U.S. patent application number 13/181078 was filed with the patent office on 2012-06-07 for antiviral therapeutic agents.
This patent application is currently assigned to BioCryst Pharmaceuticals, Inc.. Invention is credited to Yarlagadda S. Babu, Pooran Chand, Pravin Kotian, V. Satish Kumar, Minwan Wu.
Application Number | 20120142617 13/181078 |
Document ID | / |
Family ID | 41054287 |
Filed Date | 2012-06-07 |
United States Patent
Application |
20120142617 |
Kind Code |
A1 |
Babu; Yarlagadda S. ; et
al. |
June 7, 2012 |
ANTIVIRAL THERAPEUTIC AGENTS
Abstract
The invention provides compounds of Formula I: ##STR00001## as
described herein, as well as pharmaceutical compositions comprising
the compounds, and synthetic methods and intermediates that are
useful for preparing the compounds. The compounds of Formula (I)
are useful as anti-viral agents and/or as anti-cancer agents.
Inventors: |
Babu; Yarlagadda S.;
(Durham, NC) ; Chand; Pooran; (Durham, NC)
; Kotian; Pravin; (Durham, NC) ; Wu; Minwan;
(Durham, NC) ; Kumar; V. Satish; (Durham,
NC) |
Assignee: |
BioCryst Pharmaceuticals,
Inc.
Durham
NC
|
Family ID: |
41054287 |
Appl. No.: |
13/181078 |
Filed: |
July 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12398866 |
Mar 5, 2009 |
7994139 |
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13181078 |
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61034053 |
Mar 5, 2008 |
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61079370 |
Jul 9, 2008 |
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Current U.S.
Class: |
514/23 ; 435/184;
536/29.2 |
Current CPC
Class: |
C07D 491/06 20130101;
C07D 498/06 20130101; A61P 35/00 20180101; C12N 9/99 20130101; C12N
9/1241 20130101; A61P 43/00 20180101; A61P 31/20 20180101; A61P
31/14 20180101; A61P 31/18 20180101; A61P 31/00 20180101; C07D
487/06 20130101; A61P 31/12 20180101 |
Class at
Publication: |
514/23 ;
536/29.2; 435/184 |
International
Class: |
A61K 31/706 20060101
A61K031/706; C07H 11/04 20060101 C07H011/04; A61K 31/7068 20060101
A61K031/7068; A61P 35/00 20060101 A61P035/00; C12N 9/99 20060101
C12N009/99; C07H 7/06 20060101 C07H007/06; A61P 31/12 20060101
A61P031/12 |
Claims
1. A compound of formula I: ##STR00151## wherein; B represents a 5,
6, 7 or 8 membered carbocyclic or heterocyclic ring comprising one
or more double bonds, wherein B is optionally substituted with one
or more oxo, thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
wherein: R is H, alkyl or aryl; R' is OH, NH.sub.2 or alkyl;
R.sup.1 is H, NR.sub.aR.sub.b, Cl, F, OR.sub.a, SR.sub.a,
NHCOR.sub.a, NHSO.sub.2R.sub.a, NHCONHR.sub.a, CN, alkyl, aryl,
ONR.sub.aR.sub.b, or NR.sub.aC(O)OR.sub.b; R.sup.2 is a nucleoside
sugar group; W.sup.3 is absent, alkyl, or H; R.sub.a and R.sub.b
are independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted
aryl, acyl, substituted acyl, SO.sub.2-alkyl, amino, substituted
amino, and NO; or R.sub.e and R.sub.b together with the nitrogen to
which they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, or thiomorpholino ring; R.sub.c and R.sub.d
are independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, acyl, substituted acyl and
SO.sub.2-alkyl; or R.sub.c and R.sub.d together with the nitrogen
to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, or thiomorpholino ring; and each
R.sub.z is independently selected from the group consisting of H,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, acyl and substituted acyl; or a
pharmaceutically acceptable salt or prodrug thereof.
2. The compound of claim 1 wherein the compound of formula I is a
compound of formula II: ##STR00152## wherein; B represents a 5, 6,
7 or 8 membered ring comprising one or more heteratoms and one or
more double bonds, wherein B is optionally substituted with one or
more oxo, thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
wherein: R is H, alkyl or aryl; R' is OH, NH.sub.2 or alkyl;
R.sup.1 is H, NR.sub.aR.sub.b, Cl, F, OR.sub.a, SR.sub.a,
NHCOR.sub.a, NHSO.sub.2R.sub.a, NHCONHR.sub.a, CN, alkyl, aryl,
ONR.sub.aR.sub.b, or NR.sub.aC(O)OR.sub.b; R.sup.2 is a nucleoside
sugar group; W.sup.3 is absent, alkyl, or H; R.sub.a and R.sub.b
are independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted
aryl, acyl, substituted acyl, SO.sub.2-alkyl, amino, substituted
amino, and NO; or R.sub.a and R.sub.b together with the nitrogen to
which they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, or thiomorpholino ring; R.sub.c and R.sub.d
are independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, acyl, substituted acyl and
SO.sub.2-alkyl; or R.sub.c and R.sub.d together with the nitrogen
to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, or thiomorpholino ring; and each
R.sub.z is independently selected from the group consisting of H,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, acyl and substituted acyl; or a
pharmaceutically acceptable salt or prodrug thereof.
3. The compound of claim 2 wherein W.sup.3 is absent or H.
4. A compound of claim 1 which is a compound of formula III:
##STR00153## wherein: each b, c and d is independently selected
from a single and double bond provided that when b is a double
bond, c is single bond, when c is a double bond, b and d are single
bonds and when d is a double bond c is a single bond; or d is
absent when W.sup.2 is absent; and W.sup.2 and d are not absent,
when bNW.sup.3 is absent; W is C.dbd.R.sub.e, CH.sub.2, CR.sub.g or
O, provided that when W is C.dbd.R.sub.e, CH.sub.2 or O, b and c
are single bonds, or c is a single bond and bNW.sup.3 is absent;
and provided when W is CR.sub.g, one of b or c is a double bond, or
bNW.sup.3 is absent and c is a double bond; R.sub.e is O or S;
R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z; W.sup.1 is
C.dbd.R.sub.h, CR.sub.iR.sub.i', N, NR.sub.n, CR.sub.j or O
provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i,
NR.sub.n or O, c and d are single bonds or c is a single bond and
W.sup.2d is absent; and provided when W.sup.1 is CR.sub.j or N one
of c or d is a double bond or W2d is absent and c is a double bond;
R.sub.h is O or S; R.sub.i and R.sub.i' are H, CH.sub.3, NH.sub.2
or Br; R.sub.j is CH.sub.3, NH.sub.2, or H; W.sup.2 is
C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p', CR.sub.m, O, NR.sub.s,
absent or N provided that when W.sup.2 is C.dbd.R.sub.k,
CR.sub.lR.sub.l', O, or NR.sub.s d is a single bond; when W.sup.2
is N or CR.sub.m d is a double bond; and provided when W.sup.2 is
absent, d is absent; R.sub.k is O or S; R.sub.l and R.sub.l' are H,
CH.sub.3, OCH.sub.3, NH.sub.2 or SCH.sub.3; p' is 1 or 2; R.sub.m
is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.R, N.sub.3 or SO.sub.2R'; R.sub.n is H, alkyl,
or NR.sub.qR.sub.r wherein each R.sub.q and R.sub.r is H or alkyl;
R.sub.s is H, CH.sub.3, or NH.sub.2; and W.sup.3 is absent, H or
alkyl; provided that when W.sup.3 is absent b is a double bond; or
a pharmaceutically acceptable salt or prodrug thereof.
5. A compound of claim 1 which is a compound of formula IV:
##STR00154## wherein: each b, c and d is independently selected
from a single or double bond provided that when b is a double bond,
c is single bond, when c is a double bond, b and d are single bonds
and when d is a double bond c is a single bond; or d is absent when
W.sup.2 is absent; W is C.dbd.R.sub.e, CR.sub.fR.sub.f, CR.sub.g or
O, provided that when W is C.dbd.R.sub.e, CR.sub.fR.sub.f or O, b
and c are single bonds and when W is CR.sub.g, one of b or c is a
double bond; R.sub.e is O or S; R.sub.f is H; R.sub.g is H,
NR.sub.cR.sub.d, OR.sub.z or SR.sub.z; W.sup.1 is C.dbd.R.sub.h,
CR.sub.iR.sub.i', NH, CR.sub.j or O provided that when W.sup.1 is
C.dbd.R.sub.h, CR.sub.iR.sub.i, or O, c and d are single bonds;
when W.sup.1 is CR.sub.j, one of c or d is a double bond; and when
W.sup.1 is NH, W is not O and W.sup.2 is not O, NH, or N; R.sub.h
is O or S; R.sub.i and R.sub.i' are H, CH.sub.3 or Br; R.sub.j is
CH.sub.3 or H; W.sup.2 is C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p',
CR.sub.m, O, NH, absent, or N provided that when W.sup.2 is
C.dbd.R.sub.k, CR.sub.lR.sub.l', CR.sub.m, O, or NH d is a single
bond; when W.sup.2 is N or CR.sub.m d is a double bond; or when
W.sup.2 is absent, d is absent; R.sub.k is O or S; R.sub.l and
R.sub.l' are H, CH.sub.3, OCH.sub.3 or SCH.sub.3; p' is 1 or 2;
R.sub.m is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z,
alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'; and W.sup.3
is absent, H or alkyl; provided that when W.sup.3 is absent b is a
double bond; or a pharmaceutically acceptable salt or prodrug
thereof.
6. The compound of formula IV as described in claim 5 wherein: each
b, c and d is independently selected from a single or double bond
provided that when b is a double bond, c is single bond, when c is
a double bond, b and d are single bonds and when d is a double bond
c is a single bond; W is C.dbd.R.sub.e, CR.sub.fR.sub.f, CR.sub.g
or O, provided that when W is C.dbd.R.sub.e, CR.sub.fR.sub.f or O,
b and c are single bonds and when W is CR.sub.g, one of b or c is a
double bond; R.sub.e is O or S; R.sub.f is H; R.sub.g is H,
NR.sub.cR.sub.d, OR.sub.z or SR.sub.z; W.sup.1 is C.dbd.R.sub.h,
CR.sub.iCR.sub.i', CR.sub.j or O provided that when W.sup.1 is
C.dbd.R.sub.h, CR.sub.iR.sub.i', or O, c and d are single bonds and
when W.sup.1 is CR.sub.j, one of c or d is a double bond; R.sub.h
is O or S; R.sub.i and R.sub.i' are H, CH.sub.3 or Br; R.sub.j is
CH.sub.3 or H; W.sup.2 is C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p',
CR.sub.m, O, NH or N provided that when W.sup.2 is C.dbd.R.sub.k,
CR.sub.lR.sub.l', CR.sub.m, O, or NH d is a single bond and when
W.sup.2 is N or CR.sub.m d is a double bond; R.sub.k is O or S;
R.sub.l and R.sub.l' are H, CH.sub.3, OCH.sub.3 or SCH.sub.3; p' is
1 or 2; R.sub.m is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
and W.sup.3 is absent or H, provided that when W.sup.3 is absent b
is a double bond; or a pharmaceutically acceptable salt or prodrug
thereof.
7. The compound of claim 1 wherein the compound of formula I is a
compound of formula V: ##STR00155## wherein: each of b and c is
independently selected from a single or double bond provided that
when b is a double bond, c is single bond and when c is a double
bond b is a single bond; W is C.dbd.R.sub.e, CR.sub.fR.sub.f,
CR.sub.g or O, provided that when W is C.dbd.R.sub.e,
CR.sub.fR.sub.f or O, b and c are single bonds and when W is
CR.sub.g, one of b or c is a double bond; R.sub.e is O or S;
R.sub.f is H; R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z;
W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i', NH, CR.sub.j or O
provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i, or O,
c is a single bond; when W.sup.1 is CR.sub.j, c is a double bond;
and when W.sup.1 is NH, W is not O; R.sub.h is O or S; R.sub.i and
R.sub.i' are each independently H, CH.sub.3 or Br; R.sub.j is
CH.sub.3 or H; and W.sup.3 is absent, H, or alkyl, provided that
when W.sup.3 is absent b is a double bond; or a pharmaceutically
acceptable salt or prodrug thereof.
8. A compound of claim 1 which is a compound of formula I-9:
##STR00156## ##STR00157## wherein: X.sup.1 is O, S, or two
hydrogens; X.sup.2 is O, S, or two hydrogens; X.sup.3 is O or S;
X.sup.4 is O, S, or two hydrogens; X.sup.5 is O, S, or two
hydrogens; X.sup.8 is H, NH.sub.2, OCH.sub.3 or SCH.sub.3; Y.sup.1
is H, OH, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, F, Cl, Br, I,
alkoxy, alkyl SCH.sub.3, C.ident.N, C.ident.C--R, N.sub.3 or
SO.sub.2R'; Y.sup.2 is H, CH.sub.3, OCH.sub.3 or SCH.sub.3; Y.sup.3
is O or S; Y.sup.4 is O, S, or two hydrogens; Z.sup.1 is H or
CH.sub.3; Z.sup.2 is H, CH.sub.3 or Br; and t is 1 or 2; or a
pharmaceutically acceptable salt or prodrug thereof.
9. The compound of claim 1 wherein R.sup.1 is H or
NR.sub.aR.sub.b.
10. The compound of claim 1 which is selected from, ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164## ##STR00165## ##STR00166## ##STR00167## or a
pharmaceutically acceptable salt or prodrug thereof.
11. The compound of claim 1 wherein R.sup.2 is ribose,
2-methylribose, 2-deoxyribose; 2-deoxy-2-fluororibose; arabinose;
2-deoxy-2-fluoroarabinose; 2,3-dideoxyribose;
2,3-dideoxy-2-fluoroarabinose; 2,3-dideoxy-3-fluororibose;
2,3-dideoxy-2,3-didehydroribose; 2,3-dideoxy-3-azidoribose;
2,3-dideoxy-3-thiaribose; or 2,3-dideoxy-3-oxaribose; or a
pharmaceutically acceptable salt or prodrug thereof.
12. The compound of claim 1 wherein R.sup.2 is thioribose,
2-deoxythioribose; 2-deoxy-2-fluorothioribose; thioarabinose;
2-deoxy-2-fluorothioarabinose; 2,3-dideoxythioribose;
2,3-dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3-fluorothioribose;
2,3-dideoxy-2,3-didehydrothioribose; or
2,3-dideoxy-3-azidothioribose; or a pharmaceutically acceptable
salt or prodrug thereof.
13. The compound of claim 1 wherein R.sup.2 is
4-hydroxymethyl-cyclopent-2-ene;
2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene;
3-hydroxy-4-hydroxymethylcyclopentane;
2-hydroxy-4-hydroxymethylcyclopentene;
2-fluoro-3-hydroxy-4-hydroxymethylcyclopentane;
2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane;
4-hydroxymethylcyclopentane,
2,3-dihydroxy-4-hydroxymethylcyclopentane; or
2,3-dihydroxymethylcyclobutane; or a pharmaceutically acceptable
salt or prodrug thereof.
