U.S. patent application number 14/210221 was filed with the patent office on 2014-09-18 for amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv.
The applicant listed for this patent is Centre National De La Recherche Scientifique, Idenix Pharmaceuticals, Inc., Universite Montpellier 2 Sciences Et Techniques. Invention is credited to Guillaume BRANDT, Cyril B. DOUSSON, David DUKHAN, Gilles GOSSELIN, Jean-Francois GRIFFON, Christophe Claude PARSY.
Application Number | 20140271547 14/210221 |
Document ID | / |
Family ID | 51527918 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140271547 |
Kind Code |
A1 |
DUKHAN; David ; et
al. |
September 18, 2014 |
AMINO ACID PHOSPHORAMIDATE PRONUCLEOTIDES OF 2'-CYANO, AZIDO AND
AMINO NUCLEOSIDES FOR THE TREATMENT OF HCV
Abstract
Provided herein are compounds, compositions and methods for the
treatment of Flaviviridae infections, including HCV infections. In
certain embodiments, compounds and compositions of nucleoside
derivatives are disclosed, which can be administered either alone
or in combination with other anti-viral agents. In certain
embodiments, the compounds are 2'-cyano, azido or amino nucleosides
according to Formula 1001 or 2001: ##STR00001## or a
pharmaceutically acceptable salt, solvate, stereoisomeric form,
tautomeric form, or polymorphic form thereof, wherein Base, W,
R.sup.1 and R.sup.2 are as described herein.
Inventors: |
DUKHAN; David; (Saint Gely
du Fesc, FR) ; PARSY; Christophe Claude; (Jacou,
FR) ; GOSSELIN; Gilles; (Montpellier, FR) ;
GRIFFON; Jean-Francois; (Teyran, FR) ; BRANDT;
Guillaume; (Montpellier, FR) ; DOUSSON; Cyril B.;
(Canet, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Idenix Pharmaceuticals, Inc.
Universite Montpellier 2 Sciences Et Techniques
Centre National De La Recherche Scientifique |
Cambridge
Montpellier Cedex 5
Paris Cedex 16 |
MA |
US
FR
FR |
|
|
Family ID: |
51527918 |
Appl. No.: |
14/210221 |
Filed: |
March 13, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61780393 |
Mar 13, 2013 |
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61790151 |
Mar 15, 2013 |
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61889384 |
Oct 10, 2013 |
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61895992 |
Oct 25, 2013 |
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Current U.S.
Class: |
424/85.7 ;
514/49; 514/51; 536/26.8 |
Current CPC
Class: |
A61K 31/7068 20130101;
A61K 31/7072 20130101; A61K 9/0053 20130101; C07H 17/02 20130101;
C07H 19/10 20130101; A61K 31/7076 20130101; C07H 19/073 20130101;
A61K 45/06 20130101; C07H 19/173 20130101; C07H 19/20 20130101;
A61P 31/14 20180101 |
Class at
Publication: |
424/85.7 ;
536/26.8; 514/51; 514/49 |
International
Class: |
A61K 31/7072 20060101
A61K031/7072; A61K 31/7068 20060101 A61K031/7068; A61K 45/06
20060101 A61K045/06; C07H 17/02 20060101 C07H017/02 |
Claims
1. A compound according to Formula I: ##STR00241## or a
pharmaceutically acceptable salt, solvate, stereoisomeric form,
tautomeric form, or polymorphic form thereof, wherein: Base is a
nucleobase; R.sup.1 is cyano, azido or amino; and R.sup.2 is
hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.3-C.sub.7 cycloalkyl.
2. The compound of claim 1 according to Formula Ia or Ib:
##STR00242##
3. The compound of claim 1 according to Formula II:
##STR00243##
4. The compound of claim 3 according to Formula IIa or IIb:
##STR00244##
5. The compound of claim 1 according to Formula III:
##STR00245##
6. The compound of claim 5 according to Formula IIIa or IIIb:
##STR00246##
7. The compound of claim 1 according to Formula IV:
##STR00247##
8. The compound of claim 3 according to Formula IVa or IVb:
##STR00248##
9. The compound of claim 1, wherein: Base is ##STR00249## or a
tautomer thereof; R.sup.4 is hydrogen, hydroxyl, hydroxylamine,
alkylamino, halogen, sulfanyl, amino or alkoxy; R.sup.5 is
hydrogen, halogen or methyl; and R.sup.6 is hydrogen, amino, or
halo.
10. The compound of claim 9 according to any of Formulas (V)-(XVI):
##STR00250## ##STR00251## ##STR00252##
11. (canceled)
12. The compound of claim 1, wherein R.sup.2 is hydrogen, methyl,
or halo.
13. The compound of claim 1 according to any of Formulas 1-3:
##STR00253##
14. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable excipient, carrier or
diluent.
15. The pharmaceutical composition of claim 14, wherein the
composition is an oral formulation.
16. A method for the treatment of a host infected with a hepatitis
C virus, comprising the administration of an effective treatment
amount of a compound of claim 1.
17. The method of claim 16, wherein the host is a human.
18. The method of claim 16, wherein the administration directs a
substantial amount of the compound, or pharmaceutically acceptable
salt or stereoisomer thereof, to a liver of the host.
19. The method of claim 16, wherein the compound or composition is
administered in combination or alternation with a second anti-viral
agent, wherein the second anti-viral agent is an interferon, a
nucleotide analogue, a polymerase inhibitor, an NS3 protease
inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside
polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A
antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid
mRNA inhibitor, a cyclophilin inhibitor, or a combination
thereof.
20. The method of claim 19, wherein the second anti-viral agent is
telaprevir, boceprevir, samatasvir, simeprevir, sofosbuvir,
interferon alfacon-1, interferon alfa-2b, pegylated interferon
alpha 2a, pegylated interferon alpha 2b, ribavirin, or a
combination thereof.
21. The method of claim 19, wherein the second anti-viral agent is
telaprevir, boceprevir, samatasvir, simeprevir, sofosbuvir,
interferon alfacon-1, interferon alfa-2b, pegylated interferon
alpha 2a, pegylated interferon alpha 2b, ribavirin, or a
combination thereof, and further wherein the administration is not
in combination or alternation with ribavirin.
Description
FIELD
[0001] Provided herein are compounds, methods, and pharmaceutical
compositions for use in treatment of viral infections, including
hepatitis C virus infections in hosts in need thereof. In certain
embodiments, 2'-cyano, azido and amino nucleosides are provided
which display remarkable efficacy and bioavailability for the
treatment of, for example, HCV infection in a human.
BACKGROUND
[0002] The hepatitis C virus (HCV) is the leading cause of chronic
liver disease worldwide (Boyer, N. et al., J. Hepatol. 32:98-112,
2000). HCV causes a slow growing viral infection and is the major
cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A.
M. and Bacon, B. R., Scientific American, October: 80-85, 1999;
Boyer, N. et al., J. Hepatol. 32:98-112, 2000). It is estimated
there are about 130-170 million people with chronic hepatitis C
virus infection, and there are about 350,000 deaths from hepatitis
C-related liver diseases each year (Hepatitis C Fact Sheet, World
Health Organization Fact Sheet No. 164, July 2013). Cirrhosis
caused by chronic hepatitis C infection accounts for 8,000-12,000
deaths per year in the United States, and HCV infection is the
leading indication for liver transplantation.
[0003] HCV infection becomes chronic in about 75% of cases, with
many patients initially being asymptomatic. The first symptoms of
HCV infection are often those of chronic liver disease. About 20 to
30% of patients with chronic hepatitis due to HCV develop
cirrhosis, although this may take decades. Development of cirrhosis
due to HCV also increases the risk of hepatocellular cancer (The
Merck Manual Online, Chronic Hepatitis, available at
www.merckmanuals.com/professional/hepatic_and_biliary_disorders/hepatitis-
/chronic_hepatitis. html, last revision March 2013).
[0004] In light of the fact that HCV infection has reached epidemic
levels worldwide, and has tragic effects on the infected patient,
there remains a strong need to provide new effective pharmaceutical
agents to treat hepatitis C that have low toxicity to the host.
Further, given the rising threat of other flaviviridae infections,
there remains a strong need to provide new effective pharmaceutical
agents that have low toxicity to the host. Therefore, there is a
continuing need for effective treatments of flavivirus infections
and HCV infections.
SUMMARY
[0005] Provided herein are compounds useful, for example, for the
treatment of flavivirus infections such as HCV infections. The
compounds are 2'-cyano, azido, and amino nucleosides. In certain
embodiments, the 2'-cyano, azido, and amino nucleosides display
remarkable efficacy or bioavailability, or both, for the treatment
of, for example, HCV infection in a human.
[0006] In certain embodiments, the compounds provided herein are
useful in the prevention and treatment of Flaviviridae infections
and other related conditions such as anti-Flaviviridae antibody
positive and Flaviviridae-positive conditions, chronic liver
inflammation caused by HCV, cirrhosis, fibrosis, acute hepatitis,
fulminant hepatitis, chronic persistent hepatitis, and fatigue.
These compounds or formulations can also be used prophylactically
to prevent or retard the progression of clinical illness in
individuals who are anti-Flaviviridae antibody or
Flaviviridae-antigen positive or who have been exposed to a
Flaviviridae. In particular embodiments, the Flaviviridae is
hepatitis C. In certain embodiments, the compounds are used to
treat any virus that replicates through an RNA-dependent RNA
polymerase.
[0007] A method for the treatment of a Flaviviridae infection in a
host, including a human, is also provided. In certain embodiments,
the method includes administering an effective amount of a compound
provided herein, administered either alone or in combination or
alternation with another anti-Flaviviridae agent, optionally in a
pharmaceutically acceptable carrier.
[0008] In certain embodiments, provided herein are compounds
according to Formula 2001:
##STR00002##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.10 is hydrogen, halogen, alkyl,
cycloalkyl, or aryl; and R.sup.11 is alkyl, cycloalkyl, or
aryl.
[0009] In certain embodiments, provided herein are compounds
according to Formula I:
##STR00003##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; R.sup.1 is cyano, azido, or amino; and R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.3-C.sub.7 cycloalkyl.
[0010] In certain embodiments, provided herein are compounds
according to Formula 1001:
##STR00004##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.10 is hydrogen, halogen, alkyl, cycloalkyl, or aryl; and
R.sup.11 is alkyl, cycloalkyl, or aryl.
[0011] In certain embodiments, provided herein are compounds
according to Formula 3001:
##STR00005##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.11 is hydrogen, alkyl,
cycloalkyl, or aryl; R.sup.12 is alkyl; and R.sup.13 is hydrogen,
alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or
heteroaryl.
[0012] In certain embodiments, provided herein are compounds
according to Formula 4001:
##STR00006##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.11 is hydrogen, alkyl,
cycloalkyl, or aryl; R.sup.12 is alkyl; and R.sup.13 is hydrogen,
alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or
heteroaryl.
[0013] In certain embodiments, provided herein are compounds
according to Formula 1501:
##STR00007##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.10 is hydrogen, alkyl, or halo; and R.sup.11 is hydrogen,
alkyl, cycloalkyl, or aryl.
[0014] In certain embodiments, provided herein are compounds
according to Formula 2501:
##STR00008##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.10 is hydrogen, alkyl, or halo;
and R.sup.11 is hydrogen, alkyl, cycloalkyl, or aryl.
[0015] In one aspect, the compounds provided herein are provided or
administered in combination with a second therapeutic agent, such
as one useful for the treatment or prevention of HCV infections.
Exemplary second therapeutic agents are provided in detail
elsewhere herein.
[0016] In another aspect, provided herein are pharmaceutical
compositions, single unit dosage forms, and/or kits suitable for
use in treating or preventing disorders such as HCV infections. In
certain embodiments, each of the pharmaceutical compositions,
single unit dosage forms, and/or kits comprises a therapeutically
or prophylactically effective amount of a compound provided herein,
e.g., of Formula 1001-1004bii, 1101, 1501-1504bii, 2001-2004b,
2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b,
101-148, 201-248, 512-545b, or 601-648c and a therapeutically or
prophylactically effective amount of a second therapeutic agent
such as one useful for the treatment or prevention of HCV
infections.
[0017] In certain embodiments, a method of treatment of a liver
disorder is provided comprising administering to an individual in
need thereof a treatment effective amount of a 2'-cyano, azido, and
amino nucleoside compound.
[0018] Flaviviridae which can be treated are, e.g., discussed
generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and
Howley, P. M., Lippincott Williams & Wilkins Publishers,
Philadelphia, Pa., Chapters 33-35, 2006. In a particular embodiment
of the invention, the Flaviviridae is HCV. In an alternate
embodiment, the Flaviviridae is a flavivirus or pestivirus. In
certain embodiments, the Flaviviridae can be from any class of
Flaviviridae. In certain embodiments, the Flaviviridae is a
mammalian tick-borne virus. In certain embodiments, the
Flaviviridae is a seabird tick-borne virus. In certain embodiments,
the Flaviviridae is a mosquito-borne virus. In certain embodiments,
the Flaviviridae is an Aroa virus. In certain embodiments, the
Flaviviridae is a Dengue virus. In certain embodiments, the
Flaviviridae is a Japanese encephalitis virus. In certain
embodiments, the Flaviviridae is a Kokobera virus. In certain
embodiments, the Flaviviridae is a Ntaya virus. In certain
embodiments, the Flaviviridae is a Spondweni virus. In certain
embodiments, the Flaviviridae is a Yellow fever virus. In certain
embodiments, the Flaviviridae is a Entebbe virus. In certain
embodiments, the Flaviviridae is a Modoc virus. In certain
embodiments, the Flaviviridae is a Rio Bravo virus.
[0019] Specific flaviviruses which can be treated include, without
limitation: Absettarov, Aedes, Alfuy, Alkhurma, Apoi, Aroa, Bagaza,
Banzi, Bukalasa bat, Bouboui, Bussuquara, Cacipacore, Calbertado,
Carey Island, Cell fusing agent, Cowbone Ridge, Culex, Dakar bat,
Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat,
Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey
meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam,
Kamiti River, Karshi, Kedougou, Kokobera, Koutango, Kumlinge,
Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban,
Modoc, Montana myotis leukoencephalitis, Murray valley
encephalitis, Nakiwogo, Naranjal, Negishi, Ntaya, Omsk hemorrhagic
fever, Phnom-Penh bat, Powassan, Quang Binh, Rio Bravo, Rocio,
Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis
encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik,
Sokuluk, Spondweni, Stratford, Tembusu, Tick-borne encephalitis,
Turkish sheep encephalitis, Tyuleniy, Uganda S, Usutu, Wesselsbron,
West Nile, Yaounde, Yellow fever, Yokose, and Zika.
[0020] Pestiviruses which can be treated are discussed generally in
Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P.
M., Lippincott Williams & Wilkins Publishers, Philadelphia,
Pa., Chapters 33-35, 2006. Specific pestiviruses which can be
treated include, without limitation: bovine viral diarrhea virus
("BVDV"), classical swine fever virus ("CSFV," also called hog
cholera virus), and border disease virus ("BDV").
DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0021] Provided herein are compounds, compositions and methods
useful for treating liver disorders such as HCV infection in a
subject. Further provided are dosage forms useful for such
methods.
DEFINITIONS
[0022] When referring to the compounds provided herein, the
following terms have the following meanings unless indicated
otherwise. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as is commonly understood
by one of ordinary skill in the art. In the event that there is a
plurality of definitions for a term herein, those in this section
prevail unless stated otherwise.
[0023] The term "alkyl," as used herein, unless otherwise
specified, refers to a saturated straight or branched hydrocarbon.
In certain embodiments, the alkyl group is a primary, secondary, or
tertiary hydrocarbon. In certain embodiments, the alkyl group
includes one to ten carbon atoms, i.e., C.sub.1 to C.sub.10 alkyl.
In certain embodiments, the alkyl group is methyl, CF.sub.3,
CCl.sub.3, CFCl.sub.2, CF.sub.2Cl, ethyl, CH.sub.2CF.sub.3,
CF.sub.2CF.sub.3, propyl, isopropyl, butyl, isobutyl, secbutyl,
t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,
3-methylpentyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl. The term
includes both substituted and unsubstituted alkyl groups, including
halogenated alkyl groups. In certain embodiments, the alkyl group
is a fluorinated alkyl group. Non-limiting examples of moieties
with which the alkyl group can be substituted include, but not
limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl,
carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy,
nitro, cyano, 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
and Sons, Second Edition, 1991, hereby incorporated by
reference.
[0024] The term "lower alkyl," as used herein, and unless otherwise
specified, refers to a saturated straight or branched hydrocarbon
having one to six carbon atoms, i.e., C.sub.1 to C.sub.6 alkyl. In
certain embodiments, the lower alkyl group is a primary, secondary,
or tertiary hydrocarbon. The term includes both substituted and
unsubstituted moieties.
[0025] The term "upper alkyl," as used herein, and unless otherwise
specified, refers to a saturated straight or branched hydrocarbon
having seven to thirty carbon atoms, i.e., C.sub.7 to C.sub.30
alkyl. In certain embodiments, the upper alkyl group is a primary,
secondary, or tertiary hydrocarbon. The term includes both
substituted and unsubstituted moieties.
[0026] The term "cycloalkyl," as used herein, unless otherwise
specified, refers to a saturated cyclic hydrocarbon. In certain
embodiments, the cycloalkyl group may be a saturated, and/or
bridged, and/or non-bridged, and/or a fused bicyclic group. In
certain embodiments, the cycloalkyl group includes three to ten
carbon atoms, i.e., C.sub.3 to C.sub.10 cycloalkyl. In some
embodiments, the cycloalkyl has from 3 to 15 (C.sub.3-15), from 3
to 10 (C.sub.3-10), or from 3 to 7 (C.sub.3-7) carbon atoms. In
certain embodiments, the cycloalkyl group is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.
The term includes both substituted and unsubstituted cycloalkyl
groups, including halogenated cycloalkyl groups. In certain
embodiments, the cycloalkyl group is a fluorinated cycloalkyl
group. Non-limiting examples of moieties with which the cycloalkyl
group can be substituted include, but not limited to, halogen
(fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl,
amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,
sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either unprotected, or protected as necessary.
[0027] "Alkylene" refers to divalent saturated aliphatic
hydrocarbon groups particularly having from one to eleven carbon
atoms which can be straight-chained or branched. In certain
embodiments, the alkylene group contains 1 to 10 carbon atoms. The
term includes both substituted and unsubstituted moieties. This
term is exemplified by groups such as methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), the propylene isomers (e.g.,
--CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2--) and the
like. The term includes halogenated alkylene groups. In certain
embodiments, the alkylene group is a fluorinated alkylene group.
Non-limiting examples of moieties with which the alkylene group can
be substituted include, but not limited to, halogen (fluoro,
chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino,
alkylamino, alkylaryl, arylamino, alkoxy, aryloxy, nitro, cyano,
sulfonic acid, sulfate, phosphonic acid, phosphate, and
phosphonate, either unprotected, or protected as necessary.
[0028] "Alkenyl" refers to monovalent olefinically unsaturated
hydrocarbon groups, in certain embodiment, having up to about 11
carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon
atoms, which can be straight-chained or branched and having at
least 1 or from 1 to 2 sites of olefinic unsaturation. The term
includes both substituted and unsubstituted moieties. Exemplary
alkenyl groups include ethenyl (i.e., vinyl or --CH.dbd.CH.sub.2),
n-propenyl (--CH.sub.2CH.dbd.CH.sub.2), isopropenyl
(--C(CH.sub.3).dbd.CH.sub.2), and the like. The term includes
halogenated alkenyl groups. In certain embodiments, the alkenyl
group is a fluorinated alkenyl group. Non-limiting examples of
moieties with which the alkenyl group can be substituted include,
but not limited to, halogen (fluoro, chloro, bromo, or iodo),
hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy,
aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,
phosphate, or phosphonate, either unprotected, or protected as
necessary.
[0029] The term "cycloalkenyl," as used herein, unless otherwise
specified, refers to an unsaturated cyclic hydrocarbon. In certain
embodiments, cycloalkenyl refers to mono- or multicyclic ring
systems that include at least one double bond. In certain
embodiments, the cycloalkenyl group may be a bridged, non-bridged,
and/or a fused bicyclic group. In certain embodiments, the
cycloalkyl group includes three to ten carbon atoms, i.e., C.sub.3
to C.sub.10 cycloalkyl. In some embodiments, the cycloalkenyl has
from 3 to 7 (C.sub.3-10), or from 4 to 7 (C.sub.4-7) carbon atoms.
The term includes both substituted and unsubstituted cycloalkenyl
groups, including halogenated cycloalkenyl groups. In certain
embodiments, the cycloalkenyl group is a fluorinated cycloalkenyl
group. Non-limiting examples of moieties with which the
cycloalkenyl group can be substituted include, but not limited to,
halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl,
sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or
phosphonate, either unprotected, or protected as necessary.
[0030] "Alkenylene" refers to divalent olefinically unsaturated
hydrocarbon groups, in certain embodiments, having up to about 11
carbon atoms or from 2 to 6 carbon atoms which can be
straight-chained or branched and having at least 1 or from 1 to 2
sites of olefinic unsaturation. This term is exemplified by groups
such as ethenylene (--CH.dbd.CH--), the propenylene isomers (e.g.,
--CH.dbd.CHCH.sub.2-- and --C(CH.sub.3).dbd.CH-- and
--CH.dbd.C(CH.sub.3)--) and the like. The term includes both
substituted and unsubstituted alkenylene groups, including
halogenated alkenylene groups. In certain embodiments, the
alkenylene group is a fluorinated alkenylene group. Non-limiting
examples of moieties with which the alkenylene group can be
substituted include, but not limited to, halogen (fluoro, chloro,
bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino,
arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,
phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as necessary.
[0031] "Alkynyl" refers to acetylenically unsaturated hydrocarbon
groups, in certain embodiments, having up to about 11 carbon atoms
or from 2 to 6 carbon atoms which can be straight-chained or
branched and having at least 1 or from 1 to 2 sites of alkynyl
unsaturation. Non-limiting examples of alkynyl groups include
acetylenic, ethynyl (--C.ident.CH), propargyl
(--CH.sub.2C.ident.CH), and the like. The term includes both
substituted and unsubstituted alkynyl groups, including halogenated
alkynyl groups. In certain embodiments, the alkynyl group is a
fluorinated alkynyl group. Non-limiting examples of moieties with
which the alkynyl group can be substituted include, but not limited
to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl,
sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or
phosphonate, either unprotected, or protected as necessary.
[0032] The term "aryl," as used herein, and unless otherwise
specified, refers to a substituent derived from an aromatic ring.
In an embodiment, an aryl group is a C.sub.6-C.sub.12 aryl group.
In an embodiment, an aryl group is phenyl, biphenyl, or naphthyl.
The term includes both substituted and unsubstituted moieties. An
aryl group can be substituted with any described moiety, including,
but not limited to, one or more moieties selected from halogen
(fluoro, chloro, bromo, or iodo), alkyl, haloalkyl, hydroxyl,
amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,
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 and Sons, Second
Edition, 1991.
[0033] "Alkoxy" refers to the group --OR' where R' is alkyl or
cycloalkyl. Alkoxy groups include, by way of example, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0034] "Alkoxycarbonyl" refers to a radical --C(O)-alkoxy where
alkoxy is as defined herein.
[0035] "Amino" refers to the group --NR.sup.1'R.sup.2' or
--NR.sup.1'--, wherein R.sup.1' and R.sup.2' are independently
selected from hydrogen, alkyl, and cycloalkyl.
[0036] "Amino alcohol" refers to the radical --NHLOH, wherein L is
alkylene.
[0037] "Carboxyl" or "carboxy" refers to the radical --C(O)OH.
[0038] The term "alkylamino" or "arylamino" refers to an amino
group that has one or two alkyl or aryl substituents, respectively.
In certain embodiments, the alkyl substituent is upper alkyl. In
certain embodiments, the alkyl substituent is lower alkyl. In
another embodiment, the alkyl, upper alkyl, or lower alkyl is
unsubstituted.
[0039] "Halogen" or "halo" refers to chloro, bromo, fluoro, or
iodo.
[0040] "Thioalkoxy" refers to the group --SR' where R' is alkyl or
cycloalkyl.
[0041] The term "heterocyclyl" or "heterocyclic" refers to a
monovalent monocyclic non-aromatic ring system and/or multicyclic
ring system that contains at least one non-aromatic ring, wherein
one or more of the non-aromatic ring atoms are heteroatoms
independently selected from O, S, or N; and the remaining ring
atoms are carbon atoms. In certain embodiments, the heterocyclyl or
heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10,
from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Heterocyclyl
groups are bonded to the rest of the molecule through the
non-aromatic ring. In certain embodiments, the heterocyclyl is a
monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which
may include a fused or bridged ring system, and in which the
nitrogen or sulfur atoms may be optionally oxidized, the nitrogen
atoms may be optionally quaternized, and some rings may be
partially or fully saturated, or aromatic. The heterocyclyl may be
attached to the main structure at any heteroatom or carbon atom
which results in the creation of a stable compound. Examples of
such heterocyclic radicals include, but are not limited to,
azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,
benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,
benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl,
.beta.-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl,
decahydroisoquinolinyl, dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl,
dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,
dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,
1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,
isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,
oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl,
thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In
certain embodiments, heterocyclic may also be optionally
substituted as described herein.
