50 >100 47 o-NO.sub.2Bz 39.9 >50 ND 80 >100
>100 >50 >100 48 p-MeBz 0.32 0.21 ND 13.2 31.9 >100
>50 >100 49 m-MeBz 0.7 0.8 ND 57.1 34.9 149 >50 >100 50
o-MeBz 56.8 >50 ND 58.4 46.4 >100 >50 >100 51 p-EtBz
6.2 0.24 2.3 13 8.1 40.3 >50 >100 52 p-BuBz 3.1 ND ND 7.3
8.5. 29.4 ND 5.1 53 p-tBuBz 0.41 0.13 1.1 5 9.9 59.2 >50 >100
54 o-thiophenecarbonyl 1.6 1.5 ND 10.2 3.9 4.8 >50 2.3 55
Nicotinoyl 42.3 29 ND 13.8 6.7. 13.1 >50 10.3 56
benzo[b]thiophene-2- 0.29 0.3 ND 2.2 2.8 5.6 >50 1.3 carbonyl 57
cyclopentanecarbonyl 0.40 0.51 ND 52.9 19.6 87.6 >50 >100 58
Cyclohexanecarbonyl 0.6 0.38 ND 11.7 11.2 >100 >50 >100 59
Heptanoyl ND 0.23 ND ND ND ND 6.2 ND 60 Butyryl 1.89 2.4 3.1 52.4
12.2 >100 >50 >100 ND = not determined
* * * * *