14. The compound of claim 1 wherein R.sup.2 is
4-hydroxymethyl-pyrrolidine;
2,3-dihydroxy-4-hydroxymethylpyrrolidine;
2/3-hydroxy-4-hydroxymethylpyrrolidine;
2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or
3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a
pharmaceutically acceptable salt or prodrug thereof.
15. The compound of claim 1 which is: ##STR00168## or a
pharmaceutically acceptable salt or prodrug thereof.
16. The compound of claim 1 which is: ##STR00169## or a
pharmaceutically acceptable salt or prodrug thereof.
17. The compound of claim 1 which is: ##STR00170## or a
pharmaceutically acceptable salt or prodrug thereof.
18. The compound of claim 1 which is: ##STR00171## or a
pharmaceutically acceptable salt or prodrug thereof.
19. The compound of claim 1 which is: ##STR00172## or a
pharmaceutically acceptable salt or prodrug thereof.
20. The compound of claim 1 which is a prodrug.
21. A pharmaceutical composition comprising a compound as described
in claim 1 and a pharmaceutically acceptable carrier.
22. A method for treating a viral infection in an animal comprising
administering to the animal an effective amount of a compound as
described in claim 1, or a composition as described in claim
21.
23. A method for treating cancer in an animal comprising
administering to the animal an effective amount of a compound as
described in claim 1, or a composition as described in claim
21.
24. A method for inhibiting a viral RNA or DNA polymerase
comprising contacting the polymerase in vitro or in vivo with an
effective inhibitory amount of a compound as described in claim 1,
or a composition as described in claim 21.
Description
RELATED APPLICATIONS
[0001] This patent application is a continuation of U.S.
application Ser. No. 12/398,866, filed Mar. 5, 2009 and claims the
benefit of priority of U.S. Application No. 61/034,053 filed Mar.
5, 2008, and of U.S. Application No. 61/079,370, filed Jul. 9,
2008, which applications are herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Viral diseases are a major cause of death and economic loss
in the world. The Flaviviridae family of viruses consists of three
genera: the flaviviruses (including dengue, West Nile, and yellow
fever viruses), hepatitis virus (HCV), and the pestiviruses
(including bovine viral diarrhea virus, BVDV). The disease states
and conditions caused by members of this family include yellow
fever, dengue, Japanese encephalitis, St. Louis encephalitis,
Hepatitis B and C, West Nile disease, and AIDS. Currently, human
immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis
C virus (HCV) infections are responsible for the largest number of
viral related deaths worldwide. Although there are some drugs
useful for treating HIV, there are only a few drugs useful for
treating HBV, and no drugs that are broadly useful for treating
HCV.
[0003] Ribavirin
(1-.beta.-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a
synthetic, non-interferon-inducing, broad spectrum antiviral
nucleoside. Ribavirin is structurally similar to guanosine, and has
in vitro activity against several DNA and RNA viruses including
Flaviviridae (Davis. Gastroenterology 118:S104-S114, 2000).
Ribavirin reduces serum amino transferase levels to normal in 40%
of patients, but it does not lower serum levels of HCV-RNA (Davis.
Gastroenterology 118:S104-S114, 2000). Thus, ribavirin alone is not
effective in reducing viral RNA levels. Additionally, ribavirin has
significant toxicity and is known to induce anemia.
[0004] Interferons (IFNs) are compounds which have been
commercially available for the treatment of chronic hepatitis for
nearly a decade. IFNs are glycoproteins produced by immune cells in
response to viral infection. IFNs inhibit viral replication of many
viruses, including HCV. When used as the sole treatment for
hepatitis C infection, IFN suppresses serum HCV-RNA to undetectable
levels. Additionally, IFN normalizes serum amino transferase
levels. Unfortunately, the effects of IFN are temporary and a
sustained response occurs in only 8%-9% of patients chronically
infected with HCV (Davis. Gastroenterology 118:S104-S114,
2000).
[0005] HCV is a positive stranded ss RNA virus with a well
characterized RNA-dependent RNA polymerase (RdRp) and a well
characterized disease progression. HCV has infected an estimated
170 million people worldwide, leading to a major health crisis as a
result of the disease. Indeed, during the next few years the number
of deaths from HCV-related liver disease and hepatocellular
carcinoma may overtake those caused by AIDS. Egypt is the hardest
hit country in the world, with 23% of the population estimated to
be carrying the virus; whereas, in the USA the prevalence of
chronic infections has recently been determined to be around 1.87%
(2.7 million persons). HCV infections become chronic in about 50%
of cases. Of these, about 20% develop liver cirrhosis that can lead
to liver failure, including hepatocellular carcinoma.
[0006] The NS5B region of HCV encodes a 65 KDa RdRp thought to be
responsible for viral genome replication. RdRps function as the
catalytic subunit of the viral replicase required for the
replication of all positive-strand viruses. The NS5B protein has
been well characterized, shown to possess the conserved GDD motif
of RdRps and in vitro assay systems have been reported. Cellular
localization studies revealed that NS5B is membrane-associated in
the endoplasmic reticulum like NS5A, suggesting that those two
proteins may remain associated with one another after proteolytic
processing. Additional evidence suggests that NS3, NS4A and NS5B
interact with each other to form a complex that functions as part
of the replication machinery of HCV.
[0007] The X-ray crystal structure of NS5B apoenzyme has been
determined and three very recent publications describe the unusual
shape of the molecule. This unique shape for a polymerase,
resembling a flat sphere, is attributed to extensive interactions
between the fingers and thumb subdomains in such a way that the
active site is completely encircled, forming a cavity 15 .ANG.
across and 20 .ANG. deep. Modeling studies showed that the NS5B
apoenzyme can accommodate the template-primer without large
movement of the subdomains, suggesting that the structure is
preserved during the polymerization reaction. The RdRp polypeptides
from various members of the Flaviviridae family and other viral
families have been shown to be conserved (J. A. Bruenn, Nucleic
Acids Research, Vol. 19, No. 2 p. 217, 1991).
[0008] Currently, there are no safe and effective therapeutic
agents on the market that target HCV polymerase. There is currently
a need for therapeutic agents and therapeutic methods that are
useful for treating viral infections, such as HCV, HIV, and
HBV.
[0009] In addition, there is also a current need for therapeutic
agents and therapeutic methods that are useful for treating cancer.
Even though significant advances have occurred in the treatment of
cancer, it still remains a major health concern. It has been
reported that cancer is the cause of death of up to one of every
four Americans. Notwithstanding the advances in treatments for
cancer and other diseases there is still a need for novel drugs
that are effective to treat cancer.
SUMMARY OF THE INVENTION
[0010] The present invention provides compounds that are inhibitors
of viral RNA and DNA polymerases (e.g. polymerases from hepatitis
B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A
and B, Rhino, Echo, small pox, Ebola, and West Nile virus) and that
are useful for treating HCV, as well as other viral infections
(e.g. flaviviral infections), and cancer.
[0011] Accordingly, the invention provides a novel compound of
Formula I as described herebelow, or a pharmaceutically acceptable
salt or prodrug thereof.
[0012] The invention also provides a pharmaceutical composition
comprising a compound of Formula I, or a pharmaceutically
acceptable salt or prodrug thereof, and a pharmaceutically
acceptable carrier. The composition can optionally comprise one or
more additional anti-viral or anti-cancer agents.
[0013] The invention also provides a method for treating a viral
infection in an animal comprising administering to the animal an
effective amount of a compound of Formula I, or a pharmaceutically
acceptable salt or prodrug thereof.
[0014] The invention also provides a method for inhibiting a viral
RNA or DNA polymerase comprising contacting the polymerase (in
vitro or in vivo) with an effective inhibitory amount of a compound
of Formula I, or a pharmaceutically acceptable salt or prodrug
thereof.
[0015] The invention also provides a method for treating cancer in
an animal comprising administering to the animal an effective
amount of a compound of Formula I, or a pharmaceutically acceptable
salt or prodrug thereof.
[0016] The invention also provides a compound of Formula I, or a
pharmaceutically acceptable salt or prodrug thereof, for use in
medical therapy (e.g. for use in treating a viral infection or for
use in treating cancer).
[0017] The invention also provides the use of a compound of Formula
I, or a pharmaceutically acceptable salt or prodrug thereof, to
prepare a medicament useful for treating a viral infection in an
animal (e.g. a human).
[0018] The invention also provides the use of a compound of Formula
I, or a pharmaceutically acceptable salt or prodrug thereof, to
prepare a medicament useful for treating cancer in an animal (e.g.
a human).
[0019] The invention also provides a compound of Formula I, or a
pharmaceutically acceptable salt or prodrug thereof, for the
prophylactic or therapeutic treatment of a viral infection.
[0020] The invention also provides a compound of Formula I, or a
pharmaceutically acceptable salt or prodrug thereof, for the
prophylactic or therapeutic treatment of cancer.
[0021] The invention also provides novel synthetic intermediates
and synthetic methods that are disclosed herein as being useful for
preparing compounds of Formula I, or a salt or prodrug thereof.
Some compounds of Formula I may be useful as synthetic
intermediates for preparing other compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0022] The term "pharmaceutically acceptable salt" as used herein
refers to a compound of the present disclosure derived from
pharmaceutically acceptable bases, inorganic or organic acids.
Examples of suitable acids include, but are not limited to,
hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,
maleic, phosphoric, glycolic, lactic, salicyclic, succinic,
toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,
formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic
and benzenesulfonic acids. Salts derived from appropriate bases
include, but are not limited to, alkali such as sodium and
ammonia.
[0023] The terms "treat", "treating" and "treatment" as used herein
include administering a compound prior to the onset of clinical
symptoms of a disease state/condition so as to prevent any symptom,
as well as administering a compound after the onset of clinical
symptoms of a disease state/condition so as to reduce or eliminate
any symptom, aspect or characteristic of the disease
state/condition. Such treating need not be absolute to be
useful.
[0024] The term "animal" as used herein refers to any animal,
including mammals, such as, but not limited to, mice, rats, other
rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and
primates. In one specific embodiment of the invention the animal is
a human.
[0025] The term "therapeutically effective amount", in reference to
treating a disease state/condition, refers to an amount of a
compound either alone or as contained in a pharmaceutical
composition that is capable of having any detectable, positive
effect on any symptom, aspect, or characteristics of a disease
state/condition when administered as a single dose or in multiple
doses. Such effect need not be absolute to be beneficial.
[0026] The term "alkyl" as used herein refers to alkyl groups
having from 1 to 6 carbon atoms. This term is exemplified by groups
such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,
n-pentyl and the like. In a specific embodiment, the alkyl groups
have from 1-4 carbon atoms and are referred to as lower alkyl.
[0027] The term "substituted alkyl" as used herein refers to an
alkyl group having from 1 to 3 substituents, said substituents
being selected from the group consisting of alkoxy, alkoxyalkyl,
tri(C.sub.1-C.sub.4alkyl)silyl, substituted alkoxy, acyl,
substituted acyl, acylamino, acyloxy, oxyacyl, amino, substituted
amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted
aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, substituted thioalkyl, thioaryl,
substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,
thiocycloalkyl, substituted thiocycloallyl, thioheterocyclic,
substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic. In one specific embodiment of the invention, the term
"substituted alkyl" refers to an alkyl group substituted with 1 to
3 substituents, said substituents being selected from the group
consisting of alkoxy, alkoxyalkyl, tri(C.sub.1-C.sub.4alkyl)silyl,
acyl, acylamino, acyloxy, oxyacyl, amino, aminoacyl, aryl, aryloxy,
cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl, carboxyl
esters, thiol, thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl,
thioheterocyclic, cycloalkyl, heteroaryl, and heterocyclic.
[0028] The terms "alkenyl" or "alkene" as used herein refers to an
alkenyl group having from 2 to 10 carbon atoms and having at least
1 site of alkenyl unsaturation. Such groups are exemplified by
vinyl(ethen-1-yl), allyl, but-3-en-1-yl, and the like.
[0029] The term "substituted alkenyl" as used herein refers to
alkenyl groups having from 1 to 3 substituents, said substituents
being selected from those describe above for a substituted alkyl.
The term "alkynyl" or "alkyne" as used herein refers to an alkynyl
group having from 2-10 carbon atoms and having at least 1 site of
alkynyl unsaturation. Such groups are exemplified by, but not
limited to, ethyn-1-yl, propyn-1-yl, propyn-2-yl,
1-methylprop-2-yn-1-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, and the
like.
[0030] The term "substituted alkynyl" as used herein refers to
alkynyl groups having from 1 to 3 substituents, said substituents
being selected those describe above for a substituted alkyl.
[0031] The term "alkoxy" refers to the group alkyl-O--.
[0032] The term "substituted alkoxy" as used herein refers to the
group substituted alkyl-O--.
[0033] The term "acyl" as used herein refers to the groups
alkyl-C(O)--, alkenyl-C(O) alkynyl-C(O)--, cycloalkyl-C(O)--,
aryl-C(O)--, heteroaryl-C(O)--, and heterocyclic-C(O).
[0034] The term "substituted acyl" as used herein refers to the
groups substituted alkyl-C(O)--, substituted alkenyl-C(O)--,
substituted alkynyl-C(O)--, substituted cycloalkyl-C(O)--,
substituted aryl-C(O)--, substituted heteroaryl-C(O), and
substituted heterocyclic-C(O)--.
[0035] The term "acylamino" as used herein refers to the
group-C(O)NZ.sub.1Z.sub.2 where each Z.sub.1 and Z.sub.2 are
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and
substituted alkynyl, and the substituents described above in the
definition of substituted alkyl.
[0036] The term "acyloxy" as used herein refers to the groups
alkyl-C(O)O--, substituted alkyl-C(O)O--, alkenyl-C(O)O--,
substituted alkenyl-C(O)O--, alkynyl-C(O)O--, substituted
alkynyl-C(O)O--, aryl-C(O)O--, substituted aryl-C(O)O--,
cycloalkyl-C(O)O--, substituted cycloalkyl-C(O)O--,
heteroaryl-C(O)O--, substituted heteroaryl-C(O)O--,
heterocyclic-C(O)O--, and substituted heterocyclic-C(O)O--.
[0037] The term "oxyacyl" as used herein refers to the groups
alkyl-OC(O)--, substituted alkyl-OC(O)--, alkenyl-OC(O)--,
substituted alkenyl-OC(O)--, alkynyl-OC(O)--, substituted
alkynyl-OC(O)--, aryl-OC(O)--, substituted aryl-OC(O)--,
cycloalkyl-OC(O)--, substituted cycloalkyl-OC(O)--,
heteroaryl-OC(O)--, substituted heteroaryl-OC(O)--,
heterocyclic-OC(O)--, and substituted heterocyclic-OC(O)--.
[0038] The term "amino" as used herein refers to the group
--NH.sub.2.
[0039] The term "substituted amino" as used herein refers to the
group --NZ.sub.1Z.sub.2 where Z.sub.1 and Z.sub.2 are as described
above in the definition of acylamino, provided that Z.sub.1 and
Z.sub.2 are both not hydrogen.