[0042] The term "alkylheterocyclo" refers to a heterocyclo group
with an alkyl substituent. The term "heterocycloalkyl" refers to an
alkyl group with a heterocyclo substituent.
[0043] The term "heteroaryl" refers to a monovalent monocyclic
aromatic group and/or multicyclic aromatic group that contains at
least one aromatic ring, wherein at least one aromatic ring
contains one or more heteroatoms independently selected from O, S,
and N in the ring. Heteroaryl groups are bonded to the rest of the
molecule through the aromatic ring. Each ring of a heteroaryl group
can contain one or two O atoms, one or two S atoms, and/or one to
four N atoms, provided that the total number of heteroatoms in each
ring is four or less and each ring contains at least one carbon
atom. In certain embodiments, the heteroaryl has from 5 to 20, from
5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic
heteroaryl groups include, but are not limited to, furanyl,
imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl,
oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,
pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl,
and triazolyl. Examples of bicyclic heteroaryl groups include, but
are not limited to, benzopyranyl, benzimidazolyl, benzoisoxazolyl,
benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl,
benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,
imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl,
naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl,
purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl,
quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of
tricyclic heteroaryl groups include, but are not limited to,
acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,
phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, and xanthenyl. In certain
embodiments, heteroaryl may also be optionally substituted as
described herein.
[0044] The term "alkylaryl" refers to an aryl group with an alkyl
substituent. The term "aralkyl" or "arylalkyl" refers to an alkyl
group with an aryl substituent.
[0045] The term "alkylheterocyclyl" refers to a heterocyclyl group
with an alkyl substituent. The term "heterocyclylalkyl" refers to
an alkyl group with a heterocyclyl substituent.
[0046] The term "alkylheteroaryl" refers to a heteroaryl group with
an alkyl substituent. The term heteroarylalkyl refers to an alkyl
group with a heteroaryl substituent.
[0047] The term "protecting group" 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.
[0048] "Pharmaceutically acceptable salt" refers to any salt of a
compound provided herein which retains its biological properties
and which is not toxic or otherwise undesirable for pharmaceutical
use. Such salts may be derived from a variety of organic and
inorganic counter-ions well known in the art. Such salts include,
but are not limited to: (1) acid addition salts formed with organic
or inorganic acids such as hydrochloric, hydrobromic, sulfuric,
nitric, phosphoric, sulfamic, acetic, trifluoroacetic,
trichloroacetic, propionic, hexanoic, cyclopentylpropionic,
glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic,
ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic,
3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic,
lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic,
2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic,
2-naphthalenesulfonic, 4-toluenesulfonic, camphoric,
camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic,
glucoheptonic, 3-phenylpropionic, trimethylacetic,
tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic,
hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic,
muconic acid and the like acids; or (2) base addition salts formed
when an acidic proton present in the parent compound either (a) is
replaced by a metal ion, e.g., an alkali metal ion, an alkaline
earth ion or an aluminum ion, or alkali metal or alkaline earth
metal hydroxides, such as sodium, potassium, calcium, magnesium,
aluminum, lithium, zinc, and barium hydroxide, ammonia or (b)
coordinates with an organic base, such as aliphatic, alicyclic, or
aromatic organic amines, such as ammonia, methylamine,
dimethylamine, diethylamine, picoline, ethanolamine,
diethanolamine, triethanolamine, ethylenediamine, lysine, arginine,
ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine
piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium
hydroxide, and the like.
[0049] Pharmaceutically acceptable salts further include, by way of
example only and without limitation, sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium and the like, and when the
compound contains a basic functionality, salts of non-toxic organic
or inorganic acids, such as hydrohalides, e.g. hydrochloride and
hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate,
trifluoroacetate, trichloroacetate, propionate, hexanoate,
cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate,
malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate,
tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate,
picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate
(mesylate), ethanesulfonate, 1,2-ethane-disulfonate,
2-hydroxyethanesulfonate, benzenesulfonate (besylate),
4-chlorobenzenesulfonate, 2-naphthalenesulfonate,
4-toluenesulfonate, camphorate, camphorsulfonate,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate,
3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl
sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate,
salicylate, stearate, cyclohexylsulfamate, quinate, muconate and
the like.
[0050] As used herein, the term "nucleobase" refers to the base
portion of a nucleoside or nucleotide. In certain embodiments, a
nucleobase is a purine or pyrimidine base, as defined herein.
[0051] The term "purine" or "pyrimidine" base refers to, but is not
limited to, adenine, N.sup.6-alkylpurines, N.sup.6-acylpurines
(wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl),
N.sup.6-benzylpurine, N.sup.6-halopurine, N.sup.6-vinylpurine,
N.sup.6-acetylenic purine, N.sup.6-acyl purine,
N.sup.6-hydroxyalkyl purine, N.sup.6-alkylaminopurine,
N.sup.6-thioalkyl purine, N.sup.2-alkylpurines,
N.sup.2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,
5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2-
and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including
5-fluorouracil, C.sup.5-alkylpyrimidines,
C.sup.5-benzylpyrimidines, C.sup.5-halopyrimidines,
C.sup.5-vinylpyrimidine, C.sup.5-acetylenic pyrimidine,
C.sup.5-acyl pyrimidine, C.sup.5-hydroxyalkyl purine,
C.sup.5-amidopyrimidine, C.sup.5-cyanopyrimidine,
C.sup.5-iodopyrimidine, C.sup.6-iodo-pyrimidine, C.sup.5--Br-vinyl
pyrimidine, C.sup.6--Br-vinyl pyrimidine, C.sup.5-nitropyrimidine,
C.sup.5-amino-pyrimidine, N.sup.2-alkylpurines,
N.sup.2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and
pyrazolopyrimidinyl. Purine bases include, but are not limited to,
guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine,
2,6-diaminopurine, 2-amino, 6-ethoxypurine, and 6-chloropurine.
Functional oxygen and nitrogen groups on the base 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, alkyl groups, and acyl groups such as acetyl and propionyl,
methanesulfonyl, and p-toluenesulfonyl.
[0052] The term "acyl" or "O-linked ester" refers to a group of the
formula C(O)R', wherein R' is alkyl or cycloalkyl (including lower
alkyl), carboxylate reside of amino acid, aryl including phenyl,
alkaryl, arylalkyl including benzyl, alkoxyalkyl including
methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted
alkyl (including lower alkyl), aryl including phenyl optionally
substituted with chloro, bromo, fluoro, iodo, C.sub.1 to C.sub.4
alkyl or C.sub.1 to C.sub.4 alkoxy, sulfonate esters such as alkyl
or arylalkyl sulphonyl including methanesulfonyl, the mono, di or
triphosphate ester, trityl or monomethoxy-trityl, substituted
benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including
methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in
the esters optimally comprise a phenyl group. In particular, acyl
groups include acetyl, trifluoroacetyl, methylacetyl,
cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl,
octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl,
diphenylacetyl,
.alpha.-methoxy-.alpha.-trifluoromethyl-phenylacetyl, bromoacetyl,
2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl,
2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl,
trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl,
fluoroacetyl, bromodifluoroacetyl, methoxyacetyl,
2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl,
phenoxyacetyl, tert-butylacetyl, trichloroacetyl,
monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl,
perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl,
7-chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl,
7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl,
nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-dioxaheptanoyl,
perfluoroheptanoyl, methoxybenzoyl, methyl
3-amino-5-phenylthiophene-2-carboxyl,
3,6-dichloro-2-methoxy-benzoyl,
4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl,
omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl,
3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl,
pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl,
2,6-pyridinedicarboxyl, cyclopropane-carboxyl,
cyclobutane-carboxyl, perfluorocyclohexyl carboxyl,
4-methylbenzoyl, chloromethyl isoxazolyl carbonyl,
perfluorocyclohexyl carboxyl, crotonyl,
1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,
1-pyrrolidinecarbonyl, 4-phenylbenzoyl.
[0053] The term "amino acid" refers to naturally occurring and
synthetic .alpha., .beta., .gamma., or .delta. amino acids, and
includes but is not limited to, amino acids found in proteins, i.e.
glycine, alanine, valine, leucine, isoleucine, methionine,
phenylalanine, tryptophan, proline, serine, threonine, cysteine,
tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,
arginine and histidine. In certain embodiments, the amino acid is
in the L-configuration. In certain embodiments, the amino acid is
in the D-configuration. In certain embodiments, the amino acid can
be provided as a substituent of compounds described herein, such as
an alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl,
phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl,
threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl,
aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl,
.beta.-alanyl, .beta.-valinyl, .beta.-leucinyl,
.beta.-isoleuccinyl, .beta.-prolinyl, .beta.-phenylalaninyl,
.beta.-tryptophanyl, .beta.-methioninyl, .beta.-glycinyl,
.beta.-serinyl, .beta.-threoninyl, .beta.-cysteinyl,
.beta.-tyrosinyl, .beta.-asparaginyl, .beta.-glutaminyl,
.beta.-aspartoyl, .beta.-glutaroyl, .beta.-lysinyl,
.beta.-argininyl or .beta.-histidinyl substituent.
[0054] The term "amino acid derivative" refers to a group derivable
from a naturally or non-naturally occurring amino acid, as
described and exemplified herein Amino acid derivatives are
apparent to those of skill in the art and include, but are not
limited to, ester, amino alcohol, amino aldehyde, amino lactone,
and N-methyl derivatives of naturally and non-naturally occurring
amino acids. In an embodiment, an amino acid derivative is provided
as a substituent of a compound described herein, wherein the
substituent is --NR.sup.X-G(S.sub.C)--C(O)-Q.sup.1, wherein Q.sup.1
is --SR.sup.Y, --NR.sup.YR.sup.Y, or alkoxyl, R.sup.Y is hydrogen
or alkyl, S.sub.C is a side chain of a naturally occurring or
non-naturally occurring amino acid, G is C.sub.1-C.sub.2 alkyl, and
R.sup.X is hydrogen or R.sup.X and S.sub.C, together with the atoms
to which they are attached, combine to form a five-membered
heterocyclic ring. In an embodiment, an amino acid derivative is
provided as a substituent of a compound described herein, wherein
the substituent is --O--C(O)-G(S.sub.C)--NH-Q.sup.2, wherein
Q.sup.2 is hydrogen or alkoxyl, S.sub.C is a side chain of a
naturally occurring or non-naturally occurring amino acid and G is
C.sub.1-C.sub.2 alkyl. In certain embodiments, Q.sup.2 and S.sub.C,
together with the atoms to which they are attached, combine to form
a five-membered heterocyclic ring. In certain embodiments, G is
C.sub.1 alkyl and S.sub.C is hydrogen, alkyl, arylalkyl,
heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl,
hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl,
sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, or
hydroxylarylalkyl. In an embodiment, an amino acid derivative is
provided as a substituent of a compound described herein, wherein
the amino acid derivative is in the D-configuration. In an
embodiment, an amino acid derivative is provided as a substituent
of a compound described herein, wherein the amino acid derivative
is in the L-configuration.
[0055] As used herein, the term "hydroxylalkyl" refers to an alkyl
group with a hydroxyl substituent, where alkyl is as described
herein.
[0056] As used herein, the term "aminoalkyl" refers to an alkyl
group with an amino substituent, where alkyl and amino are as
described herein.
[0057] The term "alkylaryl" refers to an aryl group with an alkyl
substituent. The term "aralkyl" or "arylalkyl" refers to an alkyl
group with an aryl substituent.
[0058] The term "alkylheterocyclyl" refers to a heterocyclyl group
with an alkyl substituent. The term "heterocyclylalkyl" refers to
an alkyl group with a heterocyclyl substituent.
[0059] The term "alkylheteroaryl" refers to a heteroaryl group with
an alkyl substituent. The term "heteroarylalkyl" refers to an alkyl
group with a heteroaryl substituent.
[0060] As used herein, the term "carboxylalkyl" refers to the group
-alkyl-C(O)OH, where alkyl is as described herein.
[0061] As used herein, the term "aminoiminoaminoalkyl" refers to
the group -alkyl-amino-C(NH)-amino, where alkyl and amino are as
described herein.
[0062] As used herein, the term "aminocarbonylalkyl" refers to the
group -alkyl-C(O)-amino, where alkyl and amino are as described
herein.
[0063] As used herein, the term "sulfanylalkyl" refers to the group
-alkyl-SH, where alkyl is as described herein.
[0064] As used herein, the term "carbamoylalkyl" refers to the
group -alkyl-C(O)-amino, where alkyl and amino are as described
herein.
[0065] As used herein, the term "alkylsulfanylalkyl" refers to the
group -alkyl-S-alkyl, where alkyl is as described herein.
[0066] As used herein, the term "hydroxylarylalkyl" refers to the
group -alkyl-aryl-OH, where alkyl and aryl are as described
herein.
[0067] The term "substantially free of" or "substantially in the
absence of" with respect to a nucleoside composition refers to a
nucleoside composition that includes at least 85 or 90% by weight,
in certain embodiments 95%, 98% , 99% or 100% by weight, of the
designated diastereomer of that nucleoside. In certain embodiments,
in the methods and compounds provided herein, the compounds are
substantially free of an undesignated diastereomer.
[0068] Similarly, the term "isolated" with respect to a nucleoside
composition refers to a nucleoside composition that includes at
least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of the
nucleoside, the remainder comprising other chemical species or
enantiomers.
[0069] "Solvate" refers to a compound provided herein or a salt
thereof, that further includes a stoichiometric or
non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
[0070] "Isotopic composition" refers to the amount of each isotope
present for a given atom, and "natural isotopic composition" refers
to the naturally occurring isotopic composition or abundance for a
given atom. Atoms containing their natural isotopic composition may
also be referred to herein as "non-enriched" atoms. Unless
otherwise designated, the atoms of the compounds recited herein are
meant to represent any stable isotope of that atom. For example,
unless otherwise stated, when a position is designated specifically
as "H" or "hydrogen," the position is understood to have hydrogen
at its natural isotopic composition.
[0071] "Isotopic enrichment" refers to the percentage of
incorporation of an amount of a specific isotope at a given atom in
a molecule in the place of that atom's natural isotopic abundance.
For example, deuterium enrichment of 1% at a given position means
that 1% of the molecules in a given sample contain deuterium at the
specified position. Because the naturally occurring distribution of
deuterium is about 0.0156%, deuterium enrichment at any position in
a compound synthesized using non-enriched starting materials is
about 0.0156%. The isotopic enrichment of the compounds provided
herein can be determined using conventional analytical methods
known to one of ordinary skill in the art, including mass
spectrometry and nuclear magnetic resonance spectroscopy.
[0072] "Isotopically enriched" refers to an atom having an isotopic
composition other than the natural isotopic composition of that
atom. "Isotopically enriched" may also refer to a compound
containing at least one atom having an isotopic composition other
than the natural isotopic composition of that atom.
[0073] As used herein, "alkyl," "cycloalkyl," "alkenyl,"
"cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl,"
"amino," "carboxyl," "alkylamino," "arylamino," "thioalkyoxy,"
"heterocyclyl," "heteroaryl," "alkylheterocyclyl,"
"alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine,"
"pyrimidine," "carboxyl" and "amino acid" groups optionally
comprise deuterium at one or more positions where hydrogen atoms
are present, and wherein the deuterium composition of the atom or
atoms is other than the natural isotopic composition.
[0074] Also as used herein, "alkyl," "cycloalkyl," "alkenyl,"
"cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl,"
"carboxyl," "alkylamino," "arylamino," "thioalkyoxy,"
"heterocyclyl," "heteroaryl," "alkylheterocyclyl,"
"alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine,"
"pyrimidine," "carboxyl" and "amino acid" groups optionally
comprise carbon-13 at an amount other than the natural isotopic
composition.
[0075] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0076] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response in an assay that measures
such response.
[0077] The term "host," as used herein, refers to any unicellular
or multicellular organism in which the virus can replicate,
including cell lines and animals, and in certain embodiments, a
human. Alternatively, the host can be carrying a part of the
Flaviviridae viral genome, whose replication or function can be
altered by the compounds of the present invention. The term host
specifically includes infected cells, cells transfected with all or
part of the Flaviviridae genome and animals, in particular,
primates (including 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).
[0078] As used herein, the terms "subject" and "patient" are used
interchangeably herein. The terms "subject" and "subjects" refer to
an animal, such as a mammal including a non-primate (e.g., a cow,
pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey
such as a cynomolgous monkey, a chimpanzee and a human), and for
example, a human. In certain embodiments, the subject is refractory
or non-responsive to current treatments for hepatitis C infection.
In another embodiment, the subject is a farm animal (e.g., a horse,
a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain
embodiments, the subject is a human.
[0079] As used herein, the terms "therapeutic agent" and
"therapeutic agents" refer to any agent(s) which can be used in the
treatment or prevention of a disorder or one or more symptoms
thereof. In certain embodiments, the term "therapeutic agent"
includes a compound provided herein. In certain embodiments, a
therapeutic agent is an agent which is known to be useful for, or
has been or is currently being used for the treatment or prevention
of a disorder or one or more symptoms thereof.
[0080] "Therapeutically effective amount" refers to an amount of a
compound or composition that, when administered to a subject for
treating a disease, is sufficient to effect such treatment for the
disease. A "therapeutically effective amount" can vary depending
on, inter alia, the compound, the disease and its severity, and the
age, weight, etc., of the subject to be treated.
[0081] "Treating" or "treatment" of any disease or disorder refers,
in certain embodiments, to ameliorating a disease or disorder that
exists in a subject. In another embodiment, "treating" or
"treatment" includes ameliorating at least one physical parameter,
which may be indiscernible by the subject. In yet another
embodiment, "treating" or "treatment" includes modulating the
disease or disorder, either physically (e.g., stabilization of a
discernible symptom) or physiologically (e.g., stabilization of a
physical parameter) or both. In yet another embodiment, "treating"
or "treatment" includes delaying the onset of the disease or
disorder.
[0082] As used herein, the terms "prophylactic agent" and
"prophylactic agents" as used refer to any agent(s) which can be
used in the prevention of a disorder or one or more symptoms
thereof. In certain embodiments, the term "prophylactic agent"
includes a compound provided herein. In certain other embodiments,
the term "prophylactic agent" does not refer a compound provided
herein. For example, a prophylactic agent is an agent which is
known to be useful for, or has been or is currently being used to
prevent or impede the onset, development, progression and/or
severity of a disorder.
[0083] As used herein, the phrase "prophylactically effective
amount" refers to the amount of a therapy (e.g., prophylactic
agent) which is sufficient to result in the prevention or reduction
of the development, recurrence or onset of one or more symptoms
associated with a disorder, or to enhance or improve the
prophylactic effect(s) of another therapy (e.g., another
prophylactic agent).
[0084] Compounds
[0085] Provided herein are 2'-cyano, azido and amino nucleoside
compounds. In certain embodiments, they are useful for the
treatment of Flaviviridae infections such as HCV infection. The
2'-cyano, azido and amino nucleoside compounds can be formed as
described herein and used for the treatment of Flaviviridae
infections such as HCV infection.
[0086] In certain embodiments, provided herein are compounds
according to Formula 3001:
##STR00009##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.11 is hydrogen, alkyl,
cycloalkyl, or aryl; R.sup.12 is alkyl; and R.sup.13 is hydrogen,
alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or
heteroaryl.
[0087] In certain embodiments, provided herein are compounds
according to Formula 3001a or 3001b:
##STR00010##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as
defined in the context of Formula 3001.
[0088] In certain embodiments, provided herein are compounds
according to Formula 3002:
##STR00011##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0089] In certain embodiments, provided herein are compounds
according to Formula 3002a or 3002b:
##STR00012##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0090] In certain embodiments, provided herein are compounds
according to Formula 3003:
##STR00013##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0091] In certain embodiments, provided herein are compounds
according to Formula 3003a or 3003b:
##STR00014##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0092] In certain embodiments, provided herein are compounds
according to Formula 3004:
##STR00015##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0093] In certain embodiments, provided herein are compounds
according to Formula 3004a or 3004b:
##STR00016##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 3001.
[0094] In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each W is O. In
certain embodiments, provided herein are compounds according to any
of Formulas 3001-3004b, wherein each W is S. In certain
embodiments, provided herein are compounds according to any of
Formulas 3001-3004b, wherein each R.sup.11 is isopropyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 3001-3004b, wherein each R.sup.12 is methyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 3001-3004b, wherein each R.sup.13 is phenyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 3001-3004b, wherein each R.sup.13 is naphthyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 3001-3004b, wherein each R.sup.11 is isopropyl and each
R.sup.12 is methyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each
R.sup.11 is isopropyl, each R.sup.12 is methyl, and each R.sup.13
is phenyl or naphthyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each
R.sup.11 is isopropyl, each R.sup.12 is methyl, and each R.sup.13
is phenyl. In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each R.sup.11 is
isopropyl, each R.sup.12 is methyl, and each R.sup.13 is
naphthyl.
[0095] In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each W is O and
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 3001-3004b, wherein each
W is O and each R.sup.12 is methyl. In certain embodiments,
provided herein are compounds according to any of Formulas
3001-3004b, wherein each W is O and each R.sup.13 is phenyl. In
certain embodiments, provided herein are compounds according to any
of Formulas 3001-3004b, wherein each W is O and each R.sup.13 is
naphthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each W is O, each
R.sup.11 is isopropyl, each R.sup.12 is methyl, and each R.sup.13
is phenyl or naphthyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each W
is O, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is phenyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each W
is O, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is naphthyl.
[0096] In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each W is S and
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 3001-3004b, wherein each
W is S and each R.sup.12 is methyl. In certain embodiments,
provided herein are compounds according to any of Formulas
3001-3004b, wherein each W is S and each R.sup.13 is phenyl or
naphthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 3001-3004b, wherein each W is S, each
R.sup.11 is isopropyl, each R.sup.12 is methyl, and each R.sup.13
is phenyl or naphthyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each W
is S, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is phenyl. In certain embodiments, provided herein are
compounds according to any of Formulas 3001-3004b, wherein each W
is S, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is naphthyl.
[0097] In certain embodiments, provided herein are compounds
according to Formula 2001:
##STR00017##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.10 is hydrogen, halogen, alkyl,
cycloalkyl, or aryl; and R.sup.11 is alkyl, cycloalkyl, or
aryl.
[0098] In certain embodiments, provided herein are compounds
according to Formula 2001a or 2001b:
##STR00018##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.2, R.sup.10, and R.sup.11 are as defined in the
context of Formula 2001.
[0099] In certain embodiments, provided herein are compounds
according to Formula 2002:
##STR00019##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0100] In certain embodiments, provided herein are compounds
according to Formula 2002a or 2002b:
##STR00020##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0101] In certain embodiments, provided herein are compounds
according to Formula 2003:
##STR00021##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0102] In certain embodiments, provided herein are compounds
according to Formula 2003a or 2003b:
##STR00022##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0103] In certain embodiments, provided herein are compounds
according to Formula 2004:
##STR00023##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0104] In certain embodiments, provided herein are compounds
according to Formula 2004a or 2004b:
##STR00024##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2001.
[0105] In certain embodiments, provided herein are compounds
according to Formula 2501:
##STR00025##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.10 is hydrogen, alkyl, or halo;
and R.sup.11 is hydrogen, alkyl, cycloalkyl, or aryl.
[0106] In certain embodiments, provided herein are compounds
according to Formula 2501a or 2501b:
##STR00026##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.2, R.sup.10, and R.sup.11 are as defined in the
context of Formula 2501.
[0107] In certain embodiments, provided herein are compounds
according to Formula 2502:
##STR00027##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0108] In certain embodiments, provided herein are compounds
according to Formula 2502a or 2502b:
##STR00028##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0109] In certain embodiments, provided herein are compounds
according to Formula 2503:
##STR00029##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0110] In certain embodiments, provided herein are compounds
according to Formula 2503a or 2503b:
##STR00030##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0111] In certain embodiments, provided herein are compounds
according to Formula 2504:
##STR00031##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0112] In certain embodiments, provided herein are compounds
according to Formula 2504a or 2504b:
##STR00032##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.2, R.sup.10, and R.sup.11 are as defined in the context of
Formula 2501.
[0113] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is O. In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is S. In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 2001-2004b and
2501-2504b, wherein each R.sup.10 is hydrogen. In certain
embodiments, provided herein are compounds according to any of
Formulas 2001-2004b and 2501-2504b, wherein each R.sup.10 is
hydrogen and each R.sup.11 is isopropyl.
[0114] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is O and each R.sup.11 is isopropyl. In certain embodiments,
provided herein are compounds according to any of Formulas
2001-2004b and 2501-2504b, wherein each W is O and each R.sup.10 is
hydrogen. In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is O, each R.sup.11 is isopropyl, and each R.sup.10 is
hydrogen.
[0115] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is S and each R.sup.11 is isopropyl. In certain embodiments,
provided herein are compounds according to any of Formulas
2001-2004b and 2501-2504b, wherein each W is S and each R.sup.10 is
hydrogen. In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2004b and 2501-2504b, wherein
each W is S, each R.sup.11 is isopropyl, and each R.sup.10 is
hydrogen.
[0116] In certain embodiments, provided herein are compounds
according to Formula I:
##STR00033##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; R.sup.1 is cyano, azido, or amino; and R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.3-C.sub.7 cycloalkyl.
[0117] In certain embodiments, provided herein are compounds
according to Formula Ia or Ib:
##STR00034##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
R.sup.1, and R.sup.2 are as defined in the context of Formula
I.
[0118] In certain embodiments, provided herein are compounds
according to Formula II:
##STR00035##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0119] In certain embodiments, provided herein are compounds
according to Formula IIa or IIb:
##STR00036##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0120] In certain embodiments, provided herein are compounds
according to Formula III:
##STR00037##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0121] In certain embodiments, provided herein are compounds
according to Formula IIIa or IIIb:
##STR00038##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0122] In certain embodiments, provided herein are compounds
according to Formula IV:
##STR00039##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0123] In certain embodiments, provided herein are compounds
according to Formula IVa or IVb:
##STR00040##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula I.
[0124] In certain embodiments, provided herein are compounds
according to Formula 4001:
##STR00041##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; R.sup.11 is hydrogen, alkyl,
cycloalkyl, or aryl; R.sup.12 is alkyl; and R.sup.13 is hydrogen,
alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or
heteroaryl.
[0125] In certain embodiments, provided herein are compounds
according to Formula 4001a or 4001b:
##STR00042##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 4001.
[0126] In certain embodiments, provided herein are compounds
according to Formula 4001ai, 4001aii, 4001bi, or 4001bii:
##STR00043##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.11, R.sup.12, and R.sup.13 are as defined in the
context of Formula 4001.
[0127] In certain embodiments, provided herein are compounds
according to Formula 4002:
##STR00044##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0128] In certain embodiments, provided herein are compounds
according to Formula 4002a or 4002b:
##STR00045##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0129] In certain embodiments, provided herein are compounds
according to Formula 4002ai, 4002aii, 4002bi, or 4002bii:
##STR00046##
##STR00047##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0130] In certain embodiments, provided herein are compounds
according to Formula 4003:
##STR00048##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0131] In certain embodiments, provided herein are compounds
according to Formula 4003a or 4003b:
##STR00049##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0132] In certain embodiments, provided herein are compounds
according to Formula 4003ai, 4003aii, 4003bi, or 4003bii:
##STR00050##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0133] In certain embodiments, provided herein are compounds
according to Formula 4004:
##STR00051##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0134] In certain embodiments, provided herein are compounds
according to Formula 4004a or 4004b:
##STR00052##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0135] In certain embodiments, provided herein are compounds
according to Formula 4004ai, 4004aii, 4004bi, or 4004bii:
##STR00053##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.11, R.sup.12, and R.sup.13 are as defined in the context
of Formula 4001.
[0136] In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is O. In
certain embodiments, provided herein are compounds according to any
of Formulas 4001-4004bii, wherein each W is S.
[0137] In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each R.sup.11 is
isopropyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each R.sup.12 is
methyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each R.sup.13 is
phenyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each R.sup.13 is
naphthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each R.sup.13 is
phenyl or napthyl, and each R.sup.11 is isopropyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 4001-4004bii, wherein each R.sup.13 is phenyl and each
R.sup.11 is isopropyl. In certain embodiments, provided herein are
compounds according to any of Formulas 4001-4004bii, wherein each
R.sup.13 is napthyl and each R.sup.11 is isopropyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 4001-4004bii, wherein each R.sup.13 is phenyl, each
R.sup.12 is methyl, and each R.sup.11 is isopropyl. In certain
embodiments, provided herein are compounds according to any of
Formulas 4001-4004bii, wherein each R.sup.13 is napthyl, each
R.sup.12 is methyl, and each R.sup.11 is isopropyl.
[0138] In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is O and
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is O and each R.sup.12 is methyl. In certain embodiments,
provided herein are compounds according to any of Formulas
4001-4004bii, wherein each W is O and each R.sup.13 is phenyl or
napthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is O and
each R.sup.13 is phenyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is O and each R.sup.13 is naphthyl. In certain embodiments,
provided herein are compounds according to any of Formulas
4001-4004bii, wherein each W is O, each R.sup.11 is isopropyl, and
each R.sup.13 is phenyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is O, each R.sup.11 is isopropyl, and each R.sup.13 is
napthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is O,
each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is phenyl. In certain embodiments, provided herein are
compounds according to any of Formulas 4001-4004bii, wherein each W
is O, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is napthyl.
[0139] In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is S and
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is S and each R.sup.12 is methyl. In certain embodiments,
provided herein are compounds according to any of Formulas
4001-4004bii, wherein each W is S and each R.sup.13 is phenyl or
napthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is S and
each R.sup.13 is phenyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is S and each R.sup.13 is naphthyl. In certain embodiments,
provided herein are compounds according to any of Formulas
4001-4004bii, wherein each W is S, each R.sup.11 is isopropyl, and
each R.sup.13 is phenyl. In certain embodiments, provided herein
are compounds according to any of Formulas 4001-4004bii, wherein
each W is S, each R.sup.11 is isopropyl, and each R.sup.13 is
napthyl. In certain embodiments, provided herein are compounds
according to any of Formulas 4001-4004bii, wherein each W is S,
each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is phenyl. In certain embodiments, provided herein are
compounds according to any of Formulas 4001-4004bii, wherein each W
is S, each R.sup.11 is isopropyl, each R.sup.12 is methyl, and each
R.sup.13 is napthyl.
[0140] In certain embodiments, provided herein are compounds
according to Formula 1001:
##STR00054##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.10 is hydrogen, halogen, alkyl, cycloalkyl, or aryl; and
R.sup.11 is alkyl, cycloalkyl, or aryl.
[0141] In certain embodiments, provided herein are compounds
according to Formula 1001a or 1001b:
##STR00055##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.10, and R.sup.11 are as defined in the context of
Formula 1001.
[0142] In certain embodiments, provided herein are compounds
according to Formula 1001ai, 1001aii, 1001bi, or 1001bii:
##STR00056##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.10, and R.sup.11 are as defined in the context of
Formula 1001.
[0143] In certain embodiments, provided herein are compounds
according to Formula 1002:
##STR00057##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0144] In certain embodiments, provided herein are compounds
according to Formula 1002a:
##STR00058##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0145] In certain embodiments, provided herein are compounds
according to Formula 1002ai or 1002aii:
##STR00059##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0146] In certain embodiments, provided herein are compounds
according to Formula 1003:
##STR00060##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0147] In certain embodiments, provided herein are compounds
according to Formula 1003a:
##STR00061##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0148] In certain embodiments, provided herein are compounds
according to Formula 1003ai or 1003aii:
##STR00062##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0149] In certain embodiments, provided herein are compounds
according to Formula 1004:
##STR00063##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0150] In certain embodiments, provided herein are compounds
according to Formula 1004a:
##STR00064##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0151] In certain embodiments, provided herein are compounds
according to Formula 1004ai or 1004aii:
##STR00065##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0152] In certain embodiments, provided herein are compounds
according to Formula 1002b:
##STR00066##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0153] In certain embodiments, provided herein are compounds
according to Formula 1002bi or 1002bii:
##STR00067##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0154] In certain embodiments, provided herein are compounds
according to Formula 1003b:
##STR00068##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0155] In certain embodiments, provided herein are compounds
according to Formula 1003bi or 1003bii:
##STR00069##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0156] In certain embodiments, provided herein are compounds
according to Formula 1004b:
##STR00070##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0157] In certain embodiments, provided herein are compounds
according to Formula 1004bi or 1004bii:
##STR00071##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1001.
[0158] In certain embodiments, provided herein are compounds
according to Formula 1501:
##STR00072##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; W is O or S; R.sup.1 is cyano, azido, or amino;
R.sup.10 is hydrogen, alkyl, or halo; and R.sup.11 is hydrogen,
alkyl, cycloalkyl, or aryl.
[0159] In certain embodiments, provided herein are compounds
according to Formula 1501a or 1501b:
##STR00073##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.10, and R.sup.11 are as defined in the context of
Formula 1501.
[0160] In certain embodiments, provided herein are compounds
according to Formula 1501ai, 1501aii, 1501bi, or 1501bii:
##STR00074##
##STR00075##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.1, R.sup.10, and R.sup.11 are as defined in the context of
Formula 1501.
[0161] In certain embodiments, provided herein are compounds
according to Formula 1502:
##STR00076##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0162] In certain embodiments, provided herein are compounds
according to Formula 1502a or 1502b:
##STR00077##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0163] In certain embodiments, provided herein are compounds
according to Formula 1502ai, 1502aii, 1502bi, or 1502bii:
##STR00078##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0164] In certain embodiments, provided herein are compounds
according to Formula 1503:
##STR00079##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0165] In certain embodiments, provided herein are compounds
according to Formula 1503a or 1503b:
##STR00080##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0166] In certain embodiments, provided herein are compounds
according to Formula 1503ai, 1503aii, 1503bi, or 1503bii:
##STR00081##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0167] In certain embodiments, provided herein are compounds
according to Formula 1504:
##STR00082##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0168] In certain embodiments, provided herein are compounds
according to Formula 1504a or 1504b:
##STR00083##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0169] In certain embodiments, provided herein are compounds
according to Formula 1504ai, 1504aii, 1504bi, or 1504bii:
##STR00084##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base,
W, R.sup.10, and R.sup.11 are as defined in the context of Formula
1501.
[0170] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is O. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is S. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each R.sup.11 is isopropyl. In certain embodiments, provided herein
are compounds according to any of Formulas 1001-1004bii or
1501-1504bii, wherein each R.sup.10 is hydrogen. In certain
embodiments, provided herein are compounds according to any of
Formulas 1001-1004bii or 1501-1504bii, wherein each R.sup.10 is
hydrogen and each R.sup.11 is isopropyl.
[0171] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is O and each R.sup.11 is isopropyl. In certain embodiments,
provided herein are compounds according to any of Formulas
1001-1004bii or 1501-1504bii, wherein each W is O and each R.sup.10
is hydrogen. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is O, each R.sup.11 is isopropyl, and each R.sup.10 is
hydrogen.
[0172] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is S and each R.sup.11 is isopropyl. In certain embodiments,
provided herein are compounds according to any of Formulas
1001-1004bii or 1501-1504bii, wherein each W is S and each R.sup.10
is hydrogen. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii or 1501-1504bii, wherein
each W is S, each R.sup.11 is isopropyl, and each R.sup.10 is
hydrogen.
[0173] In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each
Base is independently
##STR00085##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl,
amino, or alkoxy; each R.sup.5 is independently hydrogen, halogen,
or methyl; and each R.sup.6 is independently hydrogen, amino, or
halogen.
[0174] In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each
Base is independently
##STR00086##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl,
amino, or alkoxy; each R.sup.5 is independently hydrogen, halogen,
or methyl; each R.sup.6 is independently hydrogen, amino, or
halogen; and W is O.
[0175] In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each
Base is independently
##STR00087##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl,
amino, or alkoxy; each R.sup.5 is independently hydrogen, halogen,
or methyl; each R.sup.6 is independently hydrogen, amino, or
halogen; and W is S.
[0176] In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each
Base is independently
##STR00088##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, or amino; and each R.sup.5 is independently
hydrogen, halogen, or methyl. In certain embodiments, provided
herein are compounds according to any of Formulas I-IVb,
1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b,
or 4001-4004bii, wherein each Base is independently
##STR00089##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, or amino; and each R.sup.5 is independently
halogen. In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii wherein each
Base is independently
##STR00090##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl or amino; and each R.sup.5 is fluoro.
[0177] In certain embodiments, provided herein are compounds
according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each
Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine.
[0178] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein:
each Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; and
each W is O. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein:
each Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; and
each W is S.
[0179] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein:
each Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each
W is O; and each R.sup.10 is hydrogen. In certain embodiments,
provided herein are compounds according to any of Formulas
1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b,
or 4001-4004bii, wherein: each Base is independently adenine,
thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or
2-amino,6-ethoxypurine; each W is O; and each R.sup.11 is
isopropyl. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 3001-3004b, or 4001-4004bii, wherein: each Base is
independently adenine, thymine, cytosine, guanine, 5-fluorouracil,
2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is O; each
R.sup.10 is hydrogen; and each R.sup.11 is isopropyl.
[0180] In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein:
each Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each
W is S; and each R.sup.10 is hydrogen. In certain embodiments,
provided herein are compounds according to any of Formulas
1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b,
or 4001-4004bii, wherein: each Base is independently adenine,
thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or
2-amino,6-ethoxypurine; each W is S; and each R.sup.11 is
isopropyl. In certain embodiments, provided herein are compounds
according to any of Formulas 1001-1004bii, 1501-1504bii,
2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein:
each Base is independently adenine, thymine, cytosine, guanine,
5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each
W is S; each R.sup.10 is hydrogen; and each R.sup.11 is
isopropyl.
[0181] In certain embodiments, provided herein are compounds
according to any of Formulas 1005-1012:
##STR00091## ##STR00092##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: W and
R.sup.1 are as described in the context of Formula 1001. In an
embodiment, a compound according to any of Formulas 1005-1012 is
provided wherein W is O. In an embodiment, a compound according to
any of Formulas 1005-1012 is provided wherein W is S.
[0182] In certain embodiments, provided herein are compounds
according to any of Formulas 2005-2012:
##STR00093## ##STR00094##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: W,
R.sup.1 and R.sup.2 are as described in the context of Formula
2001. In an embodiment, a compound according to any of Formulas
2005-2012 is provided wherein W is O. In an embodiment, a compound
according to any of Formulas 2005-2012 is provided wherein W is
S.
[0183] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2012, wherein each R.sup.2 is
independently hydrogen, methyl, or halogen; and W is O. In certain
embodiments, provided herein are compounds according to any of
Formulas 2001-2012, wherein each R.sup.2 is independently hydrogen,
methyl, or halogen; and W is S.
[0184] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2012, wherein each R.sup.2 is
hydrogen and W is O. In certain embodiments, provided herein are
compounds according to any of Formulas 2001-2012, wherein each
R.sup.2 is hydrogen and W is S.
[0185] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2012, wherein each R.sup.2 is
methyl and W is O. In certain embodiments, provided herein are
compounds according to any of Formulas 2001-2012, wherein each
R.sup.2 is methyl and W is S.
[0186] In certain embodiments, provided herein are compounds
according to any of Formulas 2001-2012, wherein each R.sup.2 is
independently halogen and W is O. In certain embodiments, provided
herein are compounds according to any of Formulas 2001-2012,
wherein each R.sup.2 is independently halogen and W is S.
[0187] In certain embodiments, provided herein are compounds
according to any of Formulas V-XIIb:
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: each
R.sup.5 is independently hydrogen, halogen, or methyl; and R.sup.1
and R.sup.2 are as defined in the context of Formula I.
[0188] In certain embodiments, provided herein are compounds
according to any of Formulas XIII-XIVb or XV-XVIb:
##STR00101## ##STR00102##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein R.sup.1
and R.sup.2 are as defined in the context of Formula I.
[0189] In certain embodiments, provided herein are compounds
according to any of Formulas I-XVIb or 2001-2012, wherein each
R.sup.2 is independently hydrogen, methyl, or halogen. In certain
embodiments, provided herein are compounds according to any of
Formulas I-XVIb or 2001-2012, wherein each R.sup.2 is hydrogen. In
certain embodiments, provided herein are compounds according to any
of Formulas I-XVIb or 2001-2012, wherein each R.sup.2 is methyl. In
certain embodiments, provided herein are compounds according to any
of Formulas I-XVIb or 2001-2012, wherein each R.sup.2 is
independently halogen.
[0190] In certain embodiments, provided herein are compounds
according to any of Formulas XVII-XVIIb:
##STR00103##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein R.sup.5
is halogen; and R.sup.1 and R.sup.2 are as defined in the context
of Formula I.
[0191] In certain embodiments, provided herein are compounds
according to any of Formulas XVII-XVIIb, wherein each R.sup.2 is
independently hydrogen, methyl, or halo. In certain embodiments,
provided herein are compounds according to any of Formulas
XVII-XVIIb, wherein each R.sup.2 is hydrogen. In certain
embodiments, provided herein are compounds according to any of
Formulas XVII-XVIIb, wherein each R.sup.2 is methyl. In certain
embodiments, provided herein are compounds according to any of
Formulas XVII-XVIIb, wherein each R.sup.2 is independently
halogen.
[0192] In certain embodiments, provided herein are compounds
according to any of Formulas XVII-XVIIb, wherein R.sup.5 is fluoro.
In certain embodiments, provided herein are compounds according to
any of Formulas XVII-XVIIb, wherein R.sup.5 is fluoro; and each
R.sup.2 is independently hydrogen, methyl, or halo. In certain
embodiments, provided herein are compounds according to any of
Formulas XVII-XVIIb, wherein R.sup.5 is fluoro; and each R.sup.2 is
hydrogen. In certain embodiments, provided herein are compounds
according to any of Formulas XVII-XVIIb, wherein R.sup.5 is fluoro;
and each R.sup.2 is methyl. In certain embodiments, provided herein
are compounds according to any of Formulas XVII-XVIIb, wherein
R.sup.5 is fluoro; and each R.sup.2 is independently halogen.
[0193] In certain embodiments, provided herein are compounds
according to any of Formulas XIX, XIXa, or XIXb:
##STR00104##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein R.sup.1
and R.sup.2 are as defined in the context of Formula I.
[0194] In certain embodiments, provided herein are compounds
according to any of Formulas XIX, XIXa, or XIXb, wherein each
R.sup.2 is independently hydrogen, methyl, or halo. In certain
embodiments, provided herein are compounds according to any of
Formulas XIX, XIXa, or XIXb, wherein each R.sup.2 is hydrogen. In
certain embodiments, provided herein are compounds according to any
of Formulas XIX, XIXa, or XIXb, wherein each R.sup.2 is methyl. In
certain embodiments, provided herein are compounds according to any
of Formulas XIX, XIXa, or XIXb, wherein each R.sup.2 is
independently halogen.
[0195] In certain embodiments, provided herein are compounds
according to Formula XVIII:
##STR00105##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; and R.sup.1 is cyano, azido, or amino.
[0196] In certain embodiments, provided herein are compounds
according to Formula XVIIIa or XVIIIb:
##STR00106##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula XVIII.
[0197] In certain embodiments, provided herein are compounds
according to Formula 1101:
##STR00107##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; and R.sup.1 is cyano, azido, or amino.
[0198] In certain embodiments, provided herein are compounds
according to Formula XXX:
##STR00108##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein: Base
is a nucleobase; and R.sup.1 is cyano, azido, or amino.
[0199] In certain embodiments, provided herein are compounds
according to Formula XXXa or XXXb:
##STR00109##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof, wherein Base
and R.sup.2 are as defined in the context of Formula XXX.
[0200] In certain embodiments, provided herein are compounds
according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or 1101,
wherein each Base is independently
##STR00110##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl,
amino, or alkoxy; each R.sup.5 is independently hydrogen, halogen,
or methyl; and each R.sup.6 is independently hydrogen, amino, or
halogen.
[0201] In certain embodiments, provided herein are compounds
according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or 1101,
wherein each Base is independently
##STR00111##
or a tautomer thereof; wherein: each R.sup.4 is independently
hydroxyl or amino; and each R.sup.5 is independently hydrogen,
halogen, or methyl. In certain embodiments, provided herein are
compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or
1101, wherein each Base is independently
##STR00112##
or a tautomer thereof. In certain embodiments, provided herein are
compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or
1101, wherein each Base is independently
##STR00113##
or a tautomer thereof. In certain embodiments, provided herein are
compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or
1101, wherein each Base is independently
##STR00114##
or a tautomer thereof.
[0202] In certain embodiments, provided herein are compounds
according to any of Formulas 1-3b:
##STR00115## ##STR00116##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0203] In certain embodiments, provided herein are compounds
according to any of Formulas 4-8b:
##STR00117## ##STR00118## ##STR00119##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0204] In certain embodiments, provided herein are compounds
according to any of Formulas 9-48b:
##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##
##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129##
##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134##
##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139##
##STR00140## ##STR00141## ##STR00142##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0205] In certain embodiments, provided herein are compounds
according to any of Formulas 512-545b:
##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147##
##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152##
##STR00153## ##STR00154## ##STR00155##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0206] In certain embodiments, provided herein are compounds
according to any of Formulas 101-148:
##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161## ##STR00162##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0207] In certain embodiments, provided herein are compounds
according to any of Formulas 201-248:
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof.
[0208] In certain embodiments provided herein is a compound
according to any of Formulas 601-624c:
##STR00171## ##STR00172##
TABLE-US-00001 # W R.sup.1 Base 601/a/ai/aii/b/bi/bii/c
602/a/ai/aii/b/bi/bii/c 603/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00173## 604/a/ai/aii/b/bi/bii/c
605/a/ai/aii/b/bi/bii/c 606/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00174## 607/a/ai/aii/b/bi/bii/c
608/a/ai/aii/b/bi/bii/c 609/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00175## 610/a/ai/aii/b/bi/bii/c
611/a/ai/aii/b/bi/bii/c 612/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00176## 613/a/ai/aii/b/bi/bii/c
614/a/ai/aii/b/bi/bii/c 615/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00177## 616/a/ai/aii/b/bi/bii/c
617/a/ai/aii/b/bi/bii/c 618/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00178## 619/a/ai/aii/b/bi/bii/c
620/a/ai/aii/b/bi/bii/c 621/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00179## 622/a/ai/aii/b/bi/bii/c
623/a/ai/aii/b/bi/bii/c 624/a/ai/aii/b/bi/bii/c S S S --CN
--N.sub.3 --NH.sub.2 ##STR00180##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof. In the table,
each row provides eight structures--one according to each of the
structures provided above: (601-624), (601a-624a), (601ai-624a0,
(601aii-624aii), (601b-624b), (601bi-624bi), (601bii-624bii), and
(601c-624c). For instance, the first row provides compounds 601,
601a, 601ai, 601aii, 601b, 601bi, 601bii, and 601c, each with the
indicated variables in the row.
[0209] In certain embodiments provided herein is a compound
according to any of Formulas 625-648c:
##STR00181##
TABLE-US-00002 # R.sup.1 Base 625/a/b/c 626/a/b/c 627/a/b/c --CN
--N.sub.3 --NH.sub.2 ##STR00182## 628/a/b/c 629/a/b/c 630/a/b/c
--CN --N.sub.3 --NH.sub.2 ##STR00183## 631/a/b/c 632/a/b/c
633/a/b/c --CN --N.sub.3 --NH.sub.2 ##STR00184## 634/a/b/c
635/a/b/c 636/a/b/c --CN --N.sub.3 --NH.sub.2 ##STR00185##
637/a/b/c 638/a/b/c 639/a/b/c --CN --N.sub.3 --NH.sub.2
##STR00186## 640/a/b/c 641/a/b/c 642/a/b/c --CN --N.sub.3
--NH.sub.2 ##STR00187## 643/a/b/c 644/a/b/c 645/a/b/c --CN
--N.sub.3 --NH.sub.2 ##STR00188## 646/a/b/c 647/a/b/c 648/a/b/c
--CN --N.sub.3 --NH.sub.2 ##STR00189##
or a pharmaceutically acceptable salt, solvate, stereoisomeric
form, tautomeric form, or polymorphic form thereof. In the table,
each row provides four structures--one according to the top left
structure (625-648), one according to the top right structure
(625a-648a), one according to the bottom left structure
(625b-648b), and one according to the bottom right structure
(625c-648c). For instance, the first row provides compound 625
according to the top left structure, compound 625a according to the
top right structure, compound 625b according to the bottom left
structure, and compound 625c according to the bottom right
structure, each with the indicated variables in the row.