[0040] The term "aminoacyl" as used herein refers to the groups
--NZ.sub.3C(O)alkyl, --NZ.sub.3C(O)substituted alkyl,
--NZ.sub.3C(O)cycloalkyl, --NZ.sub.3C(O)substituted cycloalkyl,
--NZ.sub.3C(O)alkenyl, --NZ.sub.3C(O) substituted alkenyl,
--NZ.sub.3C(O)alkynyl, --NZ.sub.3C(O) substituted alkynyl,
--NZ.sub.3C(O)aryl, --NZ.sub.3C(O) substituted aryl,
--NZ.sub.3C(O)heteroaryl, --NZ.sub.3C(O) substituted heteroaryl,
--NZ.sub.3C(O)heterocyclic, and --NZ.sub.3C(O) substituted
heterocyclic, where Z.sub.3 is hydrogen or alkyl.
[0041] The term "aryl" as used herein refers to a monovalent
aromatic cyclic group of from 6 to 14 carbon atoms having a single
ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or
anthryl) which condensed rings may or may not be aromatic.
Exemplary aryls include, but are not limited to, phenyl and
naphthyl.
[0042] The term "substituted aryl" as used herein refers to aryl
groups which are substituted with from 1 to 3 substituents selected
from alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl and substituted alkynyl, and those substituents described
above in the definition of substituted alkyl.
[0043] The term "aryloxy" as used herein refers to the group
aryl-O-- that includes, by way of example but not limitation,
phenoxy, naphthoxy, and the like.
[0044] The term "substituted aryloxy" as used herein refers to
substituted aryl-O-groups.
[0045] The term "carboxyl" as used herein refers to --COOH or salts
thereof.
[0046] The term "carboxyl esters" as used herein refers to the
groups-C(O)O-alkyl, --C(O)O-substituted alkyl, --C(O)O-aryl, and
--C(O)O-substituted aryl.
[0047] The term "cycloalkyl" as used herein refers to a saturated
or unsaturated cyclic hydrocarbon ring systems, such as those
containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary
groups include but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
[0048] The term "substituted cycloalkyl" as used herein refers to a
cycloalkyl having from 1 to 5 substituents selected from the group
consisting of oxo (.dbd.O), thioxo (.dbd.S), alkyl, substituted
alkyl, and those substituents described in the definition of
substituted alkyl.
[0049] The term "cycloalkoxy" as used herein refers to
--O-cycloalkyl groups.
[0050] The term "substituted cycloalkoxy" as used herein refers to
--O-substituted cycloalkyl groups.
[0051] The term "formyl" as used herein refers to HC(O)--.
[0052] The term "halogen" as used herein refers to fluoro, chloro,
bromo and iodo.
[0053] The term "heteroaryl" as used herein refers to an aromatic
group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected
from the group consisting of oxygen, nitrogen, sulfur in the ring.
The sulfur and nitrogen heteroatoms atoms may also be present in
their oxidized forms. Such heteroaryl groups can have a single ring
(e.g., pyridyl or furyl) or multiple condensed rings (e.g.,
indolizinyl or benzothienyl) wherein the condensed rings may or may
not be aromatic and/or contain a heteroatom. Exemplary heteroaryl
groups include, but are not limited to, heteroaryls include
pyridyl, pyrrolyl, thienyl, indolyl, thiophenyl, and furyl.
[0054] The term "substituted heteroaryl" as used herein refers to
heteroaryl groups that are substituted with from 1 to 3
substituents selected from the same group of substituents defined
for substituted aryl.
[0055] The term "heteroaryloxy" as used herein refers to the group
--O-heteroaryl.
[0056] The term "substituted heteroaryloxy" as used herein refers
to the group --O-substituted heteroaryl.
[0057] The term "heterocycle" or "heterocyclic" or
"heterocycloalkyl" refers to a saturated or unsaturated group (but
not heteroaryl) having a single ring or multiple condensed rings,
from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected
from the group consisting of nitrogen, oxygen, sulfur, within the
ring wherein, in fused ring systems, one or more the rings can be
cycloalkyl, aryl or heteroaryl provided that the point of
attachment is through the heterocyclic ring. The sulfur and
nitrogen heteroatoms atoms may also be present in their oxidized
forms.
[0058] The term "substituted heterocycle" or "substituted
heterocyclic" or "substituted heterocycloalkyl" refers to
heterocycle groups that are substituted with from 1 to 3 of the
same substituents as defined for substituted aryl.
[0059] Examples of heterocycles and heteroaryls include, but are
not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
dihydroindole, indazole, purine, quinolizine, isoquinoline,
quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,
cinnoline, pteridine, carbazole, carboline, phenanthridine,
acridine, phenanthroline, isothiazole, phenazine, isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine,
piperazine, indoline, phthalimide, 1,2, 3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine,
thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also
referred to as thiamorpholinyl), piperidinyl, pyrrolidine,
tetrahydrofuranyl, and the like.
[0060] The term "heterocyclyloxy" as used herein refers to the
group --O-heterocyclic.
[0061] The term "substituted heterocyclyloxy" as used herein refers
to the group-O-substituted heterocyclic.
[0062] The term "phosphate" as used herein refers to the groups
--OP(O)(OH).sub.2 (monophosphate or phospho),
--OP(O)(OH)OP(O)(OH).sub.2 (diphosphate or diphospho) and
--OP(O)(OH)OP(O)(OH)OP(O)(OH).sub.2 (triphosphate or triphospho) or
salts thereof including partial salts thereof. It is understood
that the initial oxygen of the mono-, di-, and triphosphate may
include the oxygen atom of a sugar.
[0063] The term "phosphate esters" as used herein refers to the
mono-, di- and tri-phosphate groups described above wherein one or
more of the hydroxyl groups is replaced by an alkoxy group.
[0064] The term "phosphonate" refers to the groups
--OP(O)(Z.sub.4)(OH) or --OP(O) (Z.sub.4)(OZ.sub.4) or salts
thereof including partial salts thereof, wherein each Z.sub.4 is
independently selected from hydrogen, alkyl, substituted alkyl,
carboxylic acid, and carboxyl ester. It is understood that the
initial oxygen of the phosphonate may include the oxygen of a
sugar.
[0065] The term "thiol" as used herein refers to the group
--SH.
[0066] The term "thioalkyl" or "alkylthioether" or "thioalkoxy"
refers to the group --S-alkyl.
[0067] The term "substituted thioalkyl" or "substituted
alkylthioether" or "substituted thioalkoxy" refers to the group
--S-substituted alkyl.
[0068] The term "thiocycloalkyl" as used herein refers to the group
--S-cycloalkyl.
[0069] The term "substituted thiocycloalkyl" as used herein refers
to the group --S-substituted cycloalkyl.
[0070] The term "thioaryl" as used herein refers to the group
--S-aryl.
[0071] The term "substituted thioaryl" as used herein refers to the
group-S-substituted aryl.
[0072] The term "thioheteroaryl" as used herein refers to the group
--S-heteroaryl.
[0073] The term "substituted thioheteroaryl" as used herein refers
to the group --S-substituted heteroaryl.
[0074] The term "thioheterocyclic" as used herein refers to the
group --S-heterocyclic.
[0075] The term "substituted thioheterocyclic as used herein refers
to the group --S-substituted heterocyclic.
[0076] The term "amino acid sidechain" refers to the Z.sub.7
substituent of .alpha.-amino acids of the formula
Z.sub.6NHCH(Z.sub.7)COOH where Z.sub.7 is selected from the group
consisting of hydrogen, alkyl, substituted alkyl and aryl and
Z.sub.6 is hydrogen or together with Z.sub.7 and the nitrogen and
carbon atoms bound thereto respectively form a heterocyclic ring.
In one embodiment, the .alpha.-amino acid sidechain is the
sidechain of one of the twenty naturally occurring L amino
acids.
[0077] Sugars described herein may either be in D or L
configuration.
Compounds of Formula I
[0078] Compounds of the invention include compounds of formula
I:
##STR00002##
wherein;
[0079] B represents a 5, 6, 7 or 8 membered carbocyclic or
heterocyclic ring comprising one or more double bonds, wherein B is
optionally substituted with one or more oxo, thioxo,
NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
wherein:
[0080] R is H, alkyl or aryl;
[0081] R' is OH, NH.sub.2 or alkyl;
[0082] R.sup.1 is H, NR.sub.aR.sub.b, Cl, F, OR.sub.a, SR.sub.a,
NHCOR.sub.a, NHSO.sub.2R.sub.a, NHCONHR.sub.a, CN, alkyl, aryl,
ONR.sub.aR.sub.b, or NR.sub.aC(O)OR.sub.b;
[0083] R.sup.2 is a nucleoside sugar group;
[0084] W.sup.3 is absent, alkyl, or H;
[0085] R.sub.a and R.sub.b are independently selected from the
group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
heterocyclic, aryl, substituted aryl, acyl, substituted acyl,
SO.sub.2-alkyl, amino, substituted amino, and NO; or R.sub.a and
R.sub.b together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or
thiomorpholino ring;
[0086] R.sub.c and R.sub.d are independently selected from the
group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
acyl, substituted acyl and SO.sub.2-alkyl; or R.sub.c and R.sub.d
together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, piperazino, azetidino, morpholino, or
thiomorpholino ring; and
[0087] each R.sub.z is independently selected from the group
consisting of H, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, acyl and
substituted acyl;
[0088] or a pharmaceutically acceptable salt or prodrug
thereof.
[0089] In one embodiment of the invention the compound of formula I
is a compound of formula II:
##STR00003##
wherein;
[0090] B represents a 5, 6, 7 or 8 membered ring comprising one or
more heteratoms and one or more double bonds, wherein B is
optionally substituted with one or more oxo, thioxo,
NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
wherein:
[0091] R is H, alkyl or aryl;
[0092] R' is OH, NH.sub.2 or alkyl;
[0093] R.sup.1 is H, NR.sub.aR.sub.b, Cl, F, OR.sub.a, SR.sub.a,
NHCOR.sub.a, NHSO.sub.2R.sub.a, NHCONHR.sub.a, CN, alkyl, aryl,
ONR.sub.aR.sub.b, or NR.sub.aC(O)OR.sub.b;
[0094] R.sup.2 is a nucleoside sugar group;
[0095] W.sup.3 is absent, alkyl, or H;
[0096] R.sub.a and R.sub.b are independently selected from the
group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
heterocyclic, aryl, substituted aryl, acyl, substituted acyl,
SO.sub.2-alkyl, amino, substituted amino, and NO; or R.sub.a and
R.sub.b together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or
thiomorpholino ring;
[0097] R.sub.c and R.sub.d are independently selected from the
group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
acyl, substituted acyl and SO.sub.2-alkyl; or R.sub.c and R.sub.d
together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, piperazino, azetidino, morpholino, or
thiomorpholino ring; and
[0098] each R.sub.z is independently selected from the group
consisting of H, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, acyl and
substituted acyl;
[0099] or a pharmaceutically acceptable salt or prodrug
thereof.
[0100] In one embodiment of the invention the compound of formula I
is a compound of formula II wherein W.sup.3 is absent or H.
[0101] In one embodiment of the invention the compound of formula I
is a compound of formula III:
##STR00004##
wherein:
[0102] each b, c and d is independently selected from a single and
double bond provided that when b is a double bond, c is single
bond, when c is a double bond, b and d are single bonds and when d
is a double bond c is a single bond; or d is absent when W.sup.2 is
absent; and W.sup.2 and d are not absent, when bNW.sup.3 is
absent;
[0103] W is C.dbd.R.sub.e, CH.sub.2, CR.sub.g or O, provided that
when W is C.dbd.R.sub.e, CH.sub.2 or O, b and c are single bonds,
or c is a single bond and bNW.sup.3 is absent; and provided when W
is CR.sub.g, one of b or c is a double bond, or bNW.sup.3 is absent
and c is a double bond;
[0104] R.sub.e is O or S;
[0105] R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z;
[0106] W.sup.1 is C.dbd.R.sub.h, N, NR.sub.n, CR.sub.j or O
provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i,
NR.sub.n or O, c and d are single bonds or c is a single bond and
W.sup.2d is absent; and provided when W.sup.1 is CR.sub.j or N one
of c or d is a double bond or W2d is absent and c is a double
bond;
[0107] R.sub.h is O or S;
[0108] R.sub.i and R.sub.i' are H, CH.sub.3, NH.sub.2 or Br;
[0109] R.sub.j is CH.sub.3, NH.sub.2, or H;
[0110] W.sup.2 is C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p',
CR.sub.m, O, NR.sub.S, absent or N provided that when W.sup.2 is
C.dbd.R.sub.k, CR.sub.lR.sub.l', O, or NR.sub.s d is a single bond;
when W.sup.2 is N or CR.sub.m d is a double bond; and provided when
W.sup.2 is absent, d is absent;
[0111] R.sub.k is O or S;
[0112] R.sub.l and R.sub.l' are H, CH.sub.3, OCH.sub.3, NH.sub.2 or
SCH.sub.3;
[0113] p' is 1 or 2;
[0114] R.sub.m is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or
SO.sub.2R';
[0115] R.sub.n is H, alkyl, or NR.sub.qR.sub.r wherein each R.sub.q
and R.sub.r is H or alkyl;
[0116] R.sub.s is H, CH.sub.3, or NH.sub.2; and
[0117] W.sup.3 is absent, H or alkyl; provided that when W.sup.3 is
absent b is a double bond;
[0118] or a pharmaceutically acceptable salt or prodrug
thereof.
[0119] In one embodiment of the invention the compound of formula I
is a compound of formula IV:
##STR00005##
wherein:
[0120] each b, c and d is independently selected from a single or
double bond provided that when b is a double bond, c is single
bond, when c is a double bond, b and d are single bonds and when d
is a double bond c is a single bond; or d is absent when W.sup.2 is
absent;
[0121] W is C.dbd.R.sub.e, CR.sub.fR.sub.f, CR.sub.g or O, provided
that when W is C.dbd.R.sub.e, CR.sub.fR.sub.f or O, b and c are
single bonds and when W is CR.sub.g, one of b or c is a double
bond;
[0122] R.sub.e is O or S;
[0123] R.sub.f is H;
[0124] R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z;
[0125] W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i', NH, CR.sub.j or
O provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i, or
O, c and d are single bonds; when W.sup.1 is CR.sub.j, one of c or
d is a double bond; and when W.sup.1 is NH, W is not O and W.sup.2
is not O, NH, or N;
[0126] R.sub.h is O or S;
[0127] R.sub.i and R.sub.i' are H, CH.sub.3 or Br;
[0128] R.sub.j is CH.sub.3 or H;
[0129] W.sup.2 is C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p',
CR.sub.m, O, NH, absent, or N provided that when W.sup.2 is
C.dbd.R.sub.k, CR.sub.lR.sub.l', CR.sub.m, O, or NH d is a single
bond; when W.sup.2 is N or CR.sub.m d is a double bond; or when
W.sup.2 is absent, d is absent;
[0130] R.sub.k is O or S;
[0131] R.sub.l and R.sub.l', are H, CH.sub.3, OCH.sub.3 or
SCH.sub.3;
[0132] p' is 1 or 2;
[0133] R.sub.m is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
and W.sup.3 is absent, H or alkyl; provided that when W.sup.3 is
absent b is a double bond;
[0134] or a pharmaceutically acceptable salt or prodrug
thereof.