[0210] In some embodiments, provided herein are: [0211] (a)
compounds as described herein, e.g., of Formula 1001-1004bii, 1101,
1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b,
4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or
601-648c, and pharmaceutically acceptable salts and compositions
thereof; [0212] (b) compounds as described herein, e.g., of Formula
1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, and pharmaceutically acceptable
salts and compositions thereof for use in the treatment and/or
prophylaxis of a liver disorder including Flaviviridae infection,
especially in individuals diagnosed as having a Flaviviridae
infection or being at risk of becoming infected by hepatitis C;
[0213] (c) processes for the preparation of compounds as described
herein, e.g., of Formula 1001-1004bii, 1101, 1501-1504bii,
2001-2004b, 2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii,
I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or 601-648c, as
described in more detail elsewhere herein; [0214] (d)
pharmaceutical formulations comprising a compound as described
herein, e.g., of Formula 1001-1004bii, 1101, 1501-1504bii,
2001-2004b, 2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii,
I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or 601-648c, or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent; [0215] (e)
pharmaceutical formulations comprising a compound as described
herein, e.g., of Formula 1001-1004bii, 1101, 1501-1504bii,
2001-2004b, 2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii,
I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or 601-648c, or a
pharmaceutically acceptable salt thereof together with one or more
other effective anti-HCV agents, optionally in a pharmaceutically
acceptable carrier or diluent; [0216] (f) a method for the
treatment and/or prophylaxis of a host infected with Flaviviridae
that includes the administration of an effective amount of a
compound as described herein, e.g., of Formula 1001-1004bii, 1101,
1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b,
4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or
601-648c, its pharmaceutically acceptable salt or composition; or
[0217] (g) a method for the treatment and/or prophylaxis of a host
infected with Flaviviridae that includes the administration of an
effective amount of a compound as described herein, e.g., of
Formula 1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, its pharmaceutically acceptable
salt or composition in combination and/or alternation with one or
more effective anti-HCV agent.
[0218] Optically Active Compounds
[0219] It is appreciated that compounds provided herein have
several chiral centers and may exist in, and be isolated in,
optically active and racemic forms. Some compounds may exhibit
polymorphism. It is to be understood that any racemic,
optically-active, diastereomeric, polymorphic, or stereoisomeric
form, or mixtures thereof, of a compound provided herein, which
possess the useful properties described herein is within the scope
of the invention. It being well known in the art how to prepare
optically active forms (for example, by 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).
[0220] In particular, since the 1' and 4' carbons of a nucleoside
are chiral, the nucleobase and the CH.sub.2O groups can be either
cis (on the same side) or trans (on opposite sides) with respect to
the sugar ring system. The four optical isomers therefore are
represented by the following configurations (when orienting the
sugar moiety in a horizontal plane such that the oxygen atom is in
the back): cis (with both groups "up", which corresponds to the
configuration of naturally occurring .beta.-D nucleosides), cis
(with both groups "down", which is a non-naturally occurring
.beta.-L configuration), trans (with the C2' substituent "up" and
the C4' substituent "down"), and trans (with the C2' substituent
"down" and the C4' substituent "up"). The "D-nucleosides" are cis
nucleosides in a natural configuration and the "L-nucleosides" are
cis nucleosides in the non-naturally occurring configuration.
[0221] Likewise, most amino acids are chiral (designated as L or D,
wherein the L enantiomer is the naturally occurring configuration)
and can exist as separate enantiomers.
[0222] Examples of methods to obtain optically active materials are
known in the art, and include at least the following. [0223] 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; [0224] 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; [0225] 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; [0226] 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;
[0227] 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; [0228] 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; [0229] 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; [0230] 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; [0231] 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; [0232] 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. The stationary phase can be
made of chiral material or the mobile phase can contain an
additional chiral material to provoke the differing interactions;
[0233] 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;
[0234] 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; [0235] 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 which allows only one enantiomer of the
racemate to pass through.
[0236] In some embodiments, provided is a composition of 2'-cyano,
azido or amino nucleoside compound that comprises a substantially
pure designated enantiomer of the 2'-cyano, azido or amino
nucleoside compound. In certain embodiments, in the methods and
compounds of this invention, the compounds are substantially free
of other enantiomers. In some embodiments, a composition includes a
compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight
of the 2'-cyano, azido or amino nucleoside compound, the remainder
comprising other chemical species or enantiomers.
[0237] Isotopically Enriched Compounds
[0238] Also provided herein are isotopically enriched compounds,
including but not limited to isotopically enriched 2'-cyano, azido
and amino nucleoside compounds.
[0239] Isotopic enrichment (for example, deuteration) of
pharmaceuticals to improve pharmacokinetics ("PK"),
pharmacodynamics ("PD"), and toxicity profiles, has been
demonstrated previously with some classes of drugs. See, for
example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982);
Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold
et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab.
Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994);
Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol.
Interact. 117: 191 (1999).
[0240] Isotopic enrichment of a drug can be used, for example, to
(1) reduce or eliminate unwanted metabolites, (2) increase the
half-life of the parent drug, (3) decrease the number of doses
needed to achieve a desired effect, (4) decrease the amount of a
dose necessary to achieve a desired effect, (5) increase the
formation of active metabolites, if any are formed, and/or (6)
decrees the production of deleterious metabolites in specific
tissues and/or create a more effective drug and/or a safer drug for
combination therapy, whether the combination therapy is intentional
or not.
[0241] Replacement of an atom for one of its isotopes often will
result in a change in the reaction rate of a chemical reaction.
This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For
example, if a C--H bond is broken during a rate-determining step in
a chemical reaction (i.e. the step with the highest transition
state energy), substitution of a deuterium for that hydrogen will
cause a decrease in the reaction rate and the process will slow
down. This phenomenon is known as the Deuterium Kinetic Isotope
Effect ("DKIE"). See, e.g., Foster et al., Adv. Drug Res., vol. 14,
pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol.
77, pp. 79-88 (1999).
[0242] The magnitude of the DKIE can be expressed as the ratio
between the rates of a given reaction in which a C--H bond is
broken, and the same reaction where deuterium is substituted for
hydrogen. The DKIE can range from about 1 (no isotope effect) to
very large numbers, such as 50 or more, meaning that the reaction
can be fifty, or more, times slower when deuterium is substituted
for hydrogen. High DKIE values may be due in part to a phenomenon
known as tunneling, which is a consequence of the uncertainty
principle. Tunneling is ascribed to the small mass of a hydrogen
atom, and occurs because transition states involving a proton can
sometimes form in the absence of the required activation energy.
Because deuterium has more mass than hydrogen, it statistically has
a much lower probability of undergoing this phenomenon.
[0243] Tritium ("T") is a radioactive isotope of hydrogen, used in
research, fusion reactors, neutron generators and
radiopharmaceuticals. Tritium is a hydrogen atom that has 2
neutrons in the nucleus and has an atomic weight close to 3. It
occurs naturally in the environment in very low concentrations,
most commonly found as T.sub.2O. Tritium decays slowly
(half-life=12.3 years) and emits a low energy beta particle that
cannot penetrate the outer layer of human skin. Internal exposure
is the main hazard associated with this isotope, yet it must be
ingested in large amounts to pose a significant health risk. As
compared with deuterium, a lesser amount of tritium must be
consumed before it reaches a hazardous level. Substitution of
tritium ("T") for hydrogen results in yet a stronger bond than
deuterium and gives numerically larger isotope effects. Similarly,
substitution of isotopes for other elements, including, but not
limited to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen, may lead to a similar kinetic isotope
effect.
[0244] For example, the DKIE was used to decrease the
hepatotoxicity of halothane by presumably limiting the production
of reactive species such as trifluoroacetyl chloride. However, this
method may not be applicable to all drug classes. For example,
deuterium incorporation can lead to metabolic switching. The
concept of metabolic switching asserts that xenogens, when
sequestered by Phase I enzymes, may bind transiently and re-bind in
a variety of conformations prior to the chemical reaction (e.g.,
oxidation). This hypothesis is supported by the relatively vast
size of binding pockets in many Phase I enzymes and the promiscuous
nature of many metabolic reactions. Metabolic switching can
potentially lead to different proportions of known metabolites as
well as altogether new metabolites. This new metabolic profile may
impart more or less toxicity.
[0245] The animal body expresses a variety of enzymes for the
purpose of eliminating foreign substances, such as therapeutic
agents, from its circulation system. Examples of such enzymes
include the cytochrome P450 enzymes ("CYPs"), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with
and convert these foreign substances to more polar intermediates or
metabolites for renal excretion. Some of the most common metabolic
reactions of pharmaceutical compounds involve the oxidation of a
carbon-hydrogen (C--H) bond to either a carbon-oxygen (C--O) or
carbon-carbon (C--C) pi-bond. The resultant metabolites may be
stable or unstable under physiological conditions, and can have
substantially different pharmacokinetic, pharmacodynamic, and acute
and long-term toxicity profiles relative to the parent compounds.
For many drugs, such oxidations are rapid. These drugs therefore
often require the administration of multiple or high daily
doses.
[0246] Therefore, isotopic enrichment at certain positions of a
compound provided herein will produce a detectable KIE that will
affect the pharmacokinetic, pharmacologic, and/or toxicological
profiles of a compound provided herein in comparison with a similar
compound having a natural isotopic composition.
[0247] Preparation of Compounds
[0248] The compounds provided herein can be prepared, isolated or
obtained by any method apparent to those of skill in the art.
Compounds provided herein can be prepared according to Exemplary
Preparation Schemes, provided below. Reaction conditions, steps and
reactants not provided in the Exemplary Preparation Schemes would
be apparent to, and known by, those skilled in the art.
##STR00190##
##STR00191##
##STR00192##
##STR00193##
##STR00194##
##STR00195##
[0249] In the Exemplary Preparation Schemes, Base, W, and R.sup.2
are as defined in the context of Formulas I, 1001, 2001, 3001, or
4001. Additional steps and reagents not provided in the Exemplary
Preparation Schemes would be known to those of skill in the art.
Exemplary methods of preparation are described in detail in the
examples below.
[0250] Pharmaceutical Compositions and Methods of
Administration
[0251] 2'-cyano, azido and amino nucleoside compounds can be
formulated into pharmaceutical compositions using methods available
in the art and those disclosed herein. Any of the compounds
disclosed herein can be provided in the appropriate pharmaceutical
composition and be administered by a suitable route of
administration.
[0252] The methods provided herein encompass administering
pharmaceutical compositions containing at least one compound as
described herein, including a compound of general Formula
1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, if appropriate in the salt form,
either used alone or in the form of a combination with one or more
compatible and pharmaceutically acceptable carriers, such as
diluents or adjuvants, or with another anti-HCV agent.
[0253] In certain embodiments, the second agent can be formulated
or packaged with the compound provided herein. Of course, the
second agent will only be formulated with the compound provided
herein when, according to the judgment of those of skill in the
art, such co-formulation should not interfere with the activity of
either agent or the method of administration. In certain
embodiments, the compound provided herein and the second agent are
formulated separately. They can be packaged together, or packaged
separately, for the convenience of the practitioner of skill in the
art.
[0254] In clinical practice the active agents provided herein may
be administered by any conventional route, in particular orally,
parenterally, rectally or by inhalation (e.g. in the form of
aerosols). In certain embodiments, the compound provided herein is
administered orally.
[0255] Use may be made, as solid compositions for oral
administration, of tablets, pills, hard gelatin capsules, powders
or granules. In these compositions, the active product is mixed
with one or more inert diluents or adjuvants, such as sucrose,
lactose or starch.
[0256] These compositions can comprise substances other than
diluents, for example a lubricant, such as magnesium stearate, or a
coating intended for controlled release.
[0257] Use may be made, as liquid compositions for oral
administration, of solutions which are pharmaceutically acceptable,
suspensions, emulsions, syrups and elixirs containing inert
diluents, such as water or liquid paraffin. These compositions can
also comprise substances other than diluents, for example wetting,
sweetening or flavoring products.
[0258] The compositions for parenteral administration can be
emulsions or sterile solutions. Use may be made, as solvent or
vehicle, of propylene glycol, a polyethylene glycol, vegetable
oils, in particular olive oil, or injectable organic esters, for
example ethyl oleate. These compositions can also contain
adjuvants, in particular wetting, isotonizing, emulsifying,
dispersing and stabilizing agents. Sterilization can be carried out
in several ways, for example using a bacteriological filter, by
radiation or by heating. They can also be prepared in the form of
sterile solid compositions which can be dissolved at the time of
use in sterile water or any other injectable sterile medium.
[0259] The compositions for rectal administration are suppositories
or rectal capsules which contain, in addition to the active
principle, excipients such as cocoa butter, semi-synthetic
glycerides or polyethylene glycols.
[0260] The compositions can also be aerosols. For use in the form
of liquid aerosols, the compositions can be stable sterile
solutions or solid compositions dissolved at the time of use in
apyrogenic sterile water, in saline or any other pharmaceutically
acceptable vehicle. For use in the form of dry aerosols intended to
be directly inhaled, the active principle is finely divided and
combined with a water-soluble solid diluent or vehicle, for example
dextran, mannitol or lactose.
[0261] In certain embodiments, a composition provided herein is a
pharmaceutical composition or a single unit dosage form.
Pharmaceutical compositions and single unit dosage forms provided
herein comprise a prophylactically or therapeutically effective
amount of one or more prophylactic or therapeutic agents (e.g., a
compound provided herein, or other prophylactic or therapeutic
agent), and a typically one or more pharmaceutically acceptable
carriers or excipients. In a specific embodiment and in this
context, the term "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans. The term
"carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant
(complete and incomplete)), excipient, or vehicle with which the
therapeutic is administered. Such pharmaceutical carriers can be
sterile liquids, such as water and oils, including those of
petroleum, animal, vegetable or synthetic origin, such as peanut
oil, soybean oil, mineral oil, sesame oil and the like. Water can
be used as a carrier when the pharmaceutical composition is
administered intravenously. Saline solutions and aqueous dextrose
and glycerol solutions can also be employed as liquid carriers,
particularly for injectable solutions. Examples of suitable
pharmaceutical carriers are described in "Remington's
Pharmaceutical Sciences" by E. W. Martin.
[0262] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well-known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients include starch, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,
glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene, glycol, water, ethanol and the like. Whether a
particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors well known in the art including, but not limited to, the
way in which the dosage form will be administered to a subject and
the specific active ingredients in the dosage form. The composition
or single unit dosage form, if desired, can also contain minor
amounts of wetting or emulsifying agents, or pH buffering
agents.
[0263] Lactose free compositions provided herein can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmocopia (USP)SP(XXI)/NF (XVI). In general,
lactose free compositions comprise an active ingredient, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Exemplary lactose free dosage
forms comprise an active ingredient, microcrystalline cellulose,
pre gelatinized starch, and magnesium stearate.
[0264] Further encompassed herein are anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long term storage in
order to determine characteristics such as shelf life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
New York, 1995, pp. 379 80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0265] Anhydrous pharmaceutical compositions and dosage forms
provided herein can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine can be anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected.
[0266] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions can be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e.g., vials), blister packs, and strip packs.
[0267] Further provided are pharmaceutical compositions and dosage
forms that comprise one or more compounds that reduce the rate by
which an active ingredient will decompose. Such compounds, which
are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0268] The pharmaceutical compositions and single unit dosage forms
can take the form of solutions, suspensions, emulsion, tablets,
pills, capsules, powders, sustained-release formulations and the
like. Oral formulation can include standard carriers such as
pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
Such compositions and dosage forms will contain a prophylactically
or therapeutically effective amount of a prophylactic or
therapeutic agent, in certain embodiments, in purified form,
together with a suitable amount of carrier so as to provide the
form for proper administration to the subject. The formulation
should suit the mode of administration. In a certain embodiment,
the pharmaceutical compositions or single unit dosage forms are
sterile and in suitable form for administration to a subject, for
example, an animal subject, such as a mammalian subject, for
example, a human subject.
[0269] A pharmaceutical composition is formulated to be compatible
with its intended route of administration. Examples of routes of
administration include, but are not limited to, parenteral, e.g.,
intravenous, intradermal, subcutaneous, intramuscular,
subcutaneous, oral, buccal, sublingual, inhalation, intranasal,
transdermal, topical, transmucosal, intra-tumoral, intra-synovial
and rectal administration. In a specific embodiment, the
composition is formulated in accordance with routine procedures as
a pharmaceutical composition adapted for intravenous, subcutaneous,
intramuscular, oral, intranasal or topical administration to human
beings. In an embodiment, a pharmaceutical composition is
formulated in accordance with routine procedures for subcutaneous
administration to human beings. Typically, compositions for
intravenous administration are solutions in sterile isotonic
aqueous buffer. Where necessary, the composition may also include a
solubilizing agent and a local anesthetic such as lignocamne to
ease pain at the site of the injection.
[0270] Examples of dosage forms include, but are not limited to:
tablets; caplets; capsules, such as soft elastic gelatin capsules;
cachets; troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a subject, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil in water emulsions, or a
water in oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a subject;
and sterile solids (e.g., crystalline or amorphous solids) that can
be reconstituted to provide liquid dosage forms suitable for
parenteral administration to a subject.
[0271] The composition, shape, and type of dosage forms provided
herein will typically vary depending on their use. For example, a
dosage form used in the initial treatment of viral infection may
contain larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the maintenance treatment of
the same infection. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease
or disorder. These and other ways in which specific dosage forms
encompassed herein will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington's
Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa.
(2000).
[0272] Generally, the ingredients of compositions are supplied
either separately or mixed together in unit dosage form, for
example, as a dry lyophilized powder or water free concentrate in a
hermetically sealed container such as an ampoule or sachette
indicating the quantity of active agent. Where the composition is
to be administered by infusion, it can be dispensed with an
infusion bottle containing sterile pharmaceutical grade water or
saline. Where the composition is administered by injection, an
ampoule of sterile water for injection or saline can be provided so
that the ingredients may be mixed prior to administration.
[0273] Typical dosage forms comprise a compound provided herein, or
a pharmaceutically acceptable salt, solvate or hydrate thereof lie
within the range of from about 0.1 mg to about 1000 mg per day,
given as a single once-a-day dose in the morning or as divided
doses throughout the day taken with food. Particular dosage forms
can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0,
15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active
compound.
[0274] Oral Dosage Forms
[0275] Pharmaceutical compositions that are suitable for oral
administration can be presented as discrete dosage forms, such as,
but are not limited to, tablets (e.g., chewable tablets), caplets,
capsules, and liquids (e.g., flavored syrups). Such dosage forms
contain predetermined amounts of active ingredients, and may be
prepared by methods of pharmacy well known to those skilled in the
art. See generally, Remington's Pharmaceutical Sciences, 20th ed.,
Mack Publishing, Easton Pa. (2000).
[0276] In certain embodiments, the oral dosage forms are solid and
prepared under anhydrous conditions with anhydrous ingredients, as
described in detail herein. However, the scope of the compositions
provided herein extends beyond anhydrous, solid oral dosage forms.
As such, further forms are described herein.
[0277] Typical oral dosage forms are prepared by combining the
active ingredient(s) in an intimate admixture with at least one
excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending
on the form of preparation desired for administration. For example,
excipients suitable for use in oral liquid or aerosol dosage forms
include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents, preservatives, and coloring agents. Examples of
excipients suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not
limited to, starches, sugars, micro crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0278] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or non-aqueous techniques. Such
dosage forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0279] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0280] Examples of excipients that can be used in oral dosage forms
include, but are not limited to, binders, fillers, disintegrants,
and lubricants. Binders suitable for use in pharmaceutical
compositions and dosage forms include, but are not limited to, corn
starch, potato starch, or other starches, gelatin, natural and
synthetic gums such as acacia, sodium alginate, alginic acid, other
alginates, powdered tragacanth, guar gum, cellulose and its
derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0281] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions is typically present in from about 50 to about 99
weight percent of the pharmaceutical composition or dosage
form.
[0282] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL PH 101, AVICEL PH
103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation,
American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and
mixtures thereof. A specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC 581. Suitable anhydrous or low moisture excipients or
additives include AVICEL PH 103.TM. and Starch 1500 LM.
[0283] Disintegrants are used in the compositions to provide
tablets that disintegrate when exposed to an aqueous environment.
Tablets that contain too much disintegrant may disintegrate in
storage, while those that contain too little may not disintegrate
at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too
little to detrimentally alter the release of the active ingredients
should be used to form solid oral dosage forms. The amount of
disintegrant used varies based upon the type of formulation, and is
readily discernible to those of ordinary skill in the art. Typical
pharmaceutical compositions comprise from about 0.5 to about 15
weight percent of disintegrant, specifically from about 1 to about
5 weight percent of disintegrant.
[0284] Disintegrants that can be used in pharmaceutical
compositions and dosage forms include, but are not limited to,
agar, alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium
starch glycolate, potato or tapioca starch, pre gelatinized starch,
other starches, clays, other algins, other celluloses, gums, and
mixtures thereof.
[0285] Lubricants that can be used in pharmaceutical compositions
and dosage forms include, but are not limited to, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl
laureate, agar, and mixtures thereof. Additional lubricants
include, for example, a syloid silica gel (AEROSIL 200,
manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated
aerosol of synthetic silica (marketed by Degussa Co. of Plano,
Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot
Co. of Boston, Mass.), and mixtures thereof. If used at all,
lubricants are typically used in an amount of less than about 1
weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0286] Delayed Release Dosage Forms
[0287] Active ingredients such as the compounds provided herein can
be administered by controlled release means or by delivery devices
that are well known to those of ordinary skill in the art. Examples
include, but are not limited to, those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719;
5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;
5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356;
5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943;
6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961;
6,589,548; 6,613,358; and 6,699,500; each of which is incorporated
herein by reference in its entirety. Such dosage forms can be used
to provide slow or controlled release of one or more active
ingredients using, for example, hydropropylmethyl cellulose, other
polymer matrices, gels, permeable membranes, osmotic systems,
multilayer coatings, microparticles, liposomes, microspheres, or a
combination thereof to provide the desired release profile in
varying proportions. Suitable controlled release formulations known
to those of ordinary skill in the art, including those described
herein, can be readily selected for use with the active ingredients
provided herein. Thus encompassed herein are single unit dosage
forms suitable for oral administration such as, but not limited to,
tablets, capsules, gelcaps, and caplets that are adapted for
controlled release.
[0288] All controlled release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled release formulations include extended activity of the
drug, reduced dosage frequency, and increased subject compliance.
In addition, controlled release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0289] Most controlled release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0290] In certain embodiments, the drug may be administered using
intravenous infusion, an implantable osmotic pump, a transdermal
patch, liposomes, or other modes of administration. In certain
embodiments, a pump may be used (see, Sefton, CRC Crit. Ref Biomed.
Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek
et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,
polymeric materials can be used. In yet another embodiment, a
controlled release system can be placed in a subject at an
appropriate site determined by a practitioner of skill, i.e., thus
requiring only a fraction of the systemic dose (see, e.g., Goodson,
Medical Applications of Controlled Release, vol. 2, pp. 115-138
(1984)). Other controlled release systems are discussed in the
review by Langer (Science 249:1527-1533 (1990)). The active
ingredient can be dispersed in a solid inner matrix, e.g.,
polymethylmethacrylate, polybutylmethacrylate, plasticized or
unplasticized polyvinylchloride, plasticized nylon, plasticized
polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone
carbonate copolymers, hydrophilic polymers such as hydrogels of
esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl
acetate, that is surrounded by an outer polymeric membrane, e.g.,
polyethylene, polypropylene, ethylene/propylene copolymers,
ethylene/ethyl acrylate copolymers, ethylene/vinylacetate
copolymers, silicone rubbers, polydimethyl siloxanes, neoprene
rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride
copolymers with vinyl acetate, vinylidene chloride, ethylene and
propylene, ionomer polyethylene terephthalate, butyl rubber
epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer, that is insoluble in body
fluids. The active ingredient then diffuses through the outer
polymeric membrane in a release rate controlling step. The
percentage of active ingredient in such parenteral compositions is
highly dependent on the specific nature thereof, as well as the
needs of the subject.
[0291] Parenteral Dosage Forms
[0292] In certain embodiments, provided are parenteral dosage
forms. Parenteral dosage forms can be administered to subjects by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
subjects' natural defenses against contaminants, parenteral dosage
forms are typically, sterile or capable of being sterilized prior
to administration to a subject. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0293] Suitable vehicles that can be used to provide parenteral
dosage forms are well known to those skilled in the art. Examples
include, but are not limited to: Water for Injection USP; aqueous
vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and Lactated Ringer's Injection; water miscible
vehicles such as, but not limited to, ethyl alcohol, polyethylene
glycol, and polypropylene glycol; and non-aqueous vehicles such as,
but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0294] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms.
[0295] Transdermal, Topical & Mucosal Dosage Forms
[0296] Also provided are transdermal, topical, and mucosal dosage
forms. Transdermal, topical, and mucosal dosage forms include, but
are not limited to, ophthalmic solutions, sprays, aerosols, creams,
lotions, ointments, gels, solutions, emulsions, suspensions, or
other forms known to one of skill in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16.sup.th, 18th and 20.sup.th
eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0297] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed herein are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied. With that fact in mind, typical excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane 1,3 diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
lotions, tinctures, creams, emulsions, gels or ointments, which are
nontoxic and pharmaceutically acceptable. Moisturizers or
humectants can also be added to pharmaceutical compositions and
dosage forms if desired. Examples of such additional ingredients
are well known in the art. See, e.g., Remington's Pharmaceutical
Sciences, 16.sup.th, 18th and 20.sup.th eds., Mack Publishing,
Easton Pa. (1980, 1990 & 2000).
[0298] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients provided. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various water
soluble or insoluble sugar esters such as Tween 80 (polysorbate 80)
and Span 60 (sorbitan monostearate).
[0299] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery enhancing or penetration
enhancing agent. Different salts, hydrates or solvates of the
active ingredients can be used to further adjust the properties of
the resulting composition.
[0300] Dosage and Unit Dosage Forms
[0301] In human therapeutics, the doctor will determine the
posology which he considers most appropriate according to a
preventive or curative treatment and according to the age, weight,
stage of the infection and other factors specific to the subject to
be treated. In certain embodiments, doses are from about 1 to about
1000 mg per day for an adult, or from about 5 to about 250 mg per
day or from about 10 to 50 mg per day for an adult. In certain
embodiments, doses are from about 5 to about 400 mg per day or 25
to 200 mg per day per adult. In certain embodiments, dose rates of
from about 50 to about 500 mg per day are also contemplated.
[0302] In further aspects, provided are methods of treating or
preventing an HCV infection in a subject by administering, to a
subject in need thereof, an effective amount of a compound provided
herein, or a pharmaceutically acceptable salt thereof. The amount
of the compound or composition which will be effective in the
prevention or treatment of a disorder or one or more symptoms
thereof will vary with the nature and severity of the disease or
condition, and the route by which the active ingredient is
administered. The frequency and dosage will also vary according to
factors specific for each subject depending on the specific therapy
(e.g., therapeutic or prophylactic agents) administered, the
severity of the disorder, disease, or condition, the route of
administration, as well as age, body, weight, response, and the
past medical history of the subject. Effective doses may be
extrapolated from dose-response curves derived from in vitro or
animal model test systems.
[0303] In certain embodiments, exemplary doses of a composition
include milligram or microgram amounts of the active compound per
kilogram of subject or sample weight (e.g., about 10 micrograms per
kilogram to about 50 milligrams per kilogram, about 100 micrograms
per kilogram to about 25 milligrams per kilogram, or about 100
microgram per kilogram to about 10 milligrams per kilogram). For
compositions provided herein, in certain embodiments, the dosage
administered to a subject is 0.140 mg/kg to 3 mg/kg of the
subject's body weight, based on weight of the active compound. In
certain embodiments, the dosage administered to a subject is
between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50
mg/kg of the subject's body weight.
[0304] In certain embodiments, the recommended daily dose range of
a composition provided herein for the conditions described herein
lie within the range of from about 0.1 mg to about 1000 mg per day,
given as a single once-a-day dose or as divided doses throughout a
day. In certain embodiments, the daily dose is administered twice
daily in equally divided doses. In certain embodiments, a daily
dose range should be from about 10 mg to about 200 mg per day, in
other embodiments, between about 10 mg and about 150 mg per day, in
further embodiments, between about 25 and about 100 mg per day. It
may be necessary to use dosages of the active ingredient outside
the ranges disclosed herein in some cases, as will be apparent to
those of ordinary skill in the art. Furthermore, it is noted that
the clinician or treating physician will know how and when to
interrupt, adjust, or terminate therapy in conjunction with subject
response.
[0305] Different therapeutically effective amounts may be
applicable for different diseases and conditions, as will be
readily known by those of ordinary skill in the art. Similarly,
amounts sufficient to prevent, manage, treat or ameliorate such
disorders, but insufficient to cause, or sufficient to reduce,
adverse effects associated with the composition provided herein are
also encompassed by the herein described dosage amounts and dose
frequency schedules. Further, when a subject is administered
multiple dosages of a composition provided herein, not all of the
dosages need be the same. For example, the dosage administered to
the subject may be increased to improve the prophylactic or
therapeutic effect of the composition or it may be decreased to
reduce one or more side effects that a particular subject is
experiencing.
[0306] In certain embodiment, the dosage of the composition
provided herein, based on weight of the active compound,
administered to prevent, treat, manage, or ameliorate a disorder,
or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg,
2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg
or more of a subject's body weight. In another embodiment, the
dosage of the composition or a composition provided herein
administered to prevent, treat, manage, or ameliorate a disorder,
or one or more symptoms thereof in a subject is a unit dose of 0.1
mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg,
0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5
mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg,
0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg,
0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg
to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
[0307] In certain embodiments, treatment or prevention can be
initiated with one or more loading doses of a compound or
composition provided herein followed by one or more maintenance
doses. In such embodiments, the loading dose can be, for instance,
about 60 to about 400 mg per day, or about 100 to about 200 mg per
day for one day to five weeks. The loading dose can be followed by
one or more maintenance doses. In certain embodiments, each
maintenance does is, independently, about from about 10 mg to about
200 mg per day, between about 25 mg and about 150 mg per day, or
between about 25 and about 80 mg per day. Maintenance doses can be
administered daily and can be administered as single doses, or as
divided doses.
[0308] In certain embodiments, a dose of a compound or composition
provided herein can be administered to achieve a steady-state
concentration of the active ingredient in blood or serum of the
subject. The steady-state concentration can be determined by
measurement according to techniques available to those of skill or
can be based on the physical characteristics of the subject such as
height, weight and age. In certain embodiments, a sufficient amount
of a compound or composition provided herein is administered to
achieve a steady-state concentration in blood or serum of the
subject of from about 300 to about 4000 ng/mL, from about 400 to
about 1600 ng/mL, or from about 600 to about 1200 ng/mL. In some
embodiments, loading doses can be administered to achieve
steady-state blood or serum concentrations of about 1200 to about
8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days.
In certain embodiments, maintenance doses can be administered to
achieve a steady-state concentration in blood or serum of the
subject of from about 300 to about 4000 ng/mL, from about 400 to
about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
[0309] In certain embodiments, administration of the same
composition may be repeated and the administrations may be
separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15
days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In other embodiments, administration of the same prophylactic or
therapeutic agent may be repeated and the administration may be
separated by at least at least 1 day, 2 days, 3 days, 5 days, 10
days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6
months.
[0310] In certain aspects, provided herein are unit dosages
comprising a compound, or a pharmaceutically acceptable salt
thereof, in a form suitable for administration. Such forms are
described in detail herein. In certain embodiments, the unit dosage
comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active
ingredient. In particular embodiments, the unit dosages comprise
about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active
ingredient. Such unit dosages can be prepared according to
techniques familiar to those of skill in the art.
[0311] The dosages of the second agents are to be used in the
combination therapies provided herein. In certain embodiments,
dosages lower than those which have been or are currently being
used to prevent or treat HCV infection are used in the combination
therapies provided herein. The recommended dosages of second agents
can be obtained from the knowledge of those of skill. For those
second agents that are approved for clinical use, recommended
dosages are described in, for example, Hardman et al., eds., 1996,
Goodman & Gilman's The Pharmacological Basis Of Basis Of
Therapeutics 9.sup.th Ed, Mc-Graw-Hill, New York; Physician's Desk
Reference (PDR) 57.sup.th Ed., 2003, Medical Economics Co., Inc.,
Montvale, N.J., which are incorporated herein by reference in its
entirety.
[0312] In various embodiments, the therapies (e.g., a compound
provided herein and the second agent) are administered less than 5
minutes apart, less than 30 minutes apart, 1 hour apart, at about 1
hour apart, at about 1 to about 2 hours apart, at about 2 hours to
about 3 hours apart, at about 3 hours to about 4 hours apart, at
about 4 hours to about 5 hours apart, at about 5 hours to about 6
hours apart, at about 6 hours to about 7 hours apart, at about 7
hours to about 8 hours apart, at about 8 hours to about 9 hours
apart, at about 9 hours to about 10 hours apart, at about 10 hours
to about 11 hours apart, at about 11 hours to about 12 hours apart,
at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24
hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52
hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours
apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or
96 hours to 120 hours apart. In various embodiments, the therapies
are administered no more than 24 hours apart or no more than 48
hours apart. In certain embodiments, two or more therapies are
administered within the same patient visit. In other embodiments,
the compound provided herein and the second agent are administered
concurrently.
[0313] In other embodiments, the compound provided herein and the
second agent are administered at about 2 to 4 days apart, at about
4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks
apart, or more than 2 weeks apart.
[0314] In certain embodiments, administration of the same agent may
be repeated and the administrations may be separated by at least 1
day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2
months, 75 days, 3 months, or 6 months. In other embodiments,
administration of the same agent may be repeated and the
administration may be separated by at least at least 1 day, 2 days,
3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75
days, 3 months, or 6 months.
[0315] In certain embodiments, a compound provided herein and a
second agent are administered to a patient, for example, a mammal,
such as a human, in a sequence and within a time interval such that
the compound provided herein can act together with the other agent
to provide an increased benefit than if they were administered
otherwise. For example, the second active agent can be administered
at the same time or sequentially in any order at different points
in time; however, if not administered at the same time, they should
be administered sufficiently close in time so as to provide the
desired therapeutic or prophylactic effect. In certain embodiments,
the compound provided herein and the second active agent exert
their effect at times which overlap. Each second active agent can
be administered separately, in any appropriate form and by any
suitable route. In other embodiments, the compound provided herein
is administered before, concurrently or after administration of the
second active agent.
[0316] In certain embodiments, the compound provided herein and the
second agent are cyclically administered to a patient. Cycling
therapy involves the administration of a first agent (e.g., a first
prophylactic or therapeutic agents) for a period of time, followed
by the administration of a second agent and/or third agent (e.g., a
second and/or third prophylactic or therapeutic agents) for a
period of time and repeating this sequential administration.
Cycling therapy can reduce the development of resistance to one or
more of the therapies, avoid or reduce the side effects of one of
the therapies, and/or improve the efficacy of the treatment.
[0317] In certain embodiments, the compound provided herein and the
second active agent are administered in a cycle of less than about
3 weeks, about once every two weeks, about once every 10 days or
about once every week. One cycle can comprise the administration of
a compound provided herein and the second agent by infusion over
about 90 minutes every cycle, about 1 hour every cycle, about 45
minutes every cycle. Each cycle can comprise at least 1 week of
rest, at least 2 weeks of rest, at least 3 weeks of rest. The
number of cycles administered is from about 1 to about 12 cycles,
more typically from about 2 to about 10 cycles, and more typically
from about 2 to about 8 cycles.
[0318] In other embodiments, courses of treatment are administered
concurrently to a patient, i.e., individual doses of the second
agent are administered separately yet within a time interval such
that the compound provided herein can work together with the second
active agent. For example, one component can be administered once
per week in combination with the other components that can be
administered once every two weeks or once every three weeks. In
other words, the dosing regimens are carried out concurrently even
if the therapeutics are not administered simultaneously or during
the same day.
[0319] The second agent can act additively or synergistically with
the compound provided herein. In certain embodiments, the compound
provided herein is administered concurrently with one or more
second agents in the same pharmaceutical composition. In another
embodiment, a compound provided herein is administered concurrently
with one or more second agents in separate pharmaceutical
compositions. In still another embodiment, a compound provided
herein is administered prior to or subsequent to administration of
a second agent. Also contemplated are administration of a compound
provided herein and a second agent by the same or different routes
of administration, e.g., oral and parenteral. In certain
embodiments, when the compound provided herein is administered
concurrently with a second agent that potentially produces adverse
side effects including, but not limited to, toxicity, the second
active agent can advantageously be administered at a dose that
falls below the threshold that the adverse side effect is
elicited.
[0320] Kits
[0321] Also provided are kits for use in methods of treatment of a
liver disorder such as HCV infections. The kits can include a
compound or composition provided herein, a second agent or
composition, and instructions providing information to a health
care provider regarding usage for treating the disorder.
Instructions may be provided in printed form or in the form of an
electronic medium such as a floppy disc, CD, or DVD, or in the form
of a website address where such instructions may be obtained. A
unit dose of a compound or composition provided herein, or a second
agent or composition, can include a dosage such that when
administered to a subject, a therapeutically or prophylactically
effective plasma level of the compound or composition can be
maintained in the subject for at least 1 days. In some embodiments,
a compound or composition can be included as a sterile aqueous
pharmaceutical composition or dry powder (e.g., lyophilized)
composition.
[0322] In some embodiments, suitable packaging is provided. As used
herein, "packaging" includes a solid matrix or material customarily
used in a system and capable of holding within fixed limits a
compound provided herein and/or a second agent suitable for
administration to a subject. Such materials include glass and
plastic (e.g., polyethylene, polypropylene, and polycarbonate)
bottles, vials, paper, plastic, and plastic-foil laminated
envelopes and the like. If e-beam sterilization techniques are
employed, the packaging should have sufficiently low density to
permit sterilization of the contents.
[0323] Methods of Use
[0324] Provided herein is a method for inhibiting replication of a
virus in a host. In certain embodiments, the method comprises
contacting the host with a therapeutically effective amount of a
2'-cyano, azido or amino nucleoside compound disclosed herein,
e.g., a 2'-cyano, azido or amino nucleoside compound of Formula
1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, including a single enantiomer, a
mixture of an enantiomeric pair, an individual diastereomer, a
mixture of diastereomers, or a tautomeric form thereof; or a
pharmaceutically acceptable salt, solvate, prodrug, phosphate, or
active metabolite thereof.
[0325] Provided herein is a method for inhibiting replication of a
virus in a cell. In certain embodiments, the method comprises
contacting the cell with a therapeutically effective amount of a
2'-cyano, azido or amino nucleoside compound disclosed herein,
e.g., a 2'-cyano, azido or amino nucleoside compound of Formula
1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, including a single enantiomer, a
mixture of an enantiomeric pair, an individual diastereomer, a
mixture of diastereomers, or a tautomeric form thereof; or a
pharmaceutically acceptable salt, solvate, prodrug, phosphate, or
active metabolite thereof.
[0326] Provided herein is a method for inhibiting replication of a
virus. In certain embodiments, the method comprises contacting the
virus with a therapeutically effective amount of a 2'-cyano, azido
or amino nucleoside compound disclosed herein, e.g., a 2'-cyano,
azido or amino nucleoside compound of Formula 1001-1004bii, 1101,
1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b,
4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or
601-648c, including a single enantiomer, a mixture of an
enantiomeric pair, an individual diastereomer, a mixture of
diastereomers, or a tautomeric form thereof; or a pharmaceutically
acceptable salt, solvate, prodrug, phosphate, or active metabolite
thereof.
[0327] Provided herein is a method for inhibiting the activity of a
polymerase. In certain embodiments, the method comprises contacting
the polymerase with a ester or malonate of a 2'-cyano, azido or
amino nucleoside compound disclosed herein, e.g., a 2'-cyano, azido
or amino nucleoside compound of Formula 1001-1004bii, 1101,
1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b,
4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or
601-648c, including a single enantiomer, a mixture of an
enantiomeric pair, an individual diastereomer, a mixture of
diastereomers, or a tautomeric form thereof; or a pharmaceutically
acceptable salt, solvate, prodrug, phosphate, or active metabolite
thereof.
[0328] In certain embodiments, provided herein are methods for the
treatment and/or prophylaxis of a host infected with Flaviviridae.
In certain embodiments, the method includes the administration of
an effective amount of a 2'-cyano, azido or amino nucleoside
compound disclosed herein, e.g., a 2'-cyano, azido or amino
nucleoside compound of Formula 1001-1004bii, 1101, 1501-1504bii,
2001-2004b, 2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii,
I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or 601-648c, including a
single enantiomer, a mixture of an enantiomeric pair, an individual
diastereomer, a mixture of diastereomers, or a tautomeric form
thereof; or a pharmaceutically acceptable salt, solvate, prodrug,
phosphate, or active metabolite thereof.
[0329] In certain embodiments, the methods encompass the step of
administering to the subject in need thereof an amount of a
compound effective for the treatment or prevention of an HCV
infection in combination with a second agent effective for the
treatment or prevention of the infection. The compound can be any
compound as described herein, and the second agent can be any
second agent described in the art or herein. In certain
embodiments, the compound is in the form of a pharmaceutical
composition or dosage form, as described elsewhere herein.
[0330] In certain embodiments, provided herein are methods for the
treatment and/or prophylaxis of a host infected with Flaviviridae
that includes the administration of an effective amount of a
compound provided herein, or a pharmaceutically acceptable salt
thereof. In certain embodiments, provided herein are methods for
treating an HCV infection in a subject. In certain embodiments, the
methods encompass the step of administering to a subject in need
thereof an amount of a compound effective for the treatment or
prevention of an HCV infection in combination with a second agent
effective for the treatment or prevention of the infection. The
compound can be any compound as described herein, and the second
agent can be any second agent described in the art or herein. In
certain embodiments, the compound is in the form of a
pharmaceutical composition or dosage form, as described elsewhere
herein.
[0331] Flaviviridae which can be treated are, e.g., discussed
generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and
Howley, P. M., Lippincott Williams & Wilkins Publishers,
Philadelphia, Pa., Chapters 33-35, 2006. In a particular embodiment
of the invention, the Flaviviridae is HCV. In an alternate
embodiment, the Flaviviridae is a flavivirus or pestivirus. In
certain embodiments, the Flaviviridae can be from any class of
Flaviviridae. In certain embodiments, the Flaviviridae is a
mammalian tick-borne virus. In certain embodiments, the
Flaviviridae is a seabird tick-borne virus. In certain embodiments,
the Flaviviridae is a mosquito-borne virus. In certain embodiments,
the Flaviviridae is an Aroa virus. In certain embodiments, the
Flaviviridae is a Dengue virus. In certain embodiments, the
Flaviviridae is a Japanese encephalitis virus. In certain
embodiments, the Flaviviridae is a Kokobera virus. In certain
embodiments, the Flaviviridae is a Ntaya virus. In certain
embodiments, the Flaviviridae is a Spondweni virus. In certain
embodiments, the Flaviviridae is a Yellow fever virus. In certain
embodiments, the Flaviviridae is a Entebbe virus. In certain
embodiments, the Flaviviridae is a Modoc virus. In certain
embodiments, the Flaviviridae is a Rio Bravo virus.
[0332] Specific flaviviruses which can be treated include, without
limitation: Absettarov, Aedes, Alfuy, Alkhurma, Apoi, Aroa, Bagaza,
Banzi, Bukalasa bat, Bouboui, Bussuquara, Cacipacore, Calbertado,
Carey Island, Cell fusing agent, Cowbone Ridge, Culex, Dakar bat,
Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat,
Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey
meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam,
Kamiti River, Karshi, Kedougou, Kokobera, Koutango, Kumlinge,
Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban,
Modoc, Montana myotis leukoencephalitis, Murray valley
encephalitis, Nakiwogo, Naranjal, Negishi, Ntaya, Omsk hemorrhagic
fever, Phnom-Penh bat, Powassan, Quang Binh, Rio Bravo, Rocio,
Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis
encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik,
Sokuluk, Spondweni, Stratford, Tembusu, Tick-borne encephalitis,
Turkish sheep encephalitis, Tyuleniy, Uganda S, Usutu, Wesselsbron,
West Nile, Yaounde, Yellow fever, Yokose, and Zika.
[0333] Pestiviruses which can be treated are discussed generally in
Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P.
M., Lippincott Williams & Wilkins Publishers, Philadelphia,
Pa., Chapters 33-35, 2006. Specific pestiviruses which can be
treated include, without limitation: bovine viral diarrhea virus
("BVDV"), classical swine fever virus ("CSFV," also called hog
cholera virus), and border disease virus ("BDV").
[0334] In certain embodiments, the subject can be any subject
infected with, or at risk for infection with, HCV. Infection or
risk for infection can be determined according to any technique
deemed suitable by the practitioner of skill in the art. In certain
embodiments, subjects are humans infected with HCV.
[0335] In certain embodiments, the subject has never received
therapy or prophylaxis for an HCV infection. In further
embodiments, the subject has previously received therapy or
prophylaxis for an HCV infection. For instance, in certain
embodiments, the subject has not responded to an HCV therapy. For
example, under current interferon therapy, up to 50% or more HCV
subjects do not respond to therapy. In certain embodiments, the
subject can be a subject that received therapy but continued to
suffer from viral infection or one or more symptoms thereof. In
certain embodiments, the subject can be a subject that received
therapy but failed to achieve a sustained virologic response. In
certain embodiments, the subject has received therapy for an HCV
infection but has failed to show, for example, a 2 log.sub.10
decline in HCV RNA levels after 12 weeks of therapy. It is believed
that subjects who have not shown more than 2 log.sub.10 reduction
in serum HCV RNA after 12 weeks of therapy have a 97-100% chance of
not responding.
[0336] In certain embodiments, the subject is a subject that
discontinued an HCV therapy because of one or more adverse events
associated with the therapy. In certain embodiments, the subject is
a subject where current therapy is not indicated. For instance,
certain therapies for HCV are associated with neuropsychiatric
events. Interferon (IFN)-alfa plus ribavirin is associated with a
high rate of depression. Depressive symptoms have been linked to a
worse outcome in a number of medical disorders. Life-threatening or
fatal neuropsychiatric events, including suicide, suicidal and
homicidal ideation, depression, relapse of drug addiction/overdose,
and aggressive behavior have occurred in subjects with and without
a previous psychiatric disorder during HCV therapy.
Interferon-induced depression is a limitation for the treatment of
chronic hepatitis C, especially for subjects with psychiatric
disorders. Psychiatric side effects are common with interferon
therapy and responsible for about 10% to 20% of discontinuations of
current therapy for HCV infection.
[0337] Accordingly, provided are methods of treating or preventing
an HCV infection in subjects where the risk of neuropsychiatric
events, such as depression, contraindicates treatment with current
HCV therapy. In certain embodiments, provided are methods of
treating or preventing HCV infection in subjects where a
neuropsychiatric event, such as depression, or risk of such
indicates discontinuation of treatment with current HCV therapy.
Further provided are methods of treating or preventing HCV
infection in subjects where a neuropsychiatric event, such as
depression, or risk of such indicates dose reduction of current HCV
therapy.
[0338] Current therapy is also contraindicated in subjects that are
hypersensitive to interferon or ribavirin, or both, or any other
component of a pharmaceutical product for administration of
interferon or ribavirin. Current therapy is not indicated in
subjects with hemoglobinopathies (e.g., thalassemia major,
sickle-cell anemia) and other subjects at risk from the hematologic
side effects of current therapy. Common hematologic side effects
include bone marrow suppression, neutropenia and thrombocytopenia.
Furthermore, ribavirin is toxic to red blood cells and is
associated with hemolysis. Accordingly, in certain embodiments,
provided are methods of treating or preventing HCV infection in
subjects hypersensitive to interferon or ribavirin, or both,
subjects with a hemoglobinopathy, for instance thalassemia major
subjects and sickle-cell anemia subjects, and other subjects at
risk from the hematologic side effects of current therapy.
[0339] In certain embodiments, the subject has received an HCV
therapy and discontinued that therapy prior to administration of a
method provided herein. In further embodiments, the subject has
received therapy and continues to receive that therapy along with
administration of a method provided herein. The methods can be
co-administered with other therapy for HBC and/or HCV according to
the judgment of one of skill in the art. In certain embodiments,
the methods or compositions provided herein can be co-administered
with a reduced dose of the other therapy for HBC and/or HCV.
[0340] In certain embodiments, provided are methods of treating a
subject that is refractory to treatment with interferon. For
instance, in some embodiments, the subject can be a subject that
has failed to respond to treatment with one or more agents selected
from the group consisting of interferon, interferon .alpha.,
pegylated interferon .alpha., interferon plus ribavirin, interferon
.alpha. plus ribavirin and pegylated interferon .alpha. plus
ribavirin. In some embodiments, the subject can be a subject that
has responded poorly to treatment with one or more agents selected
from the group consisting of interferon, interferon .alpha.,
pegylated interferon .alpha., interferon plus ribavirin, interferon
.alpha. plus ribavirin and pegylated interferon .alpha. plus
ribavirin. A pro-drug form of ribavirin, such as taribavirin, may
also be used.