[0135] In one embodiment of the invention the compound of formula I
is a compound of formula IV wherein: each b, c and d is
independently selected from a single or double bond provided that
when b is a double bond, c is single bond, when c is a double bond,
b and d are single bonds and when d is a double bond c is a single
bond;
[0136] W is C.dbd.R.sub.e, CR.sub.fR.sub.f, CR.sub.g or O, provided
that when W is C.dbd.R.sub.e, CR.sub.fR.sub.f or O, b and c are
single bonds and when W is CR.sub.g, one of b or c is a double
bond;
[0137] R.sub.e is O or S;
[0138] R.sub.f is H;
[0139] R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z;
[0140] W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i', CR.sub.j or O
provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i, or O,
c and d are single bonds and when W.sup.1 is CR.sub.j, one of c or
d is a double bond;
[0141] R.sub.h is O or S;
[0142] R, and R.sup.1, are H, CH.sub.3 or Br;
[0143] R., is CH.sub.3 or H;
[0144] W.sup.2 is C.dbd.R.sub.k, (CR.sub.lR.sub.l').sub.p',
CR.sub.m, O, NH or N provided that when W.sup.2 is C.dbd.R.sub.k,
CR.sub.lR.sub.l', CR.sub.m, O, or NH d is a single bond and when
W.sup.2 is N or CR.sub.m d is a double bond;
[0145] R.sub.k is O or S;
[0146] R.sub.l and R.sub.l' are H, CH.sub.3, OCH.sub.3 or
SCH.sub.3;
[0147] p' is 1 or 2;
[0148] R.sub.m is H, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z,
SR.sub.z, alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
and
[0149] W.sup.3 is absent or H, provided that when W.sup.3 is absent
b is a double bond;
[0150] or a pharmaceutically acceptable salt or prodrug
thereof.
[0151] In one embodiment of the invention the compound of formula I
is a compound of formula V:
##STR00006##
wherein:
[0152] each of b and c is independently selected from a single or
double bond provided that when b is a double bond, c is single bond
and when c is a double bond b is a single bond;
[0153] W is C.dbd.R.sub.e, CR.sub.fR.sub.f, CR.sub.g or O, provided
that when W is C.dbd.R.sub.e, CR.sub.fR.sub.f or O, b and c are
single bonds and when W is CR.sub.g, one of b or c is a double
bond;
[0154] R.sub.e is O or S;
[0155] R.sub.f is H;
[0156] R.sub.g is H, NR.sub.cR.sub.d, OR.sub.z or SR.sub.z;
[0157] W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i', NH, CR.sub.j or
O provided that when W.sup.1 is C.dbd.R.sub.h, CR.sub.iR.sub.i, or
O, c is a single bond; when W.sup.1 is CR.sub.j, c is a double
bond; and when W.sup.1 is NH, W is not O;
[0158] R.sub.h is O or S;
[0159] R.sub.i and R.sub.i' are each independently H, CH.sub.3 or
Br;
[0160] R.sub.j is CH.sub.3 or H; and
[0161] W.sup.3 is absent, H, or alkyl, provided that when W.sup.3
is absent b is a double bond;
[0162] or a pharmaceutically acceptable salt or prodrug
thereof.
[0163] In one embodiment of the invention the compound of formula I
is a compound of formula V wherein W.sup.3 is absent, H, or
methyl.
[0164] In one embodiment of the invention the compound of formula I
is a compound of formula V wherein W.sup.3 is methyl.
[0165] In another embodiment of the invention provides compounds of
formula I that are compounds of formula 1-9:
##STR00007## ##STR00008##
wherein:
[0166] X.sup.1 is O, S, or two hydrogens;
[0167] X.sup.2 is O, S, or two hydrogens;
[0168] X.sup.3 is O or S;
[0169] X.sup.4 is O, S, or two hydrogens;
[0170] X.sup.5 is O, S, or two hydrogens;
[0171] X.sup.8 is NH.sub.2, OCH.sub.3 or SCH.sub.3;
[0172] Y.sup.1 is H, OH, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2,
F, Cl, Br, I, OCH.sub.3, Oalkyl, alkyl SCH.sub.3, CH.sub.3,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R';
[0173] Y.sup.2 is H, CH.sub.3, OCH.sub.3 or SCH.sub.3;
[0174] Y.sup.3 is O or S;
[0175] Y.sup.4 is O, S, or two hydrogens;
[0176] Z.sup.1 is H or CH.sub.3;
[0177] Z.sup.2 is H, CH.sub.3 or Br; and
[0178] t is 1 or 2;
[0179] or a pharmaceutically acceptable salt or prodrug
thereof.
[0180] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.1 is H or
NR.sub.aR.sub.b; or a pharmaceutically acceptable salt or prodrug
thereof.
[0181] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.2 is a nucleoside sugar
group of Group A, B, C, D, E, or F described hereinbelow; or a
pharmaceutically acceptable salt or prodrug thereof.
[0182] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.2 is ribose,
2-methylribose, 2-deoxyribose; 2-deoxy-2-fluororibose; arabinose;
[0183] 2-deoxy-2-fluoroarabinose; 2,3-dideoxyribose;
2,3-dideoxy-2-fluoroarabinose; 2,3-dideoxy-3-fluororibose;
2,3-dideoxy-2,3-didehydroribose; 2,3-dideoxy-3-azidoribose;
2,3-dideoxy-3-thiaribose; or 2,3-dideoxy-3-oxaribose; or a
pharmaceutically acceptable salt or prodrug thereof.
[0184] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.2 is thioribose,
2-deoxythioribose; 2-deoxy-2-fluorothioribose; thioarabinose;
2-deoxy-2-fluorothioarabinose; 2,3-dideoxythioribose;
2,3-dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3-fluorothioribose;
2,3-dideoxy-2,3-didehydrothioribose; or
2,3-dideoxy-3-azidothioribose; or a pharmaceutically acceptable
salt or prodrug thereof.
[0185] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.2 is
4-hydroxymethylcyclopent-2-ene;
2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene;
3-hydroxy-4-hydroxymethylcyclopentane;
2-hydroxy-4-hydroxymethylcyclopentene;
2-fluoro-3-hydroxy-4-hydroxymethylcyclopentane;
2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane;
4-hydroxymethylcyclopentane,
2,3-dihydroxy-4-hydroxymethylcyclopentane; or
2,3-dihydroxymethylcyclobutane; or a pharmaceutically acceptable
salt or prodrug thereof.
[0186] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sup.2 is
4-hydroxymethylpyrrolidine;
2,3-dihydroxy-4-hydroxymethylpyrrolidine;
2/3-hydroxy-4-hydroxymethylpyrrolidine;
2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or
3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a
pharmaceutically acceptable salt or prodrug thereof.
[0187] In another embodiment the invention provides a compound of
Formula I as described above, wherein R.sub.a, R.sub.b, R.sub.c,
and R.sub.d are independently selected from the group consisting of
H, alkyl, and substituted alkyl; or R.sub.a and R.sub.b together
with the nitrogen to which they are attached form a pyrrolidino,
piperidino, piperazino, azetidino, morpholino, or thiomorpholino
ring; or R.sub.b and R.sub.c together with the nitrogen to which
they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, or thiomorpholino ring.
[0188] In another embodiment the invention provides a compound
selected from,
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017##
or a pharmaceutically acceptable salt or prodrug thereof.
[0189] In one embodiment the invention provides a compound of
formula I selected from:
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026##
or a pharmaceutically acceptable salt or prodrug thereof.
[0190] In another embodiment the invention the compound of formula
(I) is not a compound of the following formula (X):
##STR00027##
or a pharmaceutically acceptable salt or prodrug thereof; wherein X
is H or alkyl.
[0191] In another embodiment the invention the compound of formula
(I) is not a compound of the following formula:
##STR00028##
or a pharmaceutically acceptable salt or prodrug thereof; wherein X
is H or methyl; and R'.sup.7 is H or methyl.
[0192] In another embodiment the invention B is not a 6 membered
ring comprising two nitrogens and one double bond, wherein B is
substituted with NR.sub.cR.sub.d.
[0193] In another embodiment the invention B represents a 5, 7, or
8 membered ring comprising one or more heteratoms and one or more
double bonds, wherein B is optionally substituted with one or more
oxo, thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z,
alkyl, C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'.
[0194] In another embodiment the invention the compound of formula
(I) is:
##STR00029##
or a pharmaceutically acceptable salt or prodrug thereof.
[0195] In another embodiment the invention the compound of formula
(I) is:
##STR00030##
or a pharmaceutically acceptable salt or prodrug thereof. In
another embodiment the invention the compound of formula (I)
is:
##STR00031##
or a pharmaceutically acceptable salt or prodrug thereof.
[0196] In another embodiment the invention the compound of formula
(I) is:
##STR00032##
or a pharmaceutically acceptable salt or prodrug thereof.
[0197] In another embodiment the invention B represents a 5
membered ring comprising one or more heteratoms (e.g. 1, 2, or 3)
and one or more double bonds (e.g. 1, 2, or 3), wherein B is
optionally substituted with one or more (e.g. 1, 2, or 3) oxo,
thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'.
[0198] In another embodiment the invention B represents a 6
membered ring comprising one or more heteratoms (e.g. 1, 2, or 3)
and one or more double bonds (e.g. 1, 2, or 3), wherein B is
optionally substituted with one or more (e.g. 1, 2, or 3) oxo,
thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'.
[0199] In another embodiment the invention B represents a 7
membered ring comprising one or more heteratoms (e.g. 1, 2, or 3)
and one or more double bonds (e.g. 1, 2, or 3), wherein B is
optionally substituted with one or more (e.g. 1, 2, or 3) oxo,
thioxo, NR.sub.CR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'.
[0200] In another embodiment the invention B represents an 8
membered ring comprising one or more heteratoms (e.g. 1, 2, or 3)
and one or more double bonds (e.g. 1, 2, or 3), wherein B is
optionally substituted with one or more (e.g. 1, 2, or 3) oxo,
thioxo, NR.sub.cR.sub.d, F, Cl, Br, I, OR.sub.z, SR.sub.z, alkyl,
C.ident.N, C.ident.C--R, N.sub.3 or SO.sub.2R'.
Prodrugs
[0201] The term "prodrug" as used herein refers to a compound that
can be metabolized in vivo to provide a compound of Formula I. Thus
prodrugs include compounds that can be prepared by modifying one or
more functional groups in a compound of Formula I to provide a
corresponding compound that can be metabolized in vivo to provide a
compound of Formula I. Such modifications are known in the art. For
example, one or more hydroxy groups or amine groups in a compound
of Formula I can be acylated with alkyl-C(.dbd.O)-groups or with
residues from amino acids to provide a prodrug. Alternatively, one
or more pendent hydroxyl groups from a mono-, di-, or tri-phosphate
functionality in a compound of Formula I can be converted to an
alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy
group.
[0202] In one embodiment, the term prodrug includes a compound
wherein one or more hydroxy groups on a nucleoside sugar group
(e.g. a 2', 3', or 5' hydroxy group) have been converted to a group
that can be metabolized in vivo to provide a compound of Formula I.
For example, the invention provides a compound wherein one or more
hydroxy groups on a nucleoside sugar group (e.g. a 2', 3', or 5'
hydroxy group) have been converted to an acyloxy, acylamino or R--O
group, wherein R is a carboxy-linled amino acid.
[0203] In one embodiment, the term prodrug includes a compound
wherein one or more pendent hydroxyl groups from a mono-, di-, or
tri-phosphate functionality in a compound of Formula I is converted
to a group R.sub.y--O--; wherein each R.sub.y is independently a
1-20 carbon branched or unbranched, saturated or unsaturated chain,
wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is
optionally replaced with --O-- or --S-- and wherein one or more of
the carbon atoms is optionally substituted with oxo (.dbd.O) or
thioxo (.dbd.S) (See Lefebvre et al., J. Med. Chem. 1995, 38,
3941-50).
[0204] In another embodiment, the term prodrug includes a compound
wherein one or more pendent hydroxyl groups from a mono-, di-, or
tri-phosphate functionality in a compound of Formula I is converted
to a group R.sub.zN--; wherein each R.sub.z is a residue of an
amino acid. Thus, in the methods of treatment of the present
invention, the term "administering" includes administration of a
compound of Formula I, as well as administration of a prodrug which
converts to a compound of Formula I or a salt thereof in vivo.
Conventional procedures for the selection and preparation of
prodrug derivatives are described, for example, in "Design of
Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in International
Patent Application Publication Number WO 2005/084192. A variety of
prodrugs are also described in International Patent Application
Number PCT US2004/013063, which was published as International
Publication Number WO 2004/096286.
[0205] In another embodiment the prodrug comprises one of more
groups of formula:
##STR00033##
wherein:
[0206] R.sub.15 is H, alkyl, substituted alkyl, aryl, substituted
aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl, heterocyclic, substituted heterocyclic, and an amino
acid;
[0207] R.sub.16 is H, optionally substituted monocyclic aryl, or
optionally substituted monocyclic heteroaryl; and R.sub.17 is H,
halogen, CN, --CO--R.sub.20, --CON(R.sub.21).sub.2,
--CO.sub.2R.sub.20, --SO.sub.2R.sub.20,
--SO.sub.2N(R.sub.21).sub.2, --OR.sub.21, --SR.sub.21, --R.sub.21,
--N(R.sub.21).sub.2, --O--COR.sub.20, --O--CO.sub.2R.sub.20,
--SCOR.sub.20, --S--CO.sub.2R.sub.20, --NHCOR.sub.21,
--NHCO.sub.2R.sub.21, --(CH.sub.2).sub.p--OR.sub.22, or
--(CH.sub.2).sub.p--SR.sub.22; or R.sub.16 and R.sub.17 are
connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, that is fused to an aryl
group at the beta and gamma position to the O attached to the
phosphorus; or R.sub.17 and R.sub.18 are connected as described
below;
[0208] R.sub.18 and R.sub.19 are each independently H, alkyl, aryl,
heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl
or optionally substituted monocyclic heteroaryl; or R.sub.18 and
R.sub.19 are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms; or R.sub.17 and
R.sub.18 are connected via an additional 3-5 atoms to form a cyclic
group, optionally containing one heteroatom and R.sub.19 is H,
alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted
monocyclic aryl or optionally substituted monocyclic heteroaryl;
and
[0209] R.sub.20 is alkyl, aryl, heterocycloalkyl, or arylalkyl;
[0210] R.sub.21 is H, alkyl, aryl, heterocycloalkyl, or
arylalkyl;
[0211] R.sub.22 is H or lower acyl;
[0212] n is an integer from 2-5;
[0213] m is an integer from 10-20; and p is an integer from
2-3.