[0341] In certain embodiments, the subject has, or is at risk for,
co-infection of HCV with HIV. For instance, in the United States,
30% of HIV subjects are co-infected with HCV and evidence indicates
that people infected with HIV have a much more rapid course of
their hepatitis C infection. Maier and Wu, 2002, World J
Gastroenterol 8:577-57. The methods provided herein can be used to
treat or prevent HCV infection in such subjects. It is believed
that elimination of HCV in these subjects will lower mortality due
to end-stage liver disease. Indeed, the risk of progressive liver
disease is higher in subjects with severe AIDS-defining
immunodeficiency than in those without. See, e.g., Lesens et al.,
1999, J Infect Dis 179:1254-1258. In certain embodiments, compounds
provided herein have been shown to suppress HIV in HIV subjects.
Thus, in certain embodiments, provided are methods of treating or
preventing HIV infection and HCV infection in subjects in need
thereof.
[0342] In certain embodiments, the compounds or compositions are
administered to a subject following liver transplant. Hepatitis C
is a leading cause of liver transplantation in the U.S., and many
subjects that undergo liver transplantation remain HCV positive
following transplantation. In certain embodiments, provided are
methods of treating such recurrent HCV subjects with a compound or
composition provided herein. In certain embodiments, provided are
methods of treating a subject before, during or following liver
transplant to prevent recurrent HCV infection.
[0343] Second Therapeutic Agents
[0344] In certain embodiments, the compounds and compositions
provided herein are useful in methods of treatment of a liver
disorder, that comprise further administration of a second agent
effective for the treatment of the disorder, such as HCV infection
in a subject in need thereof. The second agent can be any agent
known to those of skill in the art to be effective for the
treatment of the disorder, including those currently approved by
the FDA.
[0345] In certain embodiments, a compound provided herein is
administered in combination with one second agent. In further
embodiments, a second agent is administered in combination with two
second agents. In still further embodiments, a second agent is
administered in combination with two or more second agents.
[0346] As used herein, the term "in combination" includes the use
of more than one therapy (e.g., one or more prophylactic and/or
therapeutic agents). The use of the term "in combination" does not
restrict the order in which therapies (e.g., prophylactic and/or
therapeutic agents) are administered to a subject with a disorder.
A first therapy (e.g., a prophylactic or therapeutic agent such as
a compound provided herein) can be administered prior to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4
hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1
week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12
weeks before), concomitantly with, or subsequent to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4
hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1
week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12
weeks after) the administration of a second therapy (e.g., a
prophylactic or therapeutic agent) to a subject with a
disorder.
[0347] As used herein, the term "synergistic" includes a
combination of a compound provided herein and another therapy
(e.g., a prophylactic or therapeutic agent) which has been or is
currently being used to prevent, manage or treat a disorder, which
is more effective than the additive effects of the therapies. A
synergistic effect of a combination of therapies (e.g., a
combination of prophylactic or therapeutic agents) permits the use
of lower dosages of one or more of the therapies and/or less
frequent administration of said therapies to a subject with a
disorder. The ability to utilize lower dosages of a therapy (e.g.,
a prophylactic or therapeutic agent) and/or to administer said
therapy less frequently reduces the toxicity associated with the
administration of said therapy to a subject without reducing the
efficacy of said therapy in the prevention or treatment of a
disorder). In addition, a synergistic effect can result in improved
efficacy of agents in the prevention or treatment of a disorder.
Finally, a synergistic effect of a combination of therapies (e.g.,
a combination of prophylactic or therapeutic agents) may avoid or
reduce adverse or unwanted side effects associated with the use of
either therapy alone.
[0348] The active compounds provided herein can be administered in
combination or alternation with another therapeutic agent, in
particular an anti-HCV agent. In combination therapy, effective
dosages of two or more agents are administered together, whereas in
alternation or sequential-step therapy, an effective dosage of each
agent is administered serially or sequentially. The dosages given
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. In certain embodiments, an anti-HCV (or
anti-pestivirus or anti-flavivirus) compound that exhibits an
EC.sub.50 of 10-15 .mu.M. In certain embodiments, less than 1-5
.mu.M, is desirable.
[0349] It has been recognized that drug-resistant variants of
flaviviruses, pestiviruses or HCV can emerge after prolonged
treatment with an antiviral agent. Drug resistance most typically
occurs by mutation of a gene that encodes for an enzyme used in
viral replication. The efficacy of a drug against the viral
infection can be prolonged, augmented, or restored by administering
the compound in combination or alternation with a second, and
perhaps third, antiviral compound that induces a different mutation
from that caused by the principle drug. Alternatively, the
pharmacokinetics, biodistribution or other parameter of the drug
can be altered by such combination or alternation therapy. In
general, combination therapy is typically preferred over
alternation therapy because it induces multiple simultaneous
stresses on the virus.
[0350] Any known viral treatments can be used in combination or
alternation with the compounds described herein. Non-limiting
examples of second agents include:
[0351] HCV Protease inhibitors: Examples include Medivir HCV
Protease Inhibitor (HCV-PI or TMC435) (Medivir/Tibotec); MK-7009
(Merck), RG7227 (ITMN-191) (Roche/Pharmasset/InterMune), boceprevir
(SCH 503034) (Schering), SCH 446211 (Schering), narlaprevir
SCH900518 (Schering/Merck), ABT-450 (Abbott/Enanta), ACH-1625
(Achillion), BI 201335 (Boehringer Ingelheim), PHX1766 (Phenomix),
VX-500 (Vertex) and telaprevir (VX-950) (Vertex). Further examples
of protease inhibitors include substrate-based NS3 protease
inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO
98/22496, 1998; Attwood et al., Antiviral Chemistry and
Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use
of amino acid derivatives as anti-viral agents, German Patent Pub.
DE 19914474; Tung et al., Inhibitors of serine proteases,
particularly hepatitis C virus NS3 protease, PCT WO 98/17679),
including alphaketoamides and hydrazinoureas, and inhibitors that
terminate in an electrophile such as a boronic acid or phosphonate
(Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT
WO 99/07734); Non-substrate-based NS3 protease inhibitors such as
2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,
Biochemical and Biophysical Research Communications, 1997, 238,
643-647; Sudo K. et al., Antiviral Chemistry and Chemotherapy,
1998, 9, 186), including RD3-4082 and RD3-4078, the former
substituted on the amide with a 14 carbon chain and the latter
processing a para-phenoxyphenyl group; and Sch 68631, a
phenanthrenequinone, an HCV protease inhibitor (Chu M. et al.,
Tetrahedron Letters 37:7229-7232, 1996).
[0352] SCH 351633, isolated from the fungus Penicillium
griseofulvum, was identified as a protease inhibitor (Chu M. et
al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Eglin
c, isolated from leech, is a potent inhibitor of several serine
proteases such as S. griseus proteases A and B,
.alpha.-chymotrypsin, chymase and subtilisin. Qasim M. A. et al.,
Biochemistry 36:1598-1607, 1997.
[0353] U.S. patents disclosing protease inhibitors for the
treatment of HCV include, for example, U.S. Pat. No. 6,004,933 to
Spruce et al., which discloses a class of cysteine protease
inhibitors for inhibiting HCV endopeptidase 2; U.S. Pat. No.
5,990,276 to Zhang et al., which discloses synthetic inhibitors of
hepatitis C virus NS3 protease; U.S. Pat. No. 5,538,865 to Reyes et
a; WO 02/008251 to Corvas International, Inc., and U.S. Pat. No.
7,169,760, US2005/176648, WO 02/08187 and WO 02/008256 to Schering
Corporation. HCV inhibitor tripeptides are disclosed in U.S. Pat.
Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim
and WO 02/060926 to Bristol Myers Squibb. Diaryl peptides as NS3
serine protease inhibitors of HCV are disclosed in WO 02/48172 and
U.S. Pat. No. 6,911,428 to Schering Corporation. Imidazoleidinones
as NS3 serine protease inhibitors of HCV are disclosed in WO
02/08198 and U.S. Pat. No. 6,838,475 to Schering Corporation and WO
02/48157 and U.S. Pat. No. 6,727,366 to Bristol Myers Squibb. WO
98/17679 and U.S. Pat. No. 6,265,380 to Vertex Pharmaceuticals and
WO 02/48116 and U.S. Pat. No. 6,653,295 to Bristol Myers Squibb
also disclose HCV protease inhibitors. Further examples of HCV
serine protease inhibitors are provided in U.S. Pat. No. 6,872,805
(Bristol-Myers Squibb); WO 2006000085 (Boehringer Ingelheim); U.S.
Pat. No. 7,208,600 (Vertex); US 2006/0046956 (Schering-Plough); WO
2007/001406 (Chiron); US 2005/0153877; WO 2006/119061 (Merck); WO
00/09543 (Boehringer Ingelheim), U.S. Pat. No. 6,323,180
(Boehringer Ingelheim) WO 03/064456 (Boehringer Ingelheim), U.S.
Pat. No. 6,642,204 (Boehringer Ingelheim), WO 03/064416 (Boehringer
Ingelheim), U.S. Pat. No. 7,091,184 (Boehringer Ingelheim), WO
03/053349 (Bristol-Myers Squibb), U.S. Pat. No. 6,867,185, WO
03/099316 (Bristol-Myers Squibb), U.S. Pat. No. 6,869,964, WO
03/099274 (Bristol-Myers Squibb), U.S. Pat. No. 6,995,174, WO
2004/032827 (Bristol-Myers Squibb), U.S. Pat. No. 7,041,698, WO
2004/043339 and U.S. Pat. No. 6,878,722 (Bristol-Myers Squibb).
[0354] Thiazolidine derivatives which show relevant inhibition in a
reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B
substrate (Sudo K. et al., Antiviral Research, 1996, 32, 9-18),
especially compound RD-1-6250, possessing a fused cinnamoyl moiety
substituted with a long alkyl chain, RD4 6205 and RD4 6193;
[0355] Thiazolidines and benzanilides identified in Kakiuchi N. et
al., J. EBS Letters 421, 217-220; Takeshita N. et al., Analytical
Biochemistry, 1997, 247, 242-246;
[0356] A phenanthrenequinone possessing activity against protease
in a SDS-PAGE and autoradiography assay isolated from the
fermentation culture broth of Streptomyces sp., SCH 68631 (Chu M.
et al., Tetrahedron Letters, 1996, 37, 7229-7232), and SCH 351633,
isolated from the fungus Penicillium griseofulvum, which
demonstrates activity in a scintillation proximity assay (Chu M. et
al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952);
[0357] Helicase inhibitors (Diana G. D. et al., Compounds,
compositions and methods for treatment of hepatitis C, U.S. Pat.
No. 5,633,358; Diana G. D. et al., Piperidine derivatives,
pharmaceutical compositions thereof and their use in the treatment
of hepatitis C, PCT WO 97/36554);
[0358] HCV polymerase inhibitors, including nucleoside and
non-nucleoside polymerase inhibitors, such as ribavirin,
viramidine, clemizole, filibuvir (PF-00868554), HCV POL, NM 283
(valopicitabine), MK-0608, 7-Fluoro-MK-0608, MK-3281, IDX-375,
ABT-072, ABT-333, ANA598, BI 207127, GS 9190, PSI-6130, R1626,
PSI-6206, PSI-938, PSI-7851, PSI-7977 (sofosbuvir, Sovaldi, Gilead
Pharmasset), RG1479, RG7128, HCV-796 VCH-759 or VCH-916.
[0359] Gliotoxin (Ferrari R. et al., Journal of Virology, 1999, 73,
1649-1654), and the natural product cerulenin (Lohmann V. et al.,
Virology, 1998, 249, 108-118);
[0360] Interfering RNA (iRNA) based antivirals, including short
interfering RNA (siRNA) based antivirals, such as Sirna-034 and
others described in International Patent Publication Nos.
WO/03/070750 and WO 2005/012525, and US Patent Publication No. US
2004/0209831;
[0361] Antisense phosphorothioate oligodeoxynucleotides (S-ODN)
complementary to sequence stretches in the 5' non-coding region
(NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717),
or nucleotides 326-348 comprising the 3' end of the NCR and
nucleotides 371-388 located in the core coding region of the HCV
RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599;
Galderisi U. et al., Journal of Cellular Physiology, 1999, 181,
251-257);
[0362] Inhibitors of IRES-dependent translation (Ikeda N et al.,
Agent for the prevention and treatment of hepatitis C, Japanese
Patent Pub. JP-08268890; Kai Y. et al., Prevention and treatment of
viral diseases, Japanese Patent Pub. JP-10101591);
[0363] HCV NS5A inhibitors, such as BMS-790052 (daclatasvir,
Bristol-Myers Squibb), PPI-461 (Presidio Pharmaceuticals), PPI-1301
(Presidio Pharmaceuticals), IDX-719 (samatasvir, Idenix
Pharmaceuticals), AZD7295 (Arrow Therapeutics, AstraZeneca),
EDP-239 (Enanta), ACH-2928 (Achillion), ACH-3102 (Achillion),
ABT-267 (Abbott), or GS-5885 (Gilead);
[0364] HCV entry inhibitors, such as celgosivir (MK-3253) (MIGENIX
Inc.), SP-30 (Samaritan Pharmaceuticals), ITX4520 (iTherX), ITX5061
(iTherX), PRO-206 (Progenies Pharmaceuticals) and other entry
inhibitors by Progenics Pharmaceuticals, e.g., as disclosed in U.S.
Patent Publication No. 2006/0198855;
[0365] Ribozymes, such as nuclease-resistant ribozymes (Maccjak, D.
J. et al., Hepatology 1999, 30, abstract 995) and those disclosed
in U.S. Pat. No. 6,043,077 to Barber et al., and U.S. Pat. Nos.
5,869,253 and 5,610,054 to Draper et al.; and
[0366] Nucleoside analogs have also been developed for the
treatment of Flaviviridae infections.
[0367] In certain embodiments, the compounds provided herein can be
administered in combination with any of the compounds described by
Idenix Pharmaceuticals in International Publication Nos. WO
01/90121, WO 01/92282, WO 2004/003000, WO 2004/002422, and WO
2004/002999.
[0368] Other patent applications disclosing the use of certain
nucleoside analogs that can be used as second agents to treat
hepatitis C virus include: PCT/CA00/01316 (WO 01/32153; filed Nov.
3, 2000) and PCT/CA01/00197 (WO 01/60315; filed Feb. 19, 2001)
filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.);
PCT/US02/01531 (WO 02/057425; filed Jan. 18, 2002); PCT/US02/03086
(WO 02/057287; filed Jan. 18, 2002); U.S. Pat. Nos. 7,202,224;
7,125,855; 7,105,499; and 6,777,395 by Merck & Co., Inc.;
PCT/EP01/09633 (WO 02/18404; published Aug. 21, 2001); US
2006/0040890; 2005/0038240; 2004/0121980; U.S. Pat. Nos. 6,846,810;
6,784,166; and 6,660,721 by Roche; PCT Publication Nos. WO 01/79246
(filed Apr. 13, 2001), WO 02/32920 (filed Oct. 18, 2001) and WO
02/48165; U.S. Pat. Nos. 7,094,770 and 6,927,291 by Pharmasset,
Ltd.
[0369] Further compounds that can be used as second agents to treat
hepatitis C virus are disclosed in PCT Publication No. WO 99/43691
to Emory University, entitled "2'-Fluoronucleosides." The use of
certain 2'-fluoronucleosides to treat HCV is disclosed.
[0370] Other compounds that can be used as second agents include
1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et al.),
alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin
E and other antioxidants (U.S. Pat. No. 5,922,757 to Chojkier et
al.), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964 to
Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No.
5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No.
5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S.
Pat. No. 5,496,546 to Wang et al.), 2',3'-dideoxyinosine (U.S. Pat.
No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Pat. No.
5,891,874 to Colacino et al.), plant extracts (U.S. Pat. No.
5,837,257 to Tsai et al., U.S. Pat. No. 5,725,859 to Omer et al.,
and U.S. Pat. No. 6,056,961), and piperidines (U.S. Pat. No.
5,830,905 to Diana et al.).
[0371] In certain embodiments, a compound of Formula 1001-1004bii,
1101, 1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b,
4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or
601-648c, or a composition comprising a compound of Formula
1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012,
2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148,
201-248, 512-545b, or 601-648c, is administered in combination or
alternation with a second anti-viral agent selected from the group
consisting of an interferon, a nucleotide analogue, a polymerase
inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry
inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine
immune inhibitor, an NS4A antagonist, an NS4B-RNA binding
inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin
inhibitor, or a combination thereof.
[0372] Exemplary Second Therapeutic Agents for Treatment of HCV
[0373] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus interferon, such as Intron A.RTM.
(interferon alfa-2b) and; Roferon A.RTM. (Recombinant interferon
alfa-2a), Infergen.RTM. (consensus interferon; interferon
alfacon-1), PEG-Intron.RTM. (pegylated interferon alfa-2b), and
Pegasys.RTM. (pegylated interferon alfa-2a). In certain
embodiments, one or more compounds provided herein can be
administered in combination or alternation with ribavirin and in
combination or alternation with an anti-hepatitis C virus
interferon. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
ribavirin, in combination or alternation with an anti-hepatitis C
virus interferon, and in combination or alternation with an
anti-hepatitis C virus protease inhibitor. In certain embodiments,
one or more compounds provided herein can be administered in
combination or alternation with ribavirin. In certain embodiments,
one or more compounds provided herein can be administered in
combination or alternation with an anti-hepatitis C virus
interferon and without ribavirin. In certain embodiments, one or
more compounds provided herein can be administered in combination
or alternation with an anti-hepatitis C virus interferon, in
combination or alternation with an anti-hepatitis C virus protease
inhibitor, and without ribavirin.
[0374] In certain embodiments, the anti-hepatitis C virus
interferon is infergen, IL-29 (PEG-Interferon lambda), R7025
(Maxy-alpha), Belerofon, Oral Interferon alpha, BLX-883 (Locteron),
omega interferon, multiferon, medusa interferon, Albuferon or
REBIF.RTM..
[0375] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus polymerase inhibitor, such as ribavirin,
viramidine, HCV POL, NM 283 (valopicitabine), MK-0608,
7-Fluoro-MK-0608, PSI-6130, R1626, PSI-6206, PSI-938, R1479,
HCV-796, VX-950 (Telaprevir, Vertex), GS 9190 NN (Gilead), GS 9256
(Gilead), PSI-7792 (BMS), BI 207127 (BI), R7128 (Roche), or
PSI-7977 (sofosbuvir, Sovaldi, Gilead Pharmasset), PSI-938
(Pharmasset), VX-222 (Vertex), ALS-2200 (Vertex), ALS-2158
(Vertex), MK-0608 (Merck), TMC649128 (Medivir), PF-868554 (Pfizer),
PF-4878691 (Pfizer), ANA598 (Roche), VCH-759 (Vertex), IDX184
(Idenix), IDX375 (Idenix), A-837093 (Abbott), GS 9190 (Gilead),
GSK625433 (GlaxoSmithKline), ABT-072 (Abbott), ABT-333 (Abbott),
INX-189 (Inhibitex), or EDP-239 (Enanta).
[0376] In certain embodiments, the one or more compounds provided
herein can be administered in combination with ribavarin and an
anti-hepatitis C virus interferon, such as Intron A.RTM.
(interferon alfa-2b) and Pegasys.RTM. (Peginterferon alfa-2a);
Roferon A.RTM. (Recombinant interferon alfa-2a), Infergen.RTM.
(consensus interferon; interferon alfacon-1), PEG-Intron.RTM.
(pegylated interferon alfa-2b), Zalbin (albinterferon alfa-2b),
omega interferon, pegylated interferon lambda, and Pegasys.RTM.
(pegylated interferon alfa-2a).
[0377] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus protease inhibitor such as ITMN-191, SCH
503034 (boceprevir), VX950 (telaprevir), VX985, VX500, VX813,
PHX1766, BMS-650032, GS 9256, BI 201335, IDX320, R7227, MK-7009
(vaniprevir), TMC435, BMS-791325, ACH-1625, ACH-2684, ABT-450, or
AVL-181.
[0378] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
HCV NS5A inhibitor, such as BMS-790052 (daclatasvir, Bristol-Myers
Squibb), PPI-461 (Presidio Pharmaceuticals), PPI-1301 (Presidio
Pharmaceuticals), IDX-719 (samatasvir, Idenix Pharmaceuticals),
AZD7295 (Arrow Therapeutics, AstraZeneca), EDP-239 (Enanta),
ACH-2928 (Achillion), ACH-3102 (Achillion), ABT-267 (Abbott), or
GS-5885 (Gilead).
[0379] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus vaccine, such as TG4040, PeviPROTM,
CGI-5005, HCV/MF59, GV1001, IC41, GNI-103, GenPhar HCV vaccine,
C-Vaxin, CSL123, Hepavaxx C, ChronVac-C.RTM. or INN00101 (E1).
[0380] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus monoclonal antibody, such as MBL-HCV1, AB68
or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus
polyclonal antibody, such as cicavir.
[0381] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
anti-hepatitis C virus immunomodulator, such as Zadaxin.RTM.
(thymalfasin), SCV-07, NOV-205 or Oglufanide.
[0382] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
cyclophilin inhibitor, such as Enanta cyclophilin binder, SCY-635,
or Debio-025.
[0383] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
Nexavar, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MX-3253
(Ceglosivir), Suvus (BIVN-401 or virostat), PF-03491390 (formerly
IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ,
ANA975, AVI-4065, Bavituxinab (Tarvacin), Alinia (nitrazoxanide) or
PYN17.
[0384] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b,
pegylated interferon alpha 2a, pegylated interferon alpha 2b,
ribavirin, or combinations thereof.
[0385] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with a
protease inhibitor. In certain embodiments, one or more compounds
provided herein can be administered in combination or alternation
with telaprevir. In certain embodiments, one or more compounds
provided herein can be administered in combination or alternation
with boceprevir.
[0386] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with a
protease inhibitor and in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
telaprevir and in combination or alternation with ribavirin. In
certain embodiments, one or more compounds provided herein can be
administered in combination or alternation with boceprevir and in
combination or alternation with ribavirin.
[0387] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with a
protease inhibitor and not in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
telaprevir and not in combination or alternation with ribavirin. In
certain embodiments, one or more compounds provided herein can be
administered in combination or alternation with boceprevir and not
in combination or alternation with ribavirin.
[0388] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
interferon. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
interferon alfacon-1. In certain embodiments, one or more compounds
provided herein can be administered in combination or alternation
with interferon alfa-2b. In certain embodiments, one or more
compounds provided herein can be administered in combination or
alternation with pegylated interferon alpha 2a. In certain
embodiments, one or more compounds provided herein can be
administered in combination or alternation with pegylated
interferon alpha 2b.
[0389] In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with an
interferon and in combination or alternation with ribavirin. In
certain embodiments, one or more compounds provided herein can be
administered in combination or alternation with interferon
alfacon-1 and in combination or alternation with ribavirin. In
certain embodiments, one or more compounds provided herein can be
administered in combination or alternation with interferon alfa-2b
and in combination or alternation with ribavirin. In certain
embodiments, one or more compounds provided herein can be
administered in combination or alternation with pegylated
interferon alpha 2a and in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
pegylated interferon alpha 2b and in combination or alternation
with ribavirin.
[0390] In certain embodiments, one or more compounds can be
administered in combination or alternation with one or more of the
second agents provided herein and not in combination or alternation
with ribavirin. In certain embodiments, one or more compounds
provided herein can be administered in combination or alternation
with an interferon and not in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
interferon alfacon-1 and not in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
interferon alfa-2b and not in combination or alternation with
ribavirin. In certain embodiments, one or more compounds provided
herein can be administered in combination or alternation with
pegylated interferon alpha 2a and not in combination or alternation
with ribavirin. In certain embodiments, one or more compounds
provided herein can be administered in combination or alternation
with pegylated interferon alpha 2b and not in combination or
alternation with ribavirin.
[0391] Assay Methods
[0392] Compounds can be assayed for HCV activity according to any
assay known to those of skill in the art.
[0393] Further, compounds can be assayed for accumulation in liver
cells of a subject according to any assay known to those of skill
in the art. In certain embodiments, a compound can be administered
to the subject, and a liver cell of the subject can be assayed for
the compound or a derivative thereof, e.g. a nucleoside, nucleoside
phosphate or nucleoside triphosphate derivative thereof.
[0394] In certain embodiments, a 2'-cyano, azido or amino
nucleoside compound is administered to cells, such as liver cells,
in vivo or in vitro, and the nucleoside triphosphate levels
delivered intracellularly are measured, to indicate delivery of the
compound and triphosphorylation in the cell. The levels of
intracellular nucleoside triphosphate can be measured using
analytical techniques known in the art. Methods of detecting ddATP
are described herein below by way of example, but other nucleoside
triphosphates can be readily detected using the appropriate
controls, calibration samples and assay techniques.
[0395] In certain embodiments, ddATP concentrations are measured in
a sample by comparison to calibration standards made from control
samples. The ddATP concentrations in a sample can be measured using
an analytical method such as HPLC LC MS. In certain embodiments, a
test sample is compared to a calibration curve created with known
concentrations of ddATP to thereby obtain the concentration of that
sample.
[0396] In certain embodiments, the samples are manipulated to
remove impurities such as salts (Na.sup.+, K.sup.+, etc.) before
analysis. In certain embodiments, the lower limit of quantitation
is about .about.0.2 pmol/mL for hepatocyte cellular extracts
particularly where reduced salt is present.
[0397] In certain embodiments, the method allows successfully
measuring triphosphate nucleotides formed at levels of 1-10,000
pmol per million cells in, e.g., cultured hepatocytes and HepG2
cells.
EXAMPLES
[0398] As used herein, the symbols and conventions used in these
processes, schemes and examples, regardless of whether a particular
abbreviation is specifically defined, are consistent with those
used in the contemporary scientific literature, for example, the
Journal of the American Chemical Society or the Journal of
Biological Chemistry. Specifically, but without limitation, the
following abbreviations may be used in the examples and throughout
the specification: g (grams); mg (milligrams); mL (milliliters);
.mu.L (microliters); mM (millimolar); .mu.M (micromolar); Hz
(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min
(minutes); MS (mass spectrometry); ESI (electrospray ionization);
TLC (thin layer chromatography); HPLC (high pressure liquid
chromatography); THF (tetrahydrofuran); CDCl.sub.3 (deuterated
chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO
(dimethylsulfoxide); DMSO-d.sub.6 (deuterated dimethylsulfoxide);
EtOAc (ethyl acetate); MeOH (methanol); CO.sub.2(s) (dry ice); and
BOC (t-butyloxycarbonyl).
[0399] For all of the following examples, standard work-up and
purification methods known to those skilled in the art can be
utilized. Unless otherwise indicated, all temperatures are
expressed in .degree. C. (degrees Centigrade). All reactions are
conducted at room temperature unless otherwise noted. Synthetic
methodologies illustrated herein are intended to exemplify the
applicable chemistry through the use of specific examples and are
not indicative of the scope of the disclosure.
Example 1
Preparation of 2'-Cyano, Azido and Amino Nucleosides
##STR00196## ##STR00197##
##STR00198## ##STR00199##
##STR00200## ##STR00201##
##STR00202##
[0400] Ethyl
2-cyano-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylbutanoate
(A2)
##STR00203##
[0402] A 5 L flange flask was fitted with a thermometer, nitrogen
inlet, pressure equalizing dropping funnel, bubbler, and a
subaseal. Methyl lithium solution (956 mL, 1.6M in diethylether,
1.7 equiv.) was added, and the solution was cooled to about
-25.degree. C. Diisopropyl amine (214 mL, 1.7 equiv.) was added
using the dropping funnel over about 40 minutes. The reaction was
left stirring, allowing to warm to ambient temperature overnight.
CO.sub.2(s)/acetone cooling was applied to the LDA solution,
cooling to about -70.degree. C. R-Glyceraldehyde dimethylacetal
solution (50% in DCM) was evaporated down to .about.100 mbar at a
bath temp of 35.degree. C., to remove the DCM, then azeotroped with
anhydrous hexane (2.times.100 mL), under vacuum. The fresh aldehyde
(120 g, 0.9 mol) and ethyl 2-cyanopropionionate (170 mL, 1.5
equiv.) were placed in a 1 L round bottom flask, which was filled
with toluene (800 mL). This solution was cooled in a
CO.sub.2(s)/acetone bath, and added via cannula to the LDA solution
over about 50 minutes, keeping the internal temperature of the
reaction mixture cooler than -55.degree. C. The mixture was stirred
with cooling (internal temp. slowly fell to .about.-72.degree. C.)
for 90 min, then warmed to room temperature over 30 minutes using a
water bath. This solution was added to a sodium dihydrogen
phosphate solution 300 g of NaH.sub.2PO.sub.4 in 1.5 L of
ice/water, over about 10 minutes, with ice-bath cooling. The
mixture was stirred for 20 minutes, then filtered and transferred
to a separatory funnel, and partitioned. The solid was further
washed with EtOAc (2.times..mu.L) and the washings were used to
extract the aqueous. The combined organic extracts were dried over
sodium sulfate. The volatiles were removed in vacuo. The resultant
oil was hydrolyzed crude.
3-Cyano-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one
##STR00204##
[0404] The crude oil was taken up in acetic acid (1.5 L, 66% in
water) and heated to 90.degree. C. over one hour, then held at that
temperature for one hour. Once the mixture had cooled to room
temperature, the volatiles were removed in vacuo, and azeotroped
with toluene (2.times.500 mL). The resultant oil was combined with
some mixed material from an earlier synthesis and columned in two
portions (each .about.1.25 L of silica,
0.fwdarw.12.5%.fwdarw.25.fwdarw.50% EtOAc in DCM). The lower of the
two main spots is the desired material; fractions containing this
material as the major component were combined and the solvent
removed in vacuo to give 85.4 g of a brown oil as a mixture of 3
diastereomers (15:8:2).
((2R,3S,4R)-3-(benzoyloxy)-4-cyano-4-methyl-5-oxotetrahydrofuran-2-yl)meth-
yl benzoate (A5)
##STR00205##
[0406] A 2 L 3-neck round bottom flask was fitted with an overhead
stirrer, thermometer and pressure equalizing dropping funnel under
nitrogen. 3-Cyano-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one
(85.4 g, 0.50 mol) in acetonitrile (1.5 L) was added, followed by
4-dimethylaminopyridine (700 mg) and benzoyl chloride (128 mL, 2.2
equiv.). Finally triethylamine (167 mL, 2.4 equiv.) was added over
10 minutes using the dropping funnel. The addition of the
triethylamine is accompanied by a mild exotherm, which obviated the
addition of a cold water bath to keep the internal temperature
below 25.degree. C. The reaction was stirred at ambient temperature
for 2.5 hours. The reaction mixture was transferred to a separating
funnel with EtOAc (2.5 L) and half saturated brine (2.5 L), and
partitioned. The aqueous layer was re-extracted with EtOAc (1.5 L).
The combined organic layers were washed with 50% Sodium
bicarbonate/25% Brine (1.5 L) and dried over sodium sulphate. The
resultant brown solid was twice recrystallized from
hexane/chloroform, to give .about.15 g of product of the desired
purity. The mother liquors from the recrystallizations were further
recrystallized from chloroform/hexanes several times to give a
further 15 g of product.
[0407] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. (ppm) 8.11 (dm,
J=8.3 Hz, 2H), 7.98 (dm, J=8.4 Hz, 2H), 7.66 (tm, J=7.5 Hz, 1H),
7.59 (tm, J=7.5 Hz, 1H), 7.49 (tm, J=7.6 Hz, 2H), 7.43 (tm, J=7.6
Hz, 2H), 5.54 (d, J=6.5 Hz, 1H), 4.97-5.02 (m, 1H), 4.77 (dd,
J=12.7, 3.5 Hz, 1H), 4.66 (dd, J=12.7, 4.7 Hz, 1H), 1.88 (s,
3H).
3,5-Di-O-benzoyl-2-C-cyano-2-C-methyl-D-ribofuranose (A6)
##STR00206##
[0409] To a solution of A5 (81.08 mmol) in anhydrous
tetrahydrofuran (650 mL) was added under inert atmosphere at
-35.degree. C., LiAlH(OtBu).sub.3 (1.0 M in tetrahydrofuran, 21.7
mmol) over a 20 minutes period. The reaction mixture was stirred
for 1 hour at -20.degree. C. and quenched by addition of a
saturated NH.sub.4Cl solution, keeping the temperature bellow
0.degree. C. Ethyl acetate was added and the white suspension was
filtered through a pad of celite and washed with ethyl acetate. The
filtrate was extracted with ethyl acetate twice. The combined
organic layers were dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The expected intermediate
was used without further purification for the next step. MS (ESI)
m/z=404 (MNa.sup.+).
1-O-Acetyl-3,5-di-O-benzoyl-2-C-cyano-2-C-methyl-D-arabinofuranose
(A7)
##STR00207##
[0411] To a solution of A6 (81.0 mmol) in anhydrous tetrahydrofuran
(420 mL) was added dropwise under inert atmosphere (nitrogen) at
0.degree. C., acetic anhydride (405.0 mmol) followed by
4-dimethylaminopyridine (8.1 mmol). The reaction mixture was
allowed to warm-up to room temperature and was stirred for 1 hour.
The crude was partially concentrated under reduced pressure,
partitioned with dichloromethane and a saturated NaHCO.sub.3
solution, then transferred into a separatory funnel. The organic
layer was extracted, dried, filtered and evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel [eluent: petroleum ether/ethyl acetate: 0 to 100%] to
afford a .alpha.,.beta. sugar mixture A7 in 96% overall yield (2
steps). MS (ESI) m/z=869.2 (2MNa.sup.+).
3',5'-Di-O-benzoyl-2'-C-cyano-2'-C-methyl-4-benzoyl-.alpha.,.beta.-cytidin-
e (A8)
##STR00208##
[0413] To a suspension of N-benzoyl cytosine (23.62 mmol), and a
catalytic amount of ammonium sulfate in 4-chlorobenzene (60 mL) was
added HMDS (70.85 mmol). The reaction mixture was heated at
140.degree. C. overnight. The solvent was removed under inert
atmosphere and the residue was taken in 4-chlorobenzene (20 ml).
Then, 7 (11.81 mmol) in chlorobenzene (40 mL) was added dropwise to
the rectional mixture followed by SnCl.sub.4 (23.62 mmol) dropwise.
The reaction mixture was stirred at 70.degree. C. overnight, cooled
to room temperature and diluted with dichloromethane and a
saturated NaHCO.sub.3 solution. The white suspension was filtered
through a pad of celite and washed with dichloromethane. The
filtrate was extracted with dichloromethane twice. The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to afford expected nucleoside
as an .alpha.,.beta.mixture. Crude material was used without
further purification for the next step. MS (ESI) m/z=598.2
(MH.sup.+).
2'-C-Cyano-2'-C-methyl-.alpha.,.beta.-cytidine, hydrochloride form
(A9)
##STR00209##
[0415] A suspension of A8 (11.8 mmol) in 7N methanolic ammonia (150
mL) was stirred at room temperature for 3 days in a stainless steel
pressure reactor. The mixture was evaporated to dryness, diluted
with water and transferred into a separatory funnel. The aqueous
layer was extracted with dichloromethane and water was removed
under reduced pressure. Crude residue was diluted with ethanol (50
mL) and 10 mL of 1.25 N HCl in dioxan were added. Concentration of
the reaction mixture under reduced pressure followed by 3
co-evaporations with absolute ethanol afforded a precipitate which
was filtrated-off and washed with absolute ethanol to give pure
expected compound as a white solid in 41% overall yield (2 steps)
(57/43 .alpha.,.beta. mixture).
[0416] .sup.1H NMR (DMSO, 400 MHz) .delta. (ppm) 1.15 (s,
3H.beta.), 1.51 (s, 3H.alpha.), 3.45-3.95 (m, 3H.alpha.,.beta.),
4.00-4.10 (m, 1H.alpha.,.beta.), 4.98 (brs, 1H.alpha.), 5.29 (brs,
1H.beta.), 5.80 (d, J=7.40 Hz, 1H.beta.), 5.89 (d, J=7.40 Hz,
1H.alpha.), 5.95 (s, 1H.alpha.), 6.22 (s, 1H.beta.), 6.42 (brd,
1H.alpha.,.beta.), 7.53 (brs, 1H.alpha.,.beta.), 7.76 (d, J=7.40
Hz, 1H.alpha.), 7.89 (brs, 1H.alpha.,.beta.),7.96 (d, J=7.40 Hz,
1H.beta.); MS (ESI) m/z=267 (MH.sup.+).
[0417] Reference Compound A9b: The white solid A9 was triturated
with a mixture of methanol/triethylamine/water; and filtered to
afford an off-white solid Aga as .alpha.-anomer, and a filtrate.
The filtrate was concentrated under reduced pressure and purified
by flash chromatography on silica gel [eluent: DCM/methanol:80/20,
with 1% of Et3N] to afford the expected .beta.-anomer reference
compound A9b. Off-white solid, .sup.1H NMR (DMSO, 400 MHz) .delta.
(ppm) 1.13 (s, 3H), 3.60-3.65 (m, 1H), 3.77-3.90 (m, 3H), 5.26
(brt, 1H), 5.73 (d, J=7.42 Hz, 1H), 6.24 (s, 1H), 6.38 (brd, 1H),
7.29 (brd, 2H), 7.88 (d, J=7.42 Hz, 1H); MS (ESI) m/z=267
(MH.sup.+).
##STR00210##
[0418] To a solution of compound A9 (2.31 mmol) in dry pyridine (16
mL) and DMF (was added dropwise TIPSCl.sub.2 (2.54 mmol) under
nitrogen atmosphere. The reaction was stirred for 5 hours at room
temperature. Then, DMAP (2.31 mmol) and mMTrCl (2.77 mmol) were
added at room temperature and the reaction mixture was stirred at
55.degree. C. overnight. The reaction mixture was slowly added to a
saturated solution of NaHCO.sub.3. The aqueous layer was extracted
with DCM and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude was diluted in MeOH (16 mL) and NH.sub.4F (11.55 mmol)
was added. The reaction mixture was stirred at 60.degree. C. during
1.5 hour and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel [eluent: DCM to
DCM/MeOH 95/5] to afford a mixture of expected 13 nucleoside 10
(270 mg, beige foam, 22% overall yield) and a nucleoside A11 (416
mg).
[0419] Compound A10: .delta. (ppm) 0.97 (s, 3H), 3.51-3.87 (m, 4H),
3.71 (s, 3H), 5.23 (brt, 1H), 6.06 (s, 1H), 6.26 (d, J=7.50 Hz,
1H), 6.35 (brd, J=4.50 Hz, 1H), 5.80 (d, J=7.40 Hz, 1H.beta.),
6.80-7.40 (m, 14H), 7.80 (d, J=7.50 Hz, 1H), 8.51 (brs, 1H); MS
(ESI) m/z=537.2 (MH.sup.-).
Isopropyl
(2R)-2-[[(2,3,4,5,6-pentafluorophenoxy)-phenoxy-phosphoryl]amino-
]propanoate (A12.0)
##STR00211##
[0421] To a stirred solution of D-Alanine isopropyl ester
hydrochloride (89.48 mmol) in anhydrous dichloromethane (1.05
mL/mmol) was added dropwise triethylamine (187.90 mmol) at
-70.degree. C. over 15 minutes. To this mixture was added a
solution of phenyl dichlorophosphate (89.48 mmol) in anhydrous
dichloromethane (1.05 mL/mmol) over 1 hour. The reaction mixture
was stirred at this temperature for additional 30 minutes and then
allowed to warm to 0.degree. C. over 2 hours and stirred for 1
hour. To this mixture was added a solution of
2,3,4,5,6-pentafluorophenol (89.37 mmol) and triethylamine (98.31
mmol) in dichloromethane (0.62 mL/mmol). The reaction mixture was
left in freezer overnight. The salts were filtered-off and washed
with dichloromethane. The filtrate was concentrated under reduced
pressure and the residue was triturated with TBME. The
heterogeneous mixture was filtered and the solid was rinsed with
TBME. The filtrate was concentrated and the residue was triturated
with a mixture of hexane/ethyl acetate 20%. The suspension was
filtered and the solid was rinsed with a mixture of hexane/ethyl
acetate 20% and dried to give the pure compound in 57% yield. The
R.sub.P stereochemistry was confirmed by crystal X-ray
analysis.
[0422] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm) 1.13-1.15
(m, 6H), 1.26 (d, J=7.16 Hz, 3H), 3.85-3.95 (m, 1H), 4.89-4.90 (m,
1H), 6.84-6.90 (m, 1H), 7.20-7.25 (m, 3H), 7.38-7.42 (m, 2H);
.sup.31P NMR (162 MHz, DMSO-d.sub.6) .delta. (ppm) 0.33.
##STR00212##
[0423] To as solution of compound A10 (0.39 mmol) in anhydrous THF
(2 mL) under nitrogen at -5.degree. C. was added dropwise
tert-butylmagnesium chloride (1.0M in THF) (0.82 mmol). The white
suspension was stirred at this temperature for 15 minutes and then
warmed to ambient temperature and stirred for an additional 20
minutes. The reaction mixture was cooled down to 0.degree. C. and
compound A12.0 (0.47 mmol) solubilized in THF (2 mL) was added
dropwise. DMSO (0.4 mL) was added and the mixture was stirred at
7.degree. C. overnight. The reaction mixture was diluted with
dichloromethane and washed with H.sub.2O. The organic phase was
dried, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel [eluent:
DCM/MeOH 0 to 4%] to give the expected compound in 68% yield. MS
(ESI) m/z=806.2 (MH.sup.-).
##STR00213##
[0424] To a solution of compound A12 (0.27 mmol) in DCM (10 mL) was
added dropwise TFA (2.67 mmol) under nitrogen. The reaction mixture
was stirred at room temperature overnight. The reaction mixture was
purified directly by flash chromatography on silica gel and by
preparative HPLC to give the expected compound as a white
powder.
[0425] .sup.1H NMR (DMSO, 400 MHz) .delta. (ppm) 1.15 (d, J=3.06
Hz, 3H), 1.17 (d, J=3.06 Hz, 3H), 1.25 (brd, 6H), 3.65 (brd, J=13.0
Hz, 1H), 3.77-3.91 (m, 2H), 4.00 (brd, J=7.22 Hz, 1H), 4.70 (t,
J=8.30 Hz, 1H), 4.88 (heptuplet, J=6.30 Hz, 1H), 5.28 (brs, 1H),
5.76 (d, J=7.52 Hz, 1H), 6.28 (s, 1H), 6.34 (q, J=10.30 Hz, J=10.36
Hz), 7.17-7.27 (m, 3H), 7.31-7.42 (m, 4H), 7.83 (d, J=7.57 Hz, 1H);
.sup.31P NMR (DMSO, 161.98 MHz): .delta. (ppm) 3.48 (s, 1P); MS
(ESI) m/z=536.2 (MH.sup.+).
##STR00214##
[0426] To a solution of diphenylcarbonate (20.0 mmol) in anhydrous
DMF (25 mL) under nitrogen was added nucleoside A14 (20 mmol) at
room temperature. The reaction mixture was stirred at 80.degree. C.
for 1 hour under nitrogen. Sodium hydrogen carbonate (1.6 mmol) was
added and the mixture was stirred at 150.degree. C. for 2 hours
under nitrogen. The reaction mixture was allowed to cool to room
temperature and to stand overnight. The mixture was concentrated
under reduced pressure, suspended in ethanol and 1 mL of water, and
the white solid was filtered off. The collected solid washed with
ethanol 3 times, and dried under vacuo to afford A15 as a white
solid in 85% yield.
[0427] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 1.51 (s,
3H), 3.33-3.38 (m, 2H), 3.92 (q, J=4.79 Hz, 1H), 4.16 (d, J=4.46
Hz, 1H), 4.95 (brs, 1H), 5.83-5.85 (m, 2H), 5.99 (brs, 1H), 7.79
(d, J=7.52 Hz, 1H); MS (ESI) m/z=241 (MH.sup.+).
##STR00215##
[0428] To a solution of lithium fluoride (30.07 mmol) in anhydrous
DMF (10 mL) stirred at 120.degree. C. under nitrogen was added
azidotrimethylsilane (30.11 mmol) and
N,N,N',N'-tetramethylethylenediamine (80.02 mmol). The reaction
mixture was stirred at 120.degree. C. under nitrogen for 30 minutes
and A15 was added. The reaction mixture was stirred at 120.degree.
C. under nitrogen for 7 days. The mixture was filtered and washed
with DMF. The filtrate was concentrated under reduced pressure and
purified by flash chromatography [DCM/CH.sub.3OH: 0 to 15%],
followed by RP18 chromatography [H.sub.2O/CH.sub.3CN+0.05%
HCO.sub.2H: 0 to 20%] and by MS preparative HPLC to afford
reference compound 102 as a white solid after freeze-drying in 3%
yield with 90% purity.
[0429] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 1.25 (s,
3H), 3.59-3.65 (m, 1H), 3.78-3.83 (m, 2H), 3.97-4.01 (m, 1H), 5.30
(brs, 1H), 5.64 (d, J=8.08 Hz, 1H), 5.67 (s, 1H), 6.07-6.10 (m,
1H), 8.03 (d, J=8.08 Hz, 1H); 11.44 (s, 1H); MS (ESI) m/z=284
(MH.sup.+).
##STR00216##
[0430] To a solution of reference compound 102 (0.23 mmol) in
anhydrous ethanol (2 mL) was added Palladium (10% on Carbon, 130
mg). The reaction mixture was purged 3 times vacuo/nitrogen, then 3
times vacuo/hydrogen and stirred under hydrogen atmosphere
overnight at room temperature. The mixture was filtered through a
pad of celite, and the filtrate was concentrated under reduced
pressure. The crude compound was purified by C18 chromatography to
afford the expected compound after freeze-drying as a white solid
in quantitative yield.
[0431] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 0.91 (s,
3H), 3.57-3.62 (m, 1H), 3.66-3.70 (m, 1H), 3.76-3.81 (m, 2H), 5.17
(brs, 1H), 5.34 (brs, 1H), 5.58 (d, J=8.04 Hz, 1H), 5.71 (s, 1H),
8.06 (d, J=8.04 Hz, 1H); MS (ESI) m/z=258 (MH.sup.+).
##STR00217##
[0432] To a solution of (L)-alanine isopropyl ester, HCl salt (4.24
mmol) in anhydrous dichloromethane (5 mL) (3 times vacuo/nitrogen)
under nitrogen was added dropwise at -50.degree. C.
phenyldichlorophosphate (4.24 mmol) followed by N-methylimidazole
(10.60 mmol). The reaction mixture was stirred between -50.degree.
C. and -20.degree. C. during 2 hours. The reaction was monitored by
LC/MS (the sample was quenched by methanol or water) to check the
complete formation of expected intermediate. To the previous
reaction mixture was added a solution of reference compound 102
(1.06 mmol) in anhydrous dichloromethane (3 mL) at -50.degree. C.
under nitrogen. The reaction mixture was allowed to warm up slowly
to room temperature overnight, and then diluted with
dichloromethane and a solution of HCl (0.01M). The organic layer
was extracted, dried, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography on
silica gel (eluent: dichloromethane/methanol 0 to 6%), followed by
MS preparative HPLC to afford 2 separated diastereoisomers.
[0433] Reference Compound A18, Diastereoisomer 1: 8% yield; white
solid; .sup.1H NMR (CD.sub.3CN, 400 MHz) .delta. (ppm) 1.19 (d,
J=6.20 Hz, 3H), 1.20 (d, J=6.20 Hz, 3H), 1.27-1.30 (m, 6H),
3.83-3.95 (m, 2H), 4.03-4.08 (m, 1H), 4.26-4.37 (m, 3H), 4.42-4.47
(m, 1H), 4.94 (heptuplet, J=6.22 Hz, 1H), 5.58 (d, J=8.21 Hz, 1H),
5.78 (s, 1H), 7.19-7.25 (m, 3H), 7.36-7.40 (m, 2H), 7.49 (d, J=8.23
Hz, 1H), 9.12 (brs, 1H); .sup.31P NMR (CD.sub.3CN, 161.98 MHz)
.delta. (ppm) 3.36 (s, 1P); MS (ESI) m/z=553.2 (MH.sup.+).
[0434] Reference Compound A18, Diastereoisomer 2: 4% yield; white
solid; MS (ESI) m/z=553.2 (MH.sup.+).
##STR00218##
[0435] General Method A.
[0436] The following procedure was used to obtain reference
compound A19, diastereoisomer 1 and reference compound A19,
diastereoisomer 2.
[0437] To a solution of pure reference compound A18,
diastereoisomer 1 (0.074 mmol) in anhydrous ethanol (4 mL) was
added Palladium (10% on Carbon, 40 mg). The reaction mixture was
purged 3 times vacuo/nitrogen, then 3 times vacuo/hydrogen and
stirred under hydrogen atmosphere overnight at room temperature.
The mixture was filtered through a pad of celite, and the filtrate
was concentrated under reduced pressure. The crude compound was
purified by C18 chromatography [eluent: 0.05M TEAB aqueous
solution/CH.sub.3CN] followed by MS preparative HPLC to afford the
expected reference compound A19, diastereoisomer 1 and the
corresponding by-product A20a.