[0214] Prodrug forms of a compound bearing various nitrogen
functions (amino, hydroxyamino, amide, etc.) may include the
following types of derivatives where each R.sub.p group
individually may be hydrogen, substituted or unsubstituted alkyl,
aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl,
aralkynyl, cycloalkyl or cycloalkenyl groups as defined earlier.
[0215] (a) Carboxamides, represented as --NHC(O)R.sub.p [0216] (b)
Carbamates, represented as --NHC(O)OR.sub.p [0217] (c)
(Acyloxy)alkyl Carbamates, represented as NHC(O)OROC(O)R.sub.p
[0218] (d) Enamines, represented as --NHCR(.dbd.CHCO.sub.2R.sub.p)
or --NHCR(.dbd.CHCONR.sub.pR.sub.p) [0219] (e) Schiff Bases,
represented as --N.dbd.CR.sub.pR.sub.p [0220] (f) Mannich Bases
(from carboximide compounds), represented as
RCONHCH.sub.2NR.sub.pR.sub.p Preparations of such prodrug
derivatives are discussed in various literature sources (examples
are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin
et al., PCT WO0041531, p. 30).
[0221] Prodrug forms of carboxyl-bearing compounds include esters
(--CO.sub.2R.sub.m) where the R.sub.m group corresponds to any
alcohol whose release in the body through enzymatic or hydrolytic
processes would be at pharmaceutically acceptable levels. Another
prodrug derived from a carboxylic acid form of the disclosure may
be a quaternary salt type of structure described by Bodor et al.,
J. Med. Chem. 1980, 23, 469.
##STR00034##
Nucleoside Sugar Groups
[0222] The term "nucleoside sugar group" as used herein includes
cyclic and acyclic groups that can be included as the sugar portion
of a nucleoside analog of Formula I. Many examples of such groups
are known in the field of nucleoside chemistry (See for example
Antiviral Drugs by John S. Driscoll (2002) published by Ashgate
Publishing Ltd.).
[0223] The term nucleoside sugar group includes substituted and
unsubstituted tetrahydrofuranyl and dihydrofuranyl compounds
including those set forth in group (A) below, substituted and
unsubstituted tetrahydrothiophenyl and dihydrothiophenyl compounds
including those set forth in group (B) below, substituted and
unsubstituted alkyl compounds including those set forth in group
(C) below, substituted and unsubstituted cycloalkyl and
cycloalkenyl compounds including those set forth in group (D)
below, substituted and unsubstituted dihydropyrrolidinyl and
tetrahydropyrrolidinyl compounds including those set forth in group
(E) below, and substituted and unsubstituted dioxolane, substituted
and unsubstituted thioxolane, and substituted and unsubstituted
dithiolane compounds including those set forth in group (F)
below.
Group A
[0224] Examples of substituted tetrahydro and dihydrofuranyl
compounds include those compounds represented by the general
structures:
##STR00035##
Specific examples include, but are not limited to, the following
compounds:
##STR00036##
Group B
[0225] Examples of substituted tetrahydrothiophenyl and
dihydrothiophenyl compounds include those compounds represented by
the general structures:
##STR00037##
Specific examples include, but are not limited to, the following
compounds:
##STR00038##
Group C
[0226] Examples of substituted alkyl compounds include those
compounds represented by:
##STR00039##
Specific examples include, but are not limited to, the following
compounds:
##STR00040##
Group D
[0227] Examples of substituted cycloalkyl and cycloalkenyl
compounds include those compounds represented by the general
structures:
##STR00041##
Specific examples include, but are not limited to, the following
compounds:
##STR00042##
Group E
[0228] Examples of substituted dihydropyrrolidinyl and
tetrahydropyrrolidinyl compounds include those compounds
represented by the general structures:
##STR00043##
Specific examples include, but are not limited to, the following
compounds:
##STR00044##
Group F
[0229] Examples of substituted dioxolane, substituted thioxolane
and substituted dithiolane compounds include those compounds
represented by the general structures:
##STR00045##
Specific examples include, but are not limited to, the following
compounds:
##STR00046##
[0230] For the structures in Groups A-F, the following definitions
apply:
[0231] R.sub.7 is H, OR.sub.14, N.sub.3, NH.sub.2, or F; and
R'.sub.7 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, or substituted alkynyl; or R.sub.7
and R'.sub.7 together may be .dbd.CH.sub.2, .dbd.CHF; wherein both
R.sub.7 and R'.sub.7 are not OH; and when one of R.sub.7 and
R'.sub.7 is NH.sub.2, the other is not OH; and when one of R.sub.7
and R'.sub.7 is N.sub.3, the other is not OH;
[0232] R.sub.8 is H, OR.sub.14, N.sub.3, NH.sub.2, or F; and
R'.sub.8 is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, or substituted alkynyl; or R.sub.8
and R'.sub.8 together may be .dbd.CH.sub.2, .dbd.CHF; wherein both
R.sub.8 and R'.sub.8 are not OH; and when one of R.sub.8 and
R'.sub.8 is NH.sub.2, the other is not OH; and when one of R.sub.8
and R'.sub.8 is N.sub.3, the other is not OH;
[0233] or R.sub.7 and R.sub.8 together can form
##STR00047##
wherein: R.sub.100 is C.sub.1-12 alkyl C.sub.3-8 cycloalkyl, aryl
or heteroaryl; wherein any C.sub.1-12 alkyl and C.sub.3-8
cycloalkyl of R.sub.100 is unsubstituted or is substituted with 1-3
substituents selected from halogen, hydroxy, carboxy, and C.sub.1-4
alkoxy; and wherein any aryl or heteroaryl of R.sub.100 is
unsubstituted or is substituted with 1-5 substituents independently
selected from R.sub.101;
[0234] each R.sub.101 is independently halo, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.i alkylsulfoyl, cyano,
nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy,
C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, C.sub.1-4 alkanoyl,
C.sub.1-4 alkanoyloxy, or C.sub.1-4 alkyloxycarbonyl;
[0235] R.sub.9 is H, CH.sub.3, C.sub.2H.sub.5, or N.sub.3;
[0236] R'.sub.9 is CH.sub.2OR.sub.14, CH.sub.2F, CH.sub.2SH, CHFOH,
CF.sub.2OH, CH.sub.2-diphosphate, CH.sub.2-triphosphate,
##STR00048##
[0237] R.sub.10 and R.sub.11 are each independently H, alkyl, aryl,
substituted aryl, acyloxyalkyl, or
(CH.sub.2).sub.n--O--(CH.sub.2).sub.mCH.sub.3;
[0238] R.sub.12 is an N-linked amino acid residue
(e.g.--NH--CH(CH.sub.3)CO.sub.2alkyl or
--NH--CH(isopropyl)-CO.sub.2alkyl); and
[0239] R.sub.14 is H;
[0240] n is 2-5; and
[0241] m is 10-20.
[0242] In one specific embodiment of the invention for the
structures in Groups A-F:
[0243] R.sub.7 is H, OR.sub.14, N.sub.3, NH.sub.2, or F; and
R'.sub.7 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, or substituted alkynyl; or R.sub.7
and R'.sub.7 together may be .dbd.CH.sub.2, .dbd.CHF; wherein both
R.sub.7 and R'.sub.7 are not OH; and when one of R.sub.7 and
R'.sub.7 is NH.sub.2, the other is not OH; and when one of R.sub.7
and R'.sub.7 is N.sub.3, the other is not OH; R.sub.7'' is alkyl or
substituted alkyl.
[0244] R.sub.8 is H, OR.sub.14, N.sub.3, NH.sub.2, or F; and
R'.sub.8 is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, or substituted alkynyl; or R.sub.8
and R'.sub.8 together may be .dbd.CH.sub.2, .dbd.CHF; wherein both
R.sub.8 and R'.sub.8 are not OH; and when one of R.sub.8 and
R'.sub.8 is NH.sub.2, the other is not OH; and when one of R.sub.8
and R'.sub.8 is N.sub.3, the other is not OH;
R.sub.9 is H, CH.sub.3, C.sub.2H.sub.5, or N.sub.3;
[0245] R'.sub.9 is CH.sub.2OR.sub.14, CH.sub.2F, CH.sub.2SH, CHFOH,
CF.sub.2OH,
##STR00049##
[0246] R.sub.10 and R.sub.11 are each independently H, alkyl, aryl,
substituted aryl, acyloxyalkyl, or
(CH.sub.2).sub.n--O--(CH.sub.2).sub.InCH.sub.3;
[0247] R.sub.12 is an N-linked amino acid residue
(e.g.--NH--CH(CH.sub.3)CO.sub.2alkyl or
--NH--CH(isopropyl)-CO.sub.2alkyl);
[0248] R.sub.13 is H, CH.sub.3, C.sub.2H.sub.5, CH.sub.2F,
CH.sub.2OH, CH.sub.2CH.sub.2F, CH.sub.2CH.sub.2OH, CH.sub.2N.sub.3,
CH.sub.2CH.sub.2N.sub.3,
[0249] CH.sub.2NH.sub.2, or CH.sub.2CH.sub.2NH.sub.2;
[0250] R.sub.14 is H;
[0251] n is 2-5; and
[0252] m is 10-20.
[0253] In one embodiment, for a compound of Formula I, R.sub.14 is
replaced to form a pharmaceutically acceptable prodrug, for
example, a prodrug selected from the group consisting of: acyl,
oxyacyl, phosphonate, phosphate, phosphate esters, phosphonamidate,
phosphorodiamidate, phosphoramidate mono ester, cyclic
phosphoramidate, cyclic phosphorodiamidate, phosphoramidate
diester, C(O)CHR.sub.15NH.sub.2,
##STR00050##
wherein:
[0254] R.sub.15 is H, alkyl, substituted alkyl, aryl, substituted
aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl, heterocyclic, substituted heterocyclic, or an amino
acid;
[0255] R.sub.16 is H, optionally substituted monocyclic aryl, or
optionally substituted monocyclic heteroaryl; and R.sub.17 is H,
halogen, CN, --CO--R.sub.20, --CON(R.sub.21).sub.2,
--CO.sub.2R.sub.20, --SO.sub.2R.sub.20,
--SO.sub.2N(R.sub.21).sub.2, --OR.sub.21, --SR.sub.21, --R.sub.21,
--N(R.sub.21).sub.2, --O--COR.sub.20, --O--CO.sub.2R.sub.20,
--SCOR.sub.20, --S--CO.sub.2R.sub.20, --NHCOR.sub.21,
--NHCO.sub.2R.sub.21, --(CH.sub.2).sub.p--OR.sub.22, or
--(CH.sub.2).sub.p--SR.sub.22; or R.sub.16 and R.sub.17 are
connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, that is fused to an aryl
group at the beta and gamma position to the O attached to the
phosphorus; or R.sub.17 and R.sub.18 are connected as described
below;
[0256] R.sub.18 and R.sub.19 are each independently H, alkyl, aryl,
heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl
or optionally substituted monocyclic heteroaryl; or R.sub.18 and
R.sub.19 are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms; or R.sub.17 and
R.sub.18 are connected via an additional 3-5 atoms to form a cyclic
group, optionally containing one heteroatom and R.sub.19 is H,
alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted
monocyclic aryl or optionally substituted monocyclic heteroaryl;
and
[0257] R.sub.20 is alkyl, aryl, heterocycloalkyl, or arylalkyl;
[0258] R.sub.21 is H, alkyl, aryl, heterocycloalkyl, or
arylalkyl;
[0259] R.sub.22 is H or lower acyl; and
[0260] p is an integer from 2-3.
Synthetic Processes
[0261] Processes for preparing compounds of Formula I, or a
pharmaceutically acceptable salts or prodrugs thereof, as well as
processes for preparing intermediate compounds that can be used to
prepare compounds of Formula I or pharmaceutically acceptable salts
or prodrugs thereof are provided as further embodiments of the
invention. For example in one embodiment the invention provides a
method for preparing a pharmaceutically acceptable salt of compound
of Formula I comprising converting a corresponding compound of
Formula I to the salt.
[0262] In another embodiment the invention provides a method for
preparing a prodrug of a compound of Formula I comprising
converting a corresponding compound of Formula I to the
prodrug.
[0263] In another embodiment the invention provides a method for
preparing a compound of Formula I comprising deprotecting a
corresponding compound of Formula I that comprises one or more
protecting groups to provide the compound of Formula I.
Synthetic Intermediates
[0264] The invention also provides synthetic intermediates that are
useful for preparing compounds of Formula I or a salt or prodrug
thereof. For example, the invention provides novel synthetic
intermediates such as those described in the Examples herein.
Isomers and Physical Forms
[0265] It will be appreciated by those skilled in the art that
compounds of the invention having a chiral center may exist in and
be isolated in optically active and racemic forms. Some compounds
may exhibit polymorphism. It is to be understood that the present
invention encompasses any racemic, optically-active, polymorphic,
tautomeric, or stereoisomeric form, or mixtures thereof, of a
compound of the invention (e.g. a compound of Formula I, which
possess the useful properties described herein, 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) and how to determine anti-viral or anti-cancer
activity using the standard tests described herein, or using other
similar tests which are well known in the art. Although the
invention includes all isomeric forms of the compounds described
herein, one embodiment of the invention provides compounds having
the absolute stereochemistry depicted in the Examples
hereinbelow.
Pharmaceutical Compositions, Modes of Administration and Methods of
Treatment
[0266] The present disclosure provides compounds of the general
Formula I as detailed above which are inhibitors of DNA and/or RNA
viral polymerases and anticancer agents. Various forms of DNA and
RNA viral polymerases are inhibited by the compounds disclosed,
such as but not limited to viral RdRps. The compounds of the
present disclosure therefore have utility in treating and/or
preventing viral infections in a host and in treatment and/or
preventing a variety of disease states and/or conditions caused by
or related to such viral infections. In one embodiment, the
compounds are useful in the above mentioned treating and/or
preventing by inhibiting a viral RNA and DNA polymerases. Such
viral agents include, but are not limited to, hepatitis B,
hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and
B, Rhino, Echo, small pox, Ebola, and West Nile virus. In a
particular embodiment, the causative agent of the viral infection
is a flavivirus.
[0267] The present disclosure provides for a compound of the
general Formula I and a pharmaceutical composition comprising a
pharmaceutically effective amount of at least one compound of
general Formula I as described herein. Such compounds and/or
pharmaceutical compositions may be used in the manufacture of a
medicament for treating and/or preventing a disease or condition in
which it is desirable to inhibit a viral RNA and DNA polymerases.
Such pharmaceutical compositions may also comprise a
pharmaceutically acceptable carrier and other ingredients known in
the art, or may comprise solely a compound of the general Formula
I.
[0268] The pharmaceutically acceptable carriers described herein,
including, but not limited to, vehicles, adjuvants, excipients, or
diluents, are well-known to those who are skilled in the art.
Typically, the pharmaceutically acceptable carrier is chemically
inert to the active compounds and has no detrimental side effects
or toxicity under the conditions of use. The pharmaceutically
acceptable carriers can include polymers and polymer matrices.