[0438] Reference Compound A19, Diastereoisomer 1: White solid;
.sup.1H NMR (CD.sub.3CN, 400 MHz) .delta. (ppm) 0.99 (s, 3H), 1.19
(d, J=6.20 Hz, 3H), 1.20 (d, J=6.20 Hz, 3H), 1.29 (d, J=7.09 Hz,
3H), 3.64 (d, J=8.22 Hz, 1H), 3.83-3.93 (m, 1H), 4.0-4.04 (m, 1H),
4.24-4.33 (m, 2H), 4.40-4.45 (m, 1H), 4.94 (heptuplet, J=6.24 Hz,
1H), 5.55 (d, J=8.14 Hz, 1H), 5.78 (s, 1H), 7.18-7.23 (m, 3H),
7.35-7.39 (m, 2H), 7.57 (d, J=8.14 Hz, 1H); .sup.31P NMR
(CD.sub.3CN, 161.98 MHz) .delta. (ppm) 3.20 (s, 1P); MS (ESI)
m/z=527.2 (MH.sup.+).
[0439] Reference Compound A19, diastereomer 2 was synthesized from
reference compound A18, diastereomer 2 as described for reference
compound A19, diastereomer 1.
[0440] Reference Compound A19, Diastereoisomer 2: White solid;
.sup.1H NMR (CD.sub.3CN, 400 MHz) .delta. (ppm) 1.00 (s, 3H), 1.19
(d, J=6.16 Hz, 6H), 1.32 (d, J=7.02 Hz, 3H), 3.37 (d, J=8.01 Hz,
1H), 3.86-3.96 (m, 1H), 3.98-4.03 (m, 1H), 4.23-4.31 (m, 2H),
4.37-4.42 (m, 1H), 4.94 (heptuplet, J=6.21 Hz, 1H), 5.51 (d, J=8.10
Hz, 1H), 5.77 (s, 1H), 7.18-7.25 (m, 3H), 7.35-7.40 (m, 2H), 7.55
(d, J=8.12 Hz, 1H); .sup.31P NMR (CD.sub.3CN, 161.98 MHz) .delta.
(ppm) 3.24 (s, 1P); MS (ESI) m/z=527.2 (MH.sup.+).
##STR00219##
[0441] Compound 22 was synthesized from compounds A1 (1.0 mol) and
A21: ethyl 2-chloropropionate (1.5 equiv.) as described for
compound A2.
##STR00220##
[0442] Compound A23 was synthesized from crude compound A22 as
described for compounds A3 and A4.
[0443] The crude black oil, mixture of A23 and A24, was purified
multiple times by flash chromatography [DCM/ethyl acetate: 20-70%]
to afford pure expected compound A23 in 22% 2 steps yield.
##STR00221##
[0444] Compound A25 was synthesized from compound A23 as described
for compound A5. (Triethylamine was added over 30 minutes using the
dropping funnel. The reaction was stirred at ambient temperature
for 3.5 hours).
[0445] The solid was recrystallized from 1.4 L of 1:1
toluene/trimethylpentane (100.degree. C.), to give 67 g of
product.
[0446] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. (ppm) 1.89 (s,
3H), 4.70-4.90 (m, 3H), 5.84 (d, J=3.08 Hz, 1H), 7.40-8.07 (m,
10H).
##STR00222##
[0447] To a solution of lithium fluoride (30.0 mmol) in anhydrous
DMF (20 mL) stirred at 105.degree. C. under nitrogen for 10 minutes
was added azidotrimethylsilane (40.0 mmol). The reaction mixture
was stirred at 105.degree. C. under nitrogen for 30 minutes. The
mixture was cooled to 50.degree. C. and the lactone A25 (20.0 mmol)
was added. The reaction mixture was stirred at 50.degree. C. under
nitrogen for 7 days. The mixture was poured into stirred water (200
mL), filtered off and washed twice with water. The collected solid
was triturated with toluene and filtered (5 times). The filtrate
was concentrated under reduced pressure and purified by flash
chromatography on silica gel (eluent: toluene/ethyl acetate: 95/5)
to afford the expected compound as a white solid in 85% yield.
[0448] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 1.71 (s,
3H), 4.62-4.72 (m, 2H), 5.01-5.06 (m, 1H), 5.73 (d, J=7.32 Hz, 1H),
7.45-7.49 (m, 2H), 7.54-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.69-7.73
(m, 1H), 7.92-7.95 (m, 2H), 8.02-8.04 (m, 2H); MS (ESI) m/z=396
(MH.sup.+).
##STR00223##
[0449] To a solution of compound A26 (17.9 mmol) in anhydrous THF
(150 mL) was added dropwise at -35.degree. C. under nitrogen a 1.0M
solution of Lithium tri-tert-butoxyaluminium hydride in THF (23
mmol). The reaction mixture was stirred at -35.degree. C. for 1
hour. The mixture was quenched with a saturated solution of
Rochelle's salt (100 mL) at -35.degree. C. Ethyl acetate (150 mL)
was added and the mixture was allowed to warm to room temperature.
The slurry was filtered through a Celite pad. The layers were
separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were dried, filtered and concentrated
under reduced pressure to afford crude .alpha.,.beta. sugar mixture
as a yellow gum in quantitative yield. MS (ESI) m/z=420
(MNa.sup.+).
##STR00224##
[0450] To a solution of A27 (17.9 mmol) in anhydrous THF (160 mL)
was added at room temperature under nitrogen
4-dimethylaminopyridine (17.9 mmol) followed by acetic anhydride
(179.0 mmol). The reaction mixture was stirred at room temperature
for 19 hours. Water and ethyl acetate were added and the mixture
was stirred vigorously for 10 minutes. The organic layer was
extracted and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel (eluent:
petroleum ether/ethyl acetate) to afford .alpha.,.beta. sugar
mixture as a white solid in 78% yield.
[0451] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 1.52 (s,
3H), 1.91 (s, 3H), 4.37-4.43 (m, 1H), 4.56-4.64 (m, 2H), 5.69-5.71
(m, 1H), 5.86 (s, 1H), 7.47-7.51 (m, 2H), 7.55-7.59 (m, 2H),
7.63-7.67 (m, 1H), 7.69-7.74 (m, 1H), 7.95-7.98 (m, 2H), 8.03-8.05
(m, 2H); MS (ESI) m/z=462.2 (MNa.sup.+).
##STR00225##
[0452] Compound A28 (0.44 mmol) and 6-chloro-9H-purine (0.88 mmol)
were dried under vacuum at 45.degree. C. for 2 hours. After purged
with vacuum/nitrogen refill, anhydrous toluene (12.5 mL/mmol) was
added, followed by N,O-bis(trimethylsilyl)acetamide (1.32 mmol).
The reaction mixture was stirred at 115.degree. C. for 1 hour under
nitrogen. The mixture was cooled to 0.degree. C. and trimethylsilyl
trifluoromethanesulfonate (1.10 mmol) was added. The reaction
mixture was stirred at 115.degree. C. overnight. The mixture was
cooled to room temperature and concentrated under reduced pressure.
The crude was purified by flash chromatography on silica gel
(eluent: DCM/CH.sub.3OH) followed by semi-preparative HPLC to
afford mixture of anomers as a yellowish solid in 31% yield; MS
(ESI) m/z=534.2 (MH.sup.+).
##STR00226##
[0453] Compound A29b was synthesized from compounds A28 (5.70 mmol)
and 6-amino-9H-purine (11.4 mmol) as described for compound A29a
but with 6.0 equiv. of BSA).
[0454] Purification by flash chromatography on silica gel (eluent:
DCM/CH.sub.3CN) afforded mixture of anomers as a yellow foam in 21%
yield; MS (ESI) m/z=515.2 (MH.sup.+).
##STR00227##
[0455] First procedure: To a solution of A29a (0.14 mmol) in
acetonitrile (2 mL) was added 7N methanolic ammonia (2.5 mL) in a
sealed vial. The reaction mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated under reduced pressure. The
crude was purified by SCX-2 cartridge to afford mixture of anomers.
This mixture was purified by preparative HPLC to afford
freeze-dried separated anomer. (.beta.-anomer: 51% yield).
[0456] Second procedure: To a solution of A29b (1.19 mmol) in
acetonitrile (12 mL) was added 7N methanolic ammonia (15 mL) in a
sealed vial. The reaction mixture was stirred at 90.degree. C. for
3 hours. The mixture was concentrated under reduced pressure. The
crude was purified by flash chromatography on silica gel (eluent:
DCM/EtOH) to afford mixture of anomers. This mixture was purified
by preparative HPLC to afford freeze-dried separated anomer.
(.beta.-anomer: 19% yield).
[0457] .beta.-anomer: White solid; .sup.1H NMR (MeOD, 400 MHz)
.delta. (ppm) 1.13 (s, 3H), 3.87 (dd, J=12.46 Hz and 2.49 Hz, 1H),
4.02-4.10 (m, 2H), 4.51 (d, J=8.95 Hz, 1H), 6.00 (s, 1H), 8.21 (s,
1H), 8.62 (s, 1H); MS (ESI) m/z=307 (MH.sup.+).
[0458] General Method B.
[0459] The following procedure was used to obtain compounds 201 to
208.
[0460] The appropriate nucleoside (100 mg) was dried in a flask
under vacuum overnight. Trimethylphosphate (1.9 ml) and Proton
Sponge (100 mg) were added to the flask and the reaction mixture
was stirred under nitrogen cooled by an ice/water bath. Distilled
phosphorus oxychloride (45 .mu.l) was added and the reaction
mixture was stirred during 4 hours with cooling. Tributylamine
(0.32 ml) and tributylamine pyrophosphate (4.0 ml of a 0.5 M
solution in DMF) were added and the reaction was allowed to stir
for an additional 45 min with cooling. The reaction was quenched
with triethylammonium bicarbonate (0.5 M, 20 ml) and the solvents
were concentrated under reduced pressure. The crude was dissolved
in 10 ml of water and purified using a Sephadex DEAE A-25 column
with a linear gradient of 0-1 M NaCl buffered with 20 mM Tris-HCl
(pH 7.0) (triphosphates eluted at .about.0.4 M NaCl) and desalted
on a C18 column to afford the expected compound. For compounds 206
and 207, the compounds are eluted on Dowex sodium exchange resin to
afford the expected compounds as Na.sup.+ salts.
##STR00228##
[0461] Colorless solid; MS (ESI) m/z=545 (MH.sup.-).
##STR00229##
[0462] White powder; MS (ESI) m/z=522 (MH.sup.-).
##STR00230##
[0463] White powder; MS (ESI) m/z=496 (MH.sup.-).
##STR00231##
[0464] White solid; MS (ESI) m/z=506 (MH.sup.-).
##STR00232##
[0465] Colorless solid; MS (ESI) m/z=505 (MH.sup.-).
##STR00233##
[0466] White powder; MS (ESI) m/z=495 (MH.sup.-).
##STR00234##
[0467] White solid; MS (ESI) m/z=481 (MH.sup.-).
##STR00235##
[0468] Colorless solid; MS (ESI) m/z=519 (MH.sup.-).
##STR00236##
[0469] Compounds 7, 8, A32a and A32b can be synthesized as
described above for compounds A18, A19, A20a and A20b by using
(D)-alanine isopropyl ester, HCl salt in place of (L)-alanine
isopropyl ester, HCl salt.
##STR00237##
[0470] Compound 528, diastereomers 1 and 2, were synthesized from
2'-azido-2' deoxy-uridine and (L)-alanine isopropyl ester, HCl salt
with triethylamine, according to Scheme 2. The mixture of
diastereoisomers was separated by MS-preparative HPLC.
[0471] Compound 528, Diastereoisomer 1; White solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 11.45 (brs, 1H), 7.58 (d,
J=8.11 Hz, 1H), 7.38-7.34 (m, 2H), 7.19-7.15 (m, 3H), 6.14 (d,
J=5.26 Hz, 1H), 6.06 (dd, J=12.57 Hz, 9.94 Hz, 1H), 5.86 (d, J=5.70
Hz, 1H), 5.61 (d, J=8.11 Hz, 1H), 4.85 (heptuplet, J=6.29 Hz, 1H),
4.31-4.23 (m, 2H), 4.20-4.15 (m, 1H), 4.08-4.06 (m, 1H), 3.99 (t,
J=5.56 Hz, 1H), 3.82-3.72 (m, 1H), 1.20 (d, J=7.12 Hz, 3H), 1.15
(d, J=6.24 Hz, 3H), 1.14 (d, J=6.24 Hz, 3H); .sup.31P NMR
(DMSO-d.sub.6, 161.98 MHz) .delta. (ppm) 3.92 (s, 1P); MS (ESI)
m/z=539.2 (MH.sup.+).
[0472] Compound 528, Diastereoisomer 2; White solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 11.44 (brs, 1H), 7.55 (d,
J=8.09 Hz, 1H), 7.39-7.35 (m, 2H), 7.22-7.16 (m, 3H), 6.11 (d,
J=5.07 Hz, 1H), 6.05 (dd, J=12.80 Hz, 10.03 Hz, 1H), 5.84 (d,
J=5.68 Hz, 1H), 5.55 (d, J=8.09 Hz, 1H), 4.85 (heptuplet, J=6.28
Hz, 1H), 4.32-4.28 (m, 1H), 4.24-4.19 (m, 1H), 4.15-4.10 (m, 1H),
4.06-4.02 (m, 2H), 3.86-3.75 (m, 1H), 1.22 (d, J=7.13 Hz, 3H), 1.15
(d, J=6.16 Hz, 6H); .sup.31P NMR (DMSO-d.sub.6, 161.98 MHz) .delta.
(ppm) 3.85 (s, 1P); MS (ESI) m/z=539.2 (MH.sup.+).
##STR00238##
[0473] Compound 526, diastereomers 1 and 2, was synthesized from
pure diastereoisomer of compound 528 (diastereomers 1 or 2)
according to Scheme 2.
[0474] Compound 526, Diastereoisomer 1; White solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 11.32 (brs, 1H), 7.55 (d,
J=8.12 Hz, 1H), 7.38-7.34 (m, 2H), 7.19-7.15 (m, 3H), 6.04 (dd,
J=12.65 Hz, 9.97 Hz, 1H), 5.64 (d, J=8.13 Hz, 1H), 5.59 (d, J=8.12
Hz, 1H), 5.54-5.53 (m, 1H), 4.85 (heptuplet, J=6.28 Hz, 1H),
4.16-4.13 (m, 2H), 4.03 (brs, 1H), 3.89 (brs, 1H), 3.81-3.70 (m,
1H), 3.17-3.14 (m, 1H), 1.20 (d, J=7.21 Hz, 3H), 1.15 (d, J=6.20
Hz, 3H), 1.14 (d, J=6.20 Hz, 3H); .sup.31P NMR (DMSO-d.sub.6,
161.98 MHz) .delta. (ppm) 3.85 (s, 1P).
[0475] Compound 526, Diastereoisomer 2; White solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 11.33 (brs, 1H), 7.54 (d,
J=8.08 Hz, 1H), 7.39-7.35 (m, 2H), 7.22-7.16 (m, 3H), 6.03 (dd,
J=12.87 Hz, 10.10 Hz, 1H), 5.64 (d, J=8.08 Hz, 1H), 5.51 (d, J=8.08
Hz, 1H), 4.86 (heptuplet, J=6.31 Hz, 1H), 4.16-4.05 (m, 2H),
4.00-3.99 (m, 1H), 3.90 (dd, J=5.41 Hz, 1.91 Hz, 1H), 3.84-3.74 (m,
1H), 1.22 (d, J=7.04 Hz, 3H), 1.155 (d, J=6.25 Hz, 3H), 1.15 (d,
J=6.25 Hz, 3H); .sup.31P NMR (DMSO-d.sub.6, 161.98 MHz) .delta.
(ppm) 3.82 (s, 1P).
##STR00239##
[0476] Compound 530, mixture of diastereomers, was synthesized from
2'-azido-2' deoxy-(dimethoxytrityl)-cytidine and (L)-alanine
isopropyl ester, HCl salt, according to Scheme 2.
[0477] Compound 530, Mixture of diastereoisomers; White solid;
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.65-7.51 (m,
2H), 7.41-7.34 (m, 3H), 7.22-7.15 (m, 3H), 6.10-6.04 (m, 2H), 5.90
(t, J=4.60 Hz, 1H), 5.76 (d, J=7.48 Hz, 0.5H), 5.72 (d, J=7.48 Hz,
0.5H), 4.85 (heptuplet, J=6.26 Hz, 1H), 4.29-4.10 (m, 3H),
4.08-4.02 (m, 1H), 3.93-3.87 (m, 1H), 3.83-3.73 (m, 1H), 1.22-1.19
(m, 3H), 1.16-1.14 (m, 6H); .sup.31P NMR (DMSO-d.sub.6, 161.98 MHz)
.delta. (ppm) 3.93 (s, 0.5P), 3.87 (s, 0.5P); MS (ESI) m/z=538.2
(MH.sup.+).
[0478] Compound 530, pure Sp diastereomer, was synthesized from
2'-azido-2' deoxy-(dimethoxytrityl)-cytidine and isopropyl
(2S)-2-[[(2,3,4,5,6-pentafluorophenoxy)-phenoxy-phosphoryl]amino]propanoa-
te, according to Scheme 1.
[0479] Compound 530, pure Sp diastereomer; White solid; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm) 8.37 (brs, 1H), 7.98 (brs,
1H), 7.70 (d, J=7.70 Hz, 1H), 7.39-7.35 (m, 2H), 7.22-7.16 (m, 3H),
6.12-6.06 (m, 2H), 5.85-5.82 (m, 2H), 4.85 (heptuplet, J=6.22 Hz,
1H), 4.28-4.23 (m, 2H), 4.17-4.12 (m, 1H), 4.06-4.01 (m, 2H),
3.85-3.75 (m, 1H), 1.21 (d, J=7.12 Hz, 3H), 1.14 (d, J=6.24 Hz,
6H); .sup.31P NMR (DMSO-d.sub.6, 161.98 MHz) .delta. (ppm) 3.92 (s,
1P); MS (ESI) m/z=538.2 (MH.sup.+).
##STR00240##
[0480] Compound 531, pure Sp diastereomer, was synthesized from
compound 530, pure Sp diastereomer, according to Scheme 2.
[0481] Compound 531, Pure diastereoisomer Sp; White solid; .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm) 7.50 (d, J=7.39 Hz, 1H),
7.38-7.35 (m, 2H), 7.23-7.16 (m, 5H), 6.05 (dd, J=12.84 Hz, 6.11
Hz, 1H), 5.79 (d, J=7.13 Hz, 1H), 5.71-5.68 (m, 1H), 5.67 (d,
J=7.45 Hz, 1H), 4.85 (heptuplet, J=6.27 Hz, 1H), 4.19-4.14 (m, 1H),
4.10-3.98 (m, 3H), 3.84-3.73 (m, 1H), 1.21 (d, J=7.11 Hz, 3H), 1.15
(d, J=6.23 Hz, 6H); .sup.31P NMR (DMSO-d.sub.6, 161.98 MHz) .delta.
(ppm) 3.82 (s, 1P); MS (ESI) m/z=512.2 (MH.sup.+).
Example 2
HCV Polymerase Enzyme Assay
[0482] Test compounds in the form of nucleoside triphosphates were
examined for inhibitory activity against purified HCV polymerase in
a standard assay. Bacterial expression constructs encoding the
approximately 65 kDa HCV genotype 1b NS5B protein were used to
generate recombinant HCV polymerases (with a deletion of the 21
carboxy terminal amino acids). Both the wild-type genotype 1b
protein and protein containing the S282T mutation were expressed
and purified for use in the enzymatic activity assay.
[0483] The enzymatic activity assay measured the inhibitory effect
of increasing concentrations of test compound on the incorporation
of .alpha.-[.sup.33P]-labeled nucleotide into trichloroacetic
acid-precipitable material. Recombinant polymerase and synthetic
RNA template were combined in reaction buffer containing
ribonucleoside triphosphates, .alpha.-[.sup.33P]-labeled nucleotide
and eight concentrations of test compound in three-fold dilutions.
Reactions were incubated for two hours at 30.degree. C.
[0484] Reactions were terminated by the addition of ice-cold
trichloroacetic acid and sodium pyrophosphate to promote
precipitation of newly-synthesized ribonucleic acid. Precipitable
material from the reactions was collected by filtration onto
96-well filter plates, washed extensively with water, and
quantified by liquid scintillation.
[0485] The inhibitory activity of test compounds was determined by
fitting results to dose-response curves using XLfit software.
[0486] Results are provided in Table 1.
TABLE-US-00003 TABLE 1 HCV Polymerase Enzyme Activity Wild-Type
S282T Compound IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) Compound 201 +++
+ Compound 202 +++ + Compound 203 ++ + Compound 204 ++++ ++
Compound 205 +++ Compound 206 ++ Compound 207 +++ Compound 208 ++ +
IC.sub.50 is provided as follows: ++++ .ltoreq. 250 nM, 250 nM <
+++ .ltoreq. 1 .mu.M, 1 .mu.M < ++ .ltoreq. 10 .mu.M, and 10
.mu.M < +.
Example 3
HCV Replicon Assay
[0487] Huh-7-derived cell line (Zluc) that harbors an HCV genotype
1b replicon and a luciferase reporter gene was grown in Dulbecco's
Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine
serum, 2 mM GlutaMAX, 1% MEM nonessential amino acids, 100 IU/mL
penicillin, 100 .mu.g/mL streptomycin, and 0.5 mg/mL Geneticin.RTM.
(G418). For dose response testing the cells were seeded in 96-well
plates at 7.5.times.10.sup.3 cells per well in a volume of 50
.mu.L, and incubated at 37.degree. C./5% CO.sub.2. Drug solutions
were made up freshly in Huh-7 media as 2.times. stocks. Ten
additional 5-fold dilutions were prepared from these stocks in DMEM
without G418. At least three hours after Zluc cells were seeded,
drug treatment was initiated by adding 50 .mu.L of drug dilutions
to the plates in duplicate. Final concentrations of drug ranged
from 100 .mu.M to 0.0000512 .mu.M. Cells were then incubated at
37.degree. C./5% CO.sub.2. Alternatively, compounds were tested at
two concentrations (1 .mu.M and 10 .mu.M). In all cases, Huh-7
(which do not harbors the HCV replicon) served as negative control.
After 72 hours of incubation, the inhibition of HCV replication was
measured by quantification of photons emitted after
mono-oxygenation of 5'-fluoroluciferin to oxyfluoroluciferin by
firefly luciferase. For this, media was removed from the plates via
gentle tapping. Fifty microliters of ONE-glo luciferase assay
reagent was added to each well. The plates were shaken gently for 3
min at room temperature and luminescence was measured on a
Victor.sup.3 V 1420 multilabel counter (Perkin Elmer) with a 1
second read time using a 700 nm cut-off filter. The EC.sub.50
values were calculated from dose response curves from the resulting
best-fit equations determined by Microsoft Excel and XLfit 4.1
software. When screening at two fixed concentrations, the results
were expressed as % inhibition at 1 .mu.M and 10 .mu.M.
[0488] For cytotoxicity evaluation, Zluc cells were treated with
compound as described herein, and cell viability was monitored
using the CellTiter-Blue Cell Viability Assay (Promega) by adding
20 .mu.L of the assay solution to each well. The plates were then
incubated at 37.degree. C./5% CO.sub.2 for at least 3 hours.
Fluorescence was detected in plates using excitation and emission
wavelengths of 560 and 590 nm, respectively, in a Victor.sup.3 V
1420 multilabel counter (Perkin Elmer) and CC.sub.50 values were
determined using Microsoft Excel and XLfit 4.1 software.
[0489] Compounds presented in Table 2 below were assayed according
to the replicon assay described herein.
TABLE-US-00004 TABLE 2 HCV Replicon Activity HCV HCV Compound
Replicon Compound Replicon Reference EC.sub.50 CC.sub.50 Reference
EC.sub.50 CC.sub.50 Reference + + Reference Compound + + Compound
102 103 Reference + + Reference Compound + + Compound A18 101
Diastereomer 1 Reference + + Reference Compound ++ + Compound A19
A19 Diastereomer 2 Diastereomer 1 Reference ++ + Compound 1a + +
Compound A9b Compound 528 + + Compound 528 + + Diastereomer 1
Diastereomer 2 Compound 530 + + Compound 530 + + Diastereomer 1
Diastereomer Mix Compound 531 + + Diastereomer 1 Compound 526 + +
Compound 526 + + Diastereomer 1 Diastereomer 2 EC.sub.50 is
provided as follows: ++++ .ltoreq. 250 nM < +++ .ltoreq. 1 .mu.M
< ++ .ltoreq. 10 .mu.M .ltoreq. + CC.sub.50 is provided as
follows: ++ .ltoreq. 50 .mu.M < +
[0490] All publications, patents, and patent applications cited in
this specification are herein incorporated by reference as if each
individual publication, patent, or patent application were
specifically and individually indicated to be incorporated by
reference. While the claimed subject matter has been described in
terms of various embodiments, the skilled artisan will appreciate
that various modifications, substitutions, omissions, and changes
may be made without departing from the spirit thereof. Accordingly,
it is intended that the scope of the claimed subject matter is
limited solely by the scope of the following claims, including
equivalents thereof.
* * * * *
References