[0269] The compounds described in the instant disclosure can be
administered by any conventional method available for use in
conjunction with pharmaceuticals, either as individual therapeutic
agents or in combination with additional therapeutic agents.
[0270] The compounds described are administered in a
pharmaceutically effective amount. The pharmaceutically effective
amount of the compound and the dosage of the pharmaceutical
composition administered will, of course, vary depending upon known
factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the age,
health and weight of the recipient; the severity and stage of the
disease state or condition; the kind of concurrent treatment; the
frequency of treatment; and the effect desired.
[0271] A daily dosage of active ingredient can be expected to be
about 0.001 to 1000 milligrams (mg) per kilogram (kg) of body
weight per day. In one embodiment, the total amount is between
about 0.1 mg/kg and about 100 mg/kg of body weight per day; in an
alternate embodiment between about 1.1 mg/kg and about 50 mg/kg of
body weight per day; in yet another alternate embodiment between
0.1 mg/kg and about 30 mg/kg of body weight per day. The above
described amounts may be administered as a series of smaller doses
over a period of time if desired. The pharmaceutically effective
amount can be calculated based on the weight of the parent compound
to be delivered. If the salt or prodrug exhibits activity in
itself, the pharmaceutically effective amount can be estimated as
above using the weight of the salt or prodrug, or by other means
known to those skilled in the art. The dosage of active ingredient
may be given other than daily if desired.
[0272] The total amount of the compound administered will also be
determined by the route, timing and frequency of administration as
well as the existence, nature, and extent of any adverse side
effects that might accompany the administration of the compound and
the desired physiological effect. It will be appreciated by one
skilled in the art that various conditions or disease states, in
particular chronic conditions or disease states, may require
prolonged treatment involving multiple administrations.
[0273] Dosage forms of the pharmaceutical compositions described
herein (forms of the pharmaceutical compositions suitable for
administration) contain from about 0.1 mg to about 3000 mg of
active ingredient (i.e. the compounds disclosed) per unit. In these
pharmaceutical compositions, the active ingredient will ordinarily
be present in an amount of about 0.5-95% weight based on the total
weight of the composition. Multiple dosage forms may be
administered as part of a single treatment. The active ingredient
may be administered to achieve peak plasma concentrations of the
active ingredient of from about 0.2 to 70 .mu.M, or from about 1.0
to 10 .mu.M.
[0274] The active ingredient can be administered orally in solid
dosage forms, such as capsules, tablets, and powders, or in liquid
dosage forms, such as elixirs, syrups and suspensions. It can also
be administered parenterally, in sterile liquid dosage forms. The
active ingredient can also be administered intranasally (nose
drops) or by inhalation via the pulmonary system, such as by
propellant based metered dose inhalers or dry powders inhalation
devices. Other dosage forms are potentially possible such as
administration transdermally, via patch mechanisms or ointment.
[0275] Formulations suitable for oral administration can include
(a) liquid solutions, such as a pharmaceutically effective amount
of the compound dissolved in diluents, such as water, saline, or
orange juice; (b) capsules, sachets, tablets, lozenges, and
troches, each containing a predetermined pharmaceutically effective
amount of the active ingredient, as solids or granules; (c)
powders; (d) suspensions in an appropriate liquid; and (e) suitable
emulsions. Liquid formulations may include diluents, such as water
and alcohols, for example, ethanol, benzyl alcohol, propylene
glycol, glycerin, and the polyethylene alcohols, either with or
without the addition of a pharmaceutically acceptable surfactant,
suspending agent, or emulsifying agent. Capsule forms can be of the
ordinary hard- or soft-shelled gelatin type containing, for
example, surfactants, lubricants, and inert fillers, such as
lactose, sucrose, calcium phosphate, and corn starch. Tablet forms
can include one or more of the following: lactose, sucrose,
mannitol, corn starch, potato starch, alginic acid,
microcrystalline cellulose, acacia, gelatin, guar gum, colloidal
silicon dioxide, croscarmellose sodium, talc, magnesium stearate,
calcium stearate, zinc stearate, stearic acid, and other
excipients, colorants, diluents, buffering agents, disintegrating
agents, moistening agents, preservatives, flavoring agents, and
pharmacologically compatible carriers. Lozenge forms can comprise
the active ingredient in a flavor, usually sucrose and acacia or
tragacanth, as well as pastilles comprising the active ingredient
in an inert base, such as gelatin and glycerin, or sucrose and
acadia, emulsions, and gels containing, in addition to the active
ingredient, such carriers as are known in the art.
[0276] Formulations suitable for parenteral administration include
aqueous and non-aqueous, isotonic sterile injection solutions,
which can contain anti-oxidants, buffers, bacteriostats, and
solutes that render the formulation isotonic with the blood of the
patient, and aqueous and non-aqueous sterile suspensions that can
include suspending agents, solubilizers, thickening agents,
stabilizers, and preservatives.
[0277] The compound can be administered in a physiologically
acceptable diluent in a pharmaceutically acceptable carrier, such
as a sterile liquid or mixture of liquids, including water, saline,
aqueous dextrose and related sugar solutions, an alcohol, such as
ethanol, isopropanol, or hexadecyl alcohol, glycols, such as
propylene glycol or polyethylene glycol such as
poly(ethyleneglycol) 400, glycerol ketals, such as
2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, an oil, a fatty
acid, a fatty acid ester or glyceride, or an acetylated fatty acid
glyceride with or without the addition of a pharmaceutically
acceptable surfactant, such as a soap or a detergent, suspending
agent, such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agents and other pharmaceutical adjuvants.
[0278] Oils, which can be used in parenteral formulations, include
petroleum, animal, vegetable, or synthetic oils. Specific examples
of oils include peanut, soybean, sesame, cottonseed, corn, olive,
petrolatum, and mineral. Suitable fatty acids for use in parenteral
formulations include oleic acid, stearic acid, and isostearic acid.
Ethyl oleate and isopropyl myristate are examples of suitable fatty
acid esters. Suitable soaps for use in parenteral formulations
include fatty alkali metal, ammonium, and triethanolamine salts,
and suitable detergents include (a) cationic detergents such as,
for example, dimethyldialkylammonium halides, and alkylpyridinium
halides, (b) anionic detergents such as, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates, (c) nonionic detergents such as, for
example, fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylene polypropylene copolymers, (d) amphoteric detergents
such as, for example, alkyl .beta.-aminopropionates, and
2-alkylimidazoline quaternary ammonium salts, and (e) mixtures
thereof.
[0279] The parenteral formulations typically contain from about
0.5% to about 25% by weight of the active ingredient in solution.
Suitable preservatives and buffers can be used in such
formulations. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain one or more
nonionic surfactants having a hydrophile-lipophile balance (HLB) of
from about 12 to about 17. The quantity of surfactant in such
formulations ranges from about 5% to about 15% by weight. Suitable
surfactants include polyethylene sorbitan fatty acid esters, such
as sorbitan monooleate and the high molecular weight adducts of
ethylene oxide with a hydrophobic base, formed by the condensation
of propylene oxide with propylene glycol.
[0280] Pharmaceutically acceptable excipients are also well-known
to those who are skilled in the art. The choice of excipient will
be determined in part by the particular compound, as well as by the
particular method used to administer the composition. Accordingly,
there is a wide variety of suitable formulations of the
pharmaceutical composition of the present invention. The following
methods and excipients are merely exemplary and are in no way
limiting. The pharmaceutically acceptable excipients preferably do
not interfere with the action of the active ingredients and do not
cause adverse side-effects. Suitable carriers and excipients
include solvents such as water, alcohol, and propylene glycol,
solid absorbants and diluents, surface active agents, suspending
agent, tableting binders, lubricants, flavors, and coloring
agents.
[0281] The compounds of the present invention, alone or in
combination with other suitable components, can be made into
aerosol formulations to be administered via inhalation. These
aerosol formulations can be placed into pressurized acceptable
propellants, such as dichlorodifluoromethane, propane, and
nitrogen. Such aerosol formulations may be administered by metered
dose inhalers. They also may be formulated as pharmaceuticals for
non-pressured preparations, such as in a nebulizer or an
atomizer.
[0282] The formulations can be presented in unit-dose or multi-dose
sealed containers, such as ampules and vials, and can be stored in
a freeze-dried (lyophilized) condition requiring only the addition
of the sterile liquid excipient, for example, water, for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions can be prepared from sterile powders,
granules, and tablets. The requirements for effective
pharmaceutically acceptable carriers for injectable compositions
are well known to those of ordinary skill in the art. See
Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co.,
Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and
ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630
(1986).
[0283] Formulations suitable for topical administration include
pastilles comprising the active ingredient in an inert base, such
as gelatin and glycerin, or sucrose and acacia, as well as creams,
emulsions, and gels containing, in addition to the active
ingredient, such carriers as are known in the art. Furthermore,
transdermal patches can be prepared using methods known in the
art.
[0284] Additionally, formulations suitable for rectal
administration may be presented as suppositories by mixing with a
variety of bases such as emulsifying bases or water-soluble bases.
Formulations suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams, or spray
formulas containing, in addition to the active ingredient, such
carriers as are known in the art to be appropriate.
[0285] One skilled in the art will appreciate that suitable methods
of administering a compound of the present invention to an patient
are available, and, although more than one route can be used to
administer a particular compound, a particular route can provide a
more immediate and more effective reaction than another route.
[0286] Useful embodiments of pharmaceutical dosage forms for
administration of the compounds according to the present invention
can be illustrated as follows.
[0287] A large number of hard-shell capsules are prepared by
filling standard two-piece hard gelatine capsules each with 100 mg
of powdered active ingredient, 150 mg of lactose, 50 mg of
cellulose and 6 mg of magnesium stearate.
[0288] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil is prepared and injected
by means of a positive displacement pump into molten gelatin to
form soft gelatin capsules containing 100 mg of the active
ingredient. The capsules are washed and dried. The active
ingredient can be dissolved in a mixture of polyethylene glycol,
glycerin and sorbitol to prepare a water miscible medicine mix.
[0289] A large number of tablets are prepared by conventional
procedures so that the dosage unit is 100 mg of active ingredient,
0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate,
275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg
of lactose.
[0290] Appropriate aqueous and non-aqueous coatings may be applied
to increase palatability, improve elegance and stability or delay
absorption.
[0291] Immediate release tablets/capsules are solid oral dosage
forms made by conventional and novel processes. These units are
taken orally without water for immediate dissolution and delivery
of the medication. The active ingredient is mixed in a liquid
containing ingredient such as sugar, gelatin, pectin and
sweeteners. These liquids are solidified into solid tablets or
caplets by freeze drying and solid state extraction techniques. The
drug compounds may be compressed with viscoelastic and
thermoelastic sugars and polymers or effervescent components to
produce porous matrices intended for immediate release, without the
need of water.
[0292] Moreover, the compounds of the present invention can be
administered in the form of nose drops, or metered dose and a nasal
or buccal inhaler. The drug is delivered from a nasal solution as a
fine mist or from a powder as an aerosol.
[0293] In one embodiment, the teachings of the present disclosure
provide for the use of such pharmaceutical compositions and
medicaments in a method of treating a viral infection or treating a
disease state and/or condition caused by or related to such viral
infection. In one embodiment, the treatment is the result of the
inhibition of a viral RNA or DNA polymerase, such as but not
limited to a RdRp. Such treatment or inhibition need not be
complete to be useful. The method of treatment comprises the steps
of: (i) identifying a patient in need of such treatment; (ii)
providing such pharmaceutical composition containing at least one
compound of the invention; and (iii) administering such
pharmaceutical composition in a therapeutically effective amount to
treat the viral infection in a patient in need of such treatment or
to inhibit the activity of a viral RNA or DNA polymerase in a
patient in need of such treatment.
[0294] In one embodiment, the teachings of the present disclosure
provide for the use of such pharmaceutical compositions and
medicaments in a method of preventing or suppressing a viral
infection or preventing or suppressing a disease state and/or
condition caused by or related to such viral infection. In one
embodiment, the prevention or suppression is the result of the
inhibition of a viral RNA or DNA polymerase, such as but not
limited to a R.sup.dR.sup.p. Such prevention, suppression or
inhibition need not be complete to be useful. The method of
preventing or suppressing can optionally comprises the steps of:
(i) identifying a patient in need of such prevention; (ii)
providing such pharmaceutical composition containing at least one
compound of the general Formula I; and (iii) administering such
pharmaceutical composition in a therapeutically effective amount to
prevent or suppress the viral infection in a patient in need of
such treatment or to inhibit the activity of a viral RNA and DNA
polymerase in a patient in need of such treatment.
[0295] The methods of the treating and preventing a viral infection
or a disease state and/or condition caused by or related to said
viral infection may further comprise administering a
therapeutically effective amount of a compound of the present
invention in combination with a therapeutically effective amount of
another anti-viral agent which, in particular, may be active
against HCV. Agents active against HCV include, but are not limited
to, ribavirin, levovirin, viramidine, thymosin alpha-1, an
inhibitor of HCV NS3 serine protease, an inhibitor of inosine
monophosphatedehydrognease, interferon-.alpha., pegylated
interferon-.alpha. (peginterferon-.alpha.), a combination of
interferon-.alpha. and ribavirin, a combination of
peginterferon-.alpha. and ribavirin, a combination of
interferon-.alpha. and levovirin, and a combination of
peginterferon-.alpha. and levovirin. Interferon-.alpha. includes,
but is not limited to, recombinant interferon-.alpha.2a,
interferon-alb, a consensus interferon, and a purified
interferon-.alpha. product.
[0296] The compounds and pharmaceutical compositions of the present
disclosure can be administered to patients to prevent and/or treat
a number of cancers. Cancers include, but are not limited to,
leukemias and lymphomas such as acute lymphocytic leukemia, acute
nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic
myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas,
and multiple myeloma, childhood solid tumors such as brain tumors,
neuroblastoma, retinoblastoma, Wilms Tumor, bone tumors, and
soft-tissue sarcomas, common solid tumors of adults such as lung
cancer, colon and rectum cancer, breast cancer, prostate cancer,
urinary cancers, uterine cancers, oral cancers, pancreatic cancer,
melanoma and other skin cancers, stomach cancer, ovarian cancer,
brain tumors, liver cancer, laryngeal cancer, thyroid cancer,
esophageal cancer, and testicular cancer. The cancer may be related
to a viral infection or an activity of a viral DNA or RNA
polymerase.
[0297] The methods of the treating and preventing cancer may also
comprises further administering of a chemotherapeutic agent in
combination with any of the compounds or pharmaceutical
compositions of the present disclosure. Any suitable
chemotherapeutic agent can be employed for this purpose. The
chemotherapeutic agent is typically selected from the group
consisting of alkylating agents, antimetabolites, natural products,
hormonal agents, and miscellaneous agents.
[0298] Examples of alkylating chemotherapeutic agents include
carmustine, chlorambucil, cisplatin, lomustine, cyclophosphamide,
melphalan, mechlorethamine, procarbazine, thiotepa, uracil mustard,
triethylenemelamine, busulfan, pipobroman, streptozocin,
ifosfamide, dacarbazine, carboplatin, and hexamethylmelamine.
[0299] Examples of chemotherapeutic agents that are antimetabolites
include cytosine arabinoside, fluorouracil, gemcitabine,
hydroxyurea, mercaptopurine, methotrexate, azaserine, thioguanine,
floxuridine, fludarabine, cladribine and L-asparaginase.
[0300] Examples of chemotherapeutic agents that are natural
products include actinomycin D, bleomycin, camptothecins,
daunomycin, doxorubicin, etoposide, mitomycin C, TAXOL.TM.
(paclitaxel), taxotere, teniposide, vincristine, vinorelbine,
mithramycin, idarubicin, MITHRACIN.TM.. (plicamycin), and
deoxycoformycin.
[0301] An example of a hormonal chemotherapeutic agent includes
tamoxifen. Examples of the aforesaid miscellaneous chemotherapeutic
agents include mitotane, mitoxantrone, vinblastine, and
levamisole.
[0302] The ability of a compound to inhibit viral polymerases can
be evaluated using known assays. The ability of a compound to
inhibit HCV NS5B polymerase can be evaluated using the following
assay.
HCV NS5B Polymerase Assay
[0303] Antiviral activity of the test compounds was assessed (Okuse
et al., Antiviral Res. 2005, 65, 23-34) in the stably HCV
RNA-replicating cell line, AVA5, derived by transfection of the
human hepatoblastoma cell line, Huh7 (Blight et al., Sci. 2000,
290, 1972). Compounds were added to dividing cultures once daily
for three days. Media was changed with each addition of compound.
Cultures generally started the assay at 30-50% confluence and
reached confluence during the last day of treatment. Intracellular
HCV RNA levels and cytotoxicity were assessed 24 hours after the
last dose of compound.
[0304] Triplicate cultures for HCV RNA levels (on 48-well and
96-well plates) and cytotoxicity (on 96-well plates) were used. A
total of six untreated control cultures, and triplicate cultures
treated with .alpha.-interferon and ribavirin served as positive
antiviral and toxicity controls.
[0305] Intracellular HCV RNA levels were measured using a
conventional blot hybridization method in which HCV RNA levels are
normalized to the levels of B-actin RNA in each individual culture
(Okuse et al., Antivir. Res. 2005, 65, 23-34). Cytotoxicity was
measured using a neutral red dye uptake assay (Korba and Gerin,
Antivir. Res. 1992, 19, 55). HCV RNA levels in the treated cultures
are expressed as a percentage of the mean levels of RNA detected in
untreated cultures.
[0306] A representative compound of Formula I demonstrated
significant activity in this assay.
Compound Synthesis
[0307] Compounds of Formula I can be prepared using synthetic
intermediates and synthetic procedures that are known, or they can
be prepared using the synthetic intermediates and synthetic
procedures described herein, for example, as described in the
following Schemes.
[0308] The following abbreviations are used herein. [0309] Tr:
trityl [0310] Bn: benzyl [0311] TBDPS: tert-butyldiphenylsilyl
[0312] m-CPBA: 3-chloroperoxybenzoic acid [0313] TFA:
trifluoroacetic acid [0314] TBDMSCl: tert-butyldimethylsilyl
chloride [0315] DMF: dimethylformamide [0316] THF: tetrahydrofuran
[0317] LDA: lithium diisopropylamine [0318] TEAB: triethylammonium
bicarbonate [0319] MmTrCl: monomethoxytrityl chloride [0320]
MMTrCl: monomethoxytrityl chloride [0321] DMAP:
dimethylaminopyridine [0322] DEAE: diethylaminoethyl-sepharose
[0323] CMA-80: Chloroform 80: MeOH 18: NH.sub.4OH: 2 [0324] CMA-50:
Chloroform 50: MeOH 40: NH.sub.4OH: 10 [0325] Bz: benzoyl [0326]
BnBr: benzyl bromide [0327] LiHMDS: lithium hexamethyldisalazane
[0328] TBDPSCl: tert-butyldiphenylsilyl chloride [0329] DMSO:
dimethylsulfoxide [0330] RMgBr: alkyl magnesium bromide [0331]
DIBAL: diisobutylaluminum hydride [0332] DBN:
1,5-diazabicyclo[4.3.0]non-5-ene [0333] DBU:
1,8-diazabicyclo[5.4.0]undec-7-ene [0334] MeMgBr: methylmagnesium
bromide [0335] P: Represents a suitable protecting group [0336] R:
In Schemes 41-86 R can have any of the values defined for R.sup.2
herein
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[0337] The invention will now be illustrated by the following
non-limiting Examples.
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Example 1
Synthesis of 40p
[0338] To a solution of tricyclic product (40o, 0.1 g, 0.27 mmol)
in methanol (2 mL) was added aqueous 1 N HCl (2 mL) and stirred at
room temperature overnight. The reaction mixture was concentrated
in vacuo to dryness. The residue obtained was triturated with
methanol/ether and the solid obtained was collected by filtration
washed with ether and dried in vacuo at acetone reflux temperature
to furnish 40p (0.08 g, 90%) as a yellow solid; MP 240-242.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.39-10.93 (m, 1H),
8.04 (s, 1H), 7.12 (d, J=11.9, 1H), 7.00 (s, 1H), 6.09 (s, 3H),
5.76 (d, J=11.9, 1H), 5.31 (s, 1H), 3.76 (d, J=10.6, 2H), 3.68 (s,
2H), 0.84 (s, 3H); MS (ES) 330.9.
[0339] The intermediate 40o was prepared as follows.
a. To a stirred solution of freshly distilled pyrrole (6.79 g,
100.89 mmol) in diethyl ether (100 mL) was added ethyl magnesium
bromide (33.6 mL, 100.89 mmol, 3M solution in ether) slowly at
20.degree. C. The reaction mixture was further stirred at
20.degree. C. for 1 h and the solvent was removed under vacuum to
give 40b. To 40b in dichloromethane (500 mL) at 0.degree. C. was
added a solution of 40c (WO 2006/050161, 10.96 g, 25.22 mmol) in
dichloromethane (100 mL) and further stirred at 4.degree. C. for 72
h. The reaction mixture was quenched by adding saturated solution
of ammonium chloride (200 mL) and organic layer was separated. The
aqueous layer was further extracted with dichloromethane
(2.times.200 mL). The combined organic extracts were washed with
water (2.times.50 mL) and brine (1.times.50 mL) and dried. After
filtration, the filtrate containing 40d was treated with
trifluoroacetic acid (4.14 g, 36.34 mmol) at 20.degree. C. and
stirred for 14 h. The reaction mixture was washed with water
(2.times.100 mL) and brine (1.times.50 mL) and dried. After
filtration, the filtrate was concentrated to give 12.5 g of crude
40e. NOTE: THF was also used to make Grignard reagent instead of
diethyl ether. THF was removed by distillation and the traces by
azeotroping with toluene. b. Phosphorusoxy chloride (19.33 g, 126.1
mmol) was added to N,N-dimethylformamide (100 mL) at 0.degree. C.
and stirred for 30 min. To this solution was added 40e (12.1 g,
25.22 mmol) in dichloromethane (50 mL) slowly over a period of 15
min. at 0.degree. C. and stirring was continued for 1 h. The
reaction mixture was quenched by adding saturated solution of
sodium acetate (100 mL) and stirred for 30 min. The reaction
mixture was concentrated to remove dichloromethane and the residue
was diluted with ethyl acetate (200 mL). The organic layer was
separated and washed with water (2.times.100 mL) and brine
(1.times.50 mL) and dried. After filtration, the filtrate was
concentrated and the residue was purified by flash chromatography
using ethyl acetate in hexanes (0 to 12%) to give 2.92 g (22.6%
from 40c) of 40f as dark brown syrup. MS (ES.sup.-): 510.2. NOTE:
Only DMF was also used as solvent; there was no need of
dichloromethane. For workup, 2N NaOH was used in place of sodium
acetate. c. To a stirred solution of above obtained 40f (2.5 g,
4.88 mmol) in tetrahydrofuran (50 mL) was added sodium hydride
(0.39 g, 9.77 mmol, 60% dispersion in mineral oil) at 0.degree. C.
After stirring for 30 min at 0.degree. C.,
O-(mesitylsulfonyl)hydroxylamine (40 g, 1.15 g, 5.37 mmol, prepared
by the method of Krause, J. G. Synthesis, 1972, 140) was added at
0.degree. C. and further stirred for 2 h. The reaction mixture was
quenched by adding water (20 mL) and extracted with ethyl acetate
(2.times.50 mL). The combined organic extracts were washed with
water (2.times.25 mL) and brine (1.times.25 mL) and dried. After
filtration, the filtrate was concentrated to give 2.75 g of 1 h as
dark syrup. MS (ES.sup.+): 527.43.
[0340] The compound 40h can also be prepared as follows.
d. Aldehyde 40f (5.2 Kg, 10.16 moles) was dissolved in methyl
tert-butyl ether (72.8 L) and charged into a clean SS reactor (600
L). Aliquot 336 (0.25 Kg, 0.61 mole) and ammonium chloride (6.53
Kg, 122.07 moles) were added to the reactor and reaction mixture
was cooled to 0-5.degree. C. Ammonium hydroxide (19.08 L, 137
moles, 28% solution in water) was added at 0-5.degree. C. followed
by addition of a cold (0-5.degree. C.) sodium hydroxide solution
(16.59 Kg in 66 L water, 414.75 moles) at the same temperature over
a period of 3 h. Sodium hypochlorite (251 L, 222.58 moles, 6%
solution) addition was started at 0.degree. C. and during the
addition the temperature was allowed to rise to 15.degree. C. The
reaction mixture was further stirred at room temperature for 2 h.
TLC showed completion of the reaction. Ethyl acetate (104 L) was
added to the reaction mixture and layers were separated. The
aqueous layer was re-extracted with ethyl acetate (2.times.104 L).
The combined organic layers were washed with water (52 L), sodium
thiosulfate (2.times.156 L, 10% solution), water (52 L) and brine
(70 L) and dried over sodium sulfate (10.4 Kg). After filtration,
the filtrate was concentrated under vacuum below 40.degree. C. to
afford crude compound 40h (4.4 kg) as dark syrup. e. To a stirred
solution of 40h (2.56 g, 4.88 mmol) in dioxane (50 mL) was added
water (15 mL) and cooled to 0.degree. C. To this cooled solution at
0.degree. C. was added hydroxylamine-O-sulfonic acid (1.93 g, 17.10
mmol). After stirring for 1 h, a cold solution of potassium
hydroxide (2.19 g, 39.0 mmol) in water and dioxane (20 mL+20 mL)
was added and further stirred at 0.degree. C. for 1 h. The reaction
mixture was diluted with ethyl acetate (100 mL), the organic layer
was separated and washed with water (2.times.50 mL) and brine
(1.times.50 mL) and dried. After filtration, the filtrate was
concentrated to afford 2.6 g of 40i, which was used as such for the
next step. f. To a stirred solution of 40i (2.55 g, 4.88 mmol) in
N,N-dimethylacetamide (70 mL) was added formamidine acetate (5.08
g, 48.88 mmol) and the reaction mixture was stirred at 140.degree.
C. for 3 h. Most of the N,N-dimethylacetamide was removed under
vacuum and the residue was suspended in water (100 mL), which was
extracted with ethyl acetate (2.times.250 mL). The combined organic
extracts were washed with water (50 mL) and brine (50 mL) and
dried. After filtration, the filtrate was concentrated and the
residue was purified by flash chromatography using a mixture of
ethyl acetate and methanol (9:1) in hexanes (0 to 30%) to provide
impure compound (1.25 g). Further purification by chromatography on
silica gel gave 0.48 g (17.8% from 40f) of 40j as a light brown
solid. .sup.1H NMR (CDCl.sub.3): .delta. 7.87 (s, 1H), 7.43-7.21
(m, 15H), 6.88 (d, J=4.5 Hz, 1H), 6.50 (d, J=4.5 Hz, 1H), 5.87 (s,
1H), 5.36 (b, 2H, D.sub.2O exchangeable), 4.83 (dd, J=31.8, 12.2
Hz, 2H), 4.68-4.52 (m, 4H), 4.40-4.35 (m, 1H), 4.04 (d, J=8.8 Hz,
1H), 3.88 (dd, J=10.9, 2.3 Hz, 1H), 3.69 (dd, J=11.1, 3.6 Hz, 1H),
1.00 (s, 3H). MS (ES.sup.+): 551.40. NOTE: Acetic acid and n-BuOH
can also be used as solvent in place of dimethyl acetamide. g. To a
stirred solution of 40j (0.27 g, 0.484 mmol) in dichloromethane (25
mL) was added boron trichloride (4.84 mL, 4.84 mmol, 1M solution in
dichloromethane) at -40.degree. C. and the mixture was further
stirred at -40.degree. C. for 30 min and slowly brought to
0.degree. C. in about 30 min and stirred at 0.degree. C. for 20
min. The reaction was quenched by adding ethyl alcohol (50 mL) and
concentrated under reduced pressure. Again, ethyl alcohol (50 mL)
was added and concentrated. This operation was repeated 4 times.
After concentration, the residue was dissolved in mixture of
isopropyl alcohol and methanol (20 and 2 mL) and methanol was
removed by concentration under vacuum. Solid separated out, which
was collected by filtration and dried at 60.degree. C. under vacuum
to provide 39 mg (25%) of 40k as a colorless solid. .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.71 (bs, 1H, D.sub.2O
exchangeable), 8.99 (bs, 1H, D.sub.2O exchangeable), 8.16 (s, 1H),
7.41 (d, J=4.5 Hz, 1H), 6.97 (d, J=4.7 Hz, 1H), 5.34 (s, 1H),
4.8-4.0 (m, 3H, D.sub.2O exchangeable), 3.81-3.56 (m, 4H), 0.79 (s,
3H). MS (ES.sup.+): 281.6.
[0341] Compound 40k can also be prepared as follows.
h. To a solution of compound 40j (128 g) in methanol (1.4 L), conc.
HCl (130 mL) was added followed by 10% Pd/C (12 g) and the mixture
was hydrogenated at 70 psi for 10 h. Since the compound
precipitated out of the solution, water (500 mL) was added to the
mixture and heated at 60.degree. C. for about 1 h and filtered
through a Celite pad. The Celite pad with palladium was
re-suspended in a mixture of water (400 mL) and methanol (400 mL)
and heated at 60.degree. C. for about 1 h and again filtered
through Celite. This operation was repeated until there was no
compound left un-dissolved. The combined filtrates were
concentrated under vacuum and recrystallized from water and ethanol
(1:20) to afford 32.5 g of the desired product 40k as pale yellow
crystals. The mother liquor was concentrated and recrystallized
again to afford another crop of 5.6 g. i. To a suspension of 40k
(0.962 g, 3.4 mmol) in DMF (30 mL) and acetone (30 mL) was added
2,2-dimethoxypropane (4.2 mL, 98%, 34 mmol) and p-TsOH (650 mg,
98.5%, 3.4 mmol) and stirred at room temperature for 3 days. The
reaction mixture was neutralized with 2N NaOH (aq.) and
concentrated in vacuo to dryness. The residue was taken in water
(90 mL) and extracted with ethyl acetate (3.times.30 mL). The
organic layers were combined dried, filtered and concentrated in
vacuo to dryness. The residue obtained was purified by flash column
chromatography (silica gel, 40 g, eluting with 0-100% CMA 80 in
chloroform) to give 40l (360 mg, 33%) as a yellow solid. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 7.83 (s, 1H), 7.67 (s, 2H),
6.87 (d, J=4.5, 1H), 6.63 (d, J=4.4, 1H), 5.54 (s, 1H), 4.97 (t,
J=5.7, 1H), 4.37 (d, J=2.4, 1H), 4.03-3.95 (m, 1H), 3.57 (dd,
J=5.4, 9.7, 2H), 1.55 (s, 3H), 1.33 (s, 3H), 1.15 (s, 3H). j. To a
solution of 40l (375 mg, 1.2 mmol) in DMF (10 mL) was added
iodosuccinimide (290 mg, 1.3 mmol) and stirred at room temperature
overnight. The reaction mixture was diluted with water (30 mL) and
extracted with ethyl acetate (3.times.25 mL). The organic layers
were combined washed with water (25 mL), brine (25 mL), dried,
filtered, and concentrated in vacuo. The residue obtained was
purified by flash column chromatography (silica gel 12 g, eluting
with 0-100% CMA 80 in chloroform) to give 40m (0.44 g, 83%) as an
off white solid; MP 88-91.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.88 (s, 1H), 6.91 (s, 1H), 5.50 (s, 1H),
4.98 (t, J=5.9, 1H), 4.38 (d, J=2.5, 1H), 4.02 (ddd, J=2.3, 4.7,
7.2, 1H), 3.63-3.52 (m, 2H), 1.54 (s, 3H), 1.33 (s, 3H), 1.10 (s,
3H); MS (ES) 444.83. k. To a solution of 40m (2.6 g, 5.8 mmol) in
DMF (70 mL) was added copper iodide (440 mg, 2.3 mmol), methyl
acrylate (22.7 ml, 252 mmol), triethylamine (3.5 mL, 25.2 mmol) and
tetrakis(triphenylphosphine)Palladium (1.85 g, 1.16 mmol) and
heated with stirring at 70.degree. C. for 3 days. The reaction was
diluted with water (90 mL) and extracted with ethyl acetate
(3.times.70 mL). The organic layers were combined washed with water
(70 mL); brine (70 mL) dried, filtered, and concentrated in vacuo
to dryness. The residue obtained was purified by flash column
chromatography (silica gel 110 g, eluting with 0-100% 9:1
EtOAc:MeOH in hexane) to give 40n (0.43 g, 18%) as a yellow solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.05 (d, J=15.4, 1H),
7.94 (s, 1H), 7.61 (s, 2H), 7.27 (s, 1H), 6.45 (d, J=15.3, 1H),
5.52 (s, 1H), 4.96 (t, J=6.0, 1H), 4.40 (d, J=2.4, 1H), 4.07-4.00
(m, 1H), 3.71 (s, 3H), 3.65-3.57 (m, 2H), 1.55 (s, 3H), 1.34 (s,
3H), 1.13 (s, 3H); MS (ES) 402.8. l. To a freshly prepared solution
of sodium methoxide (69 mg sodium in 30 ml methanol, 0.1 M) in
methanol was added 40n (0.29 g, 0.72 mmol) and heated with stirring
at reflux for 4 h and then at room temperature overnight. The
reaction mixture neutralized with glacial acetic acid (0.18 mL) and
the solid obtained was collected by filtration washed with methanol
and dried in vacuo to furnish tricyclic product (40o, 0.126 g, 47%)
as a yellow solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.15 (s, 1H), 8.04 (s, 1H), 7.14 (d, J=11.9, 1H), 6.91 (s, 1H),
5.77 (d, J=11.9, 1H), 5.44 (s, 1H), 5.01 (t, J=5.5, 1H), 4.41 (d,
J=2.3, 1H), 4.05 (td, J=2.3, 4.9, 1H), 3.58 (dt, J=5.6, 11.5, 2H),
1.55 (s, 3H), 1.34 (s, 3H), 1.12 (s, 3H); MS (ES) 370.9 (100%,
M-1).
##STR00139## ##STR00140## ##STR00141##
Example 2
Synthesis of 87j
[0342] A solution of 87i (90 mg, 0.2 mmol) in methanol (1 mL) was
added to a solution of freshly prepared NaOMe solution in methanol
(0.17 M, 5 mL, 0.84 mmol) and stirred at room temperature
overnight. The reaction mixture was neutralized by acetic acid (0.5
mL) and concentrated in vacuo. The residue obtained was purified by
flash column chromatography (silica gel, 5 g, eluting with 0 to
100% CMA80 in chloroform) to yield 87j (27 mg, 48%) as a bright
yellow solid; mp 212.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
7.51 (s, 1H), 6.53 (s, 1H), 6.37 (s, 2H), 5.12 (s, 1H), 5.01 (d,
J=6.9 Hz, 1H), 4.79 (s, 1H), 4.74 (t, J=5.4 Hz, 1H), 3.84-3.67 (m,
2H), 3.60 (dd, J=4.7, 10.4 Hz, 2H), 3.36 (s, 3H), 0.86 (s, 3H). MS
(ES.sup.+) 335.1.
[0343] The intermediate 87i was prepared as follows:
a. To a solution of 40i (11.1 g, 21.3 mmol) in EtOH (500 mL) was
added conc. NH.sub.4OH (28-30%, 200 mL) followed by dropwise
addition of H.sub.2O.sub.2 (30% in H.sub.2O, 7.2 mL). After the
addition, the reaction mixture was stirred at room temperature
overnight and concentrated in vacuo to dryness. The residue
obtained was dissolved in chloroform (500 mL) washed with water,
brine, dried, filtered and the filtrate was concentrated in vacuo
to dryness. The residue obtained was purified by flash column
chromatography (silica gel 300 g, eluting with 0-100%, ethyl
acetate in hexane) to furnish 87a (3.45 g, 30%) as a brown oil.
.sup.1H NMR (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.45-7.26 (m,
15H), 6.67 (d, j=4.3, 1H), 6.02 (d, J=4.3, 1H), 5.29 (s, 1H),
4.66-4.55 (m, 6H), 4.15 (s, 1H), 3.92 (d, j=6.6, 1H), 3.73 (m, 2H),
1.10 (s, 3H); MS (ES.sup.+): 542.2. b. To a solution of 87a (3 g,
5.5 mmol) in triethyl orthoformate (60 mL) was added TFA (0.43 mL,
5.5 mmol) and heated at 80.degree. C. for 45 min. The reaction
mixture was concentrated in vacuo to dryness and the residue
obtained was purified by flash column chromatography (silica gel,
eluting with hexanes/EtOAc, 1:0 to 1:1) to furnish 87b (1.783 g,
58.4%) as a light brown syrup. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 11.70 (bs, 1H), 7.90 (d, J=3.1 Hz, 1H), 7.43-7.24 (m, 15H),
6.85 (d, J=4.4 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 5.57 (s, 1H),
4.80-4.56 (m, 6H), 4.27-4.13 (m, 1H), 4.01-3.96 (m, 1H), 3.82 (dd,
J=2.6, 11.0 Hz, 1H), 3.70 (dd, J=4.3, 11.0 Hz, 1H), 1.07 (s, 3H);
MS (ES): 550.0. c. To a solution of 87b (3.8 g, 6.9 mmol) in
methanol (100 mL) was added Pd on carbon (10%, 580 mg) and conc.
HCl (3 mL). The reaction mixture was hydrogenated at 50 psi for 4
h. The reaction mixture was filtered through a pad of Celite and
the filtrate was concentrated in vacuo to dryness to furnish 87c
(2.18 g, 100%) as brown syrup which was pure enough to be used as
such for next step. MS (ES+): 282.1; (ES-): 280.4. d. To a solution
of 87c (2.18 g, 7.75 mmol) in pyridine (30 mL) was added acetic
anhydride (6.5 mL, 69 mmol), DMAP (10 mg) and stirred at 70.degree.
C. overnight. The reaction mixture was cooled to room temperature,
diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous
layer was separated and extracted with ethyl acetate (50 mL). The
organic layers were combined, washed with water (50 mL), brine (50
mL), dried and concentrated in vacuo to dryness. The residue
obtained was purified by flash column chromatography (silica gel 80
g, eluting with methanol in chloroform 0-20%) to afford 87d (1.88
g, 70%) as off white solid, MP 147-154.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 11.78 (s, 1H), 8.32 (s, 1H), 7.93 (s,
1H), 6.93 (d, J=4.4 Hz, 1H), 6.62 (d, J=4.4 Hz, 1H), 5.60 (s, 1H),
5.20 (d, J=4.1 Hz, 1H), 4.47-4.32 (m, 1H), 4.21 (dd, J=7.8, 19.6
Hz, 111), 2.70 (s, 6H), 2.01 (s, 3H), 1.87 (s, 3H); MS (ES.sup.+):
430.0 (M+Na). e. To a solution of 87d (1.08 g, 2.66 mmol) in
dichloromethane (75 mL) at 0.degree. C. was added N-iodosuccinimide
(719.2 mg, 3.2 mmol). The reaction was allowed to warm to room
temperature overnight and concentrated in vacuo. The residue
obtained was purified by flash column chromatography (silica gel 40
g, eluting with 0 to 100% ethyl acetate in hexane) to afford 87e
(1.09 g, 77%) as an orange solid; mp 212.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.83 (s, 1H), 7.94 (s, 1H), 6.81
(s, 1H), 5.56 (s, 1H), 5.17 (d, J=4.2 Hz, 1H), 4.35 (s, 1H), 4.20
(d, J=11.7 Hz, 2H), 2.07 (d, J=2.2 Hz, 611), 2.00 (s, 3H), 1.39 (s,
3H). f. To hot refluxing pyridine (14 mL) was added a solution of
87e (1.09 g, 2.04 mmol) in pyridine (2 mL) and copper cyanide (2.15
g, 24 mmol). The reaction mixture was heated at reflux overnight,
cooled to room temperature and diluted with water (50 mL) and ethyl
acetate (50 mL). The insoluble inorganic impurities were removed by
filtration; the aqueous layer was separated and extracted with
ethyl acetate (2.times.100 mL). The organic layers were combined
washed with brine (100 mL), dried, filtered, and concentrated in
vacuo. The residue obtained was purified by flash column
chromatography (silica gel, 20 g, eluting with 10 to 90% [9:1] of
ethyl acetate:methanol in hexane) to yield 87f (270 mg, 31%) as a
colorless oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.48
(s, 1H), 8.16 (s, 1H), 7.21 (s, 1H), 5.56 (s, 1H), 5.17 (s, 1H),
4.35 (s, 1H), 4.17 (s, 2H), 2.07 (s, 6H), 1.99 (s, 3H), 1.38 (s,
3H). g. A solution of 87f (460 mg, 1.06 mmol) in phosphorous
oxychloride (10 mL) was heated at reflux temperature for 2 h. The
reaction was cooled with ice water, quenched with ice water and
stirred vigorously until all phosphorous oxychloride was destroyed.
This aqueous layer was extracted with ethyl acetate (3.times.100
mL). The organic layers were combined washed with brine (100 mL),
dried, filtered, and concentrated in vacuo to yield 87g (653 mg).
h. To a solution of crude 87g in chloroform (15 mL) and ethanol (30
mL) was added methyl hydrazine (0.1 mL, 1.74 mmol) and stirred at
room temperature overnight. The reaction mixture was concentrated
in vacuo and the residue purified by flash column chromatography
(silica gel, 12g, eluting with 0 to 100% [9:1] of ethyl
acetate:methanol in hexane) to yield 87h (140 mg, 28%) as an yellow
solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.07 (s, 111),
7.27 (s, 1H), 5.75 (s, 1H), 5.48 (s, 2H), 5.21 (d, J=4.2 Hz, 1H),
4.37 (s, 1H), 4.22 (d, J=11.6 Hz, 2H), 3.36 (d, J=11.0 Hz, 3H),
2.08 (s, 611), 1.99 (s, 3H), 1.40 (s, 3H). i. To a solution of 87h
(140 mg, 0.29 mmol) in ethanol (20 mL) was added concentrated
hydrochloric acid (2 drops) and heated at reflux temperature for 2
h. The reaction mixture was concentrated in vacuo to give 87i (90
mg, 64.3%).
##STR00142##
Example 3
Synthesis of 88e
[0344] To a solution of 88d (1.31 g, 2.21 mmol) in MeOH (110 mL)
and EtOAc (60 mL) was added 1N HCl (9.5 mL), Pd/C (10%, 200 mg) and
hydrogenated at 60 psi for 24 h. The reaction mixture was filtered
through Celite, and the filtrate was concentrated in vacuo. The
residue obtained was purified by flash column chromatography
(silica gel, eluting with CMA80/CMA50 1:0 to 1:1) to give 88e (489
mg) as a yellow solid. The product obtained was triturated with
water, collected by filtration and dried in vacuo to furnish 88e
(251 mg, 35%) as an off-white solid; mp 210.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6): 11.07 (bs, 1H), 10.53 (bs, 1H), 7.70 (s,
1H), 6.18 (s, 1H), 5.16 (s, 1H), 4.95 (d, J=6.1 Hz, 1H), 4.84 (t,
J=5.2 Hz, 1H), 4.80 (s, 1H), 3.80-3.65 (m, 3H), 3.61-3.50 (m, 1H),
0.84 (s, 3H); MS (ES.sup.+): 322.1.
[0345] The intermediate 88d was prepared as follows:
a. To a solution of 40j (100 mg, 0.18 mmol) in CH.sub.2Cl.sub.2 (9
mL) cold (ice water bath) was added NBS (32 mg, 0.18 mmol) and
stirred at room temperature for 1 h. The reaction mixture was
concentrated in vacuo and the residue obtained was purified by
flash column chromatography (silica gel, eluting with
chloroform/methanol, 1:0 to 20:1) to furnish 88a (102 mg, 90%) as a
yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.89 (s,
1H), 7.42-7.25 (m, 15H), 6.91 (s, 1H), 5.64 (s, 1H), 4.74 (s, 2H),
4.66-4.52 (m, 4H), 4.22-4.16 (m, 1H), 4.03 (d, J=8.7 Hz, 1H),
3.90-3.68 (m, 2H), 1.05 (s, 3H); MS (ES.sup.+): 631.3. b. A
solution of 88a (35 g, 55.6 mmol) in methanol (350 mL) in a 2-L
stainless steel bomb was added triethylamine (7.7 mL, 55.6 mmol),
Pd(OAc).sub.2 (3.5 g) and 1,1-bis(diphosphino)-ferrocene (3.5 g).
The bomb was vacuum flushed and charged with CO to 150 psi. The
reactor was heated with stirring at 150.degree. C. overnight and
cooled to room temperature. The catalyst was filtered through a pad
of Celite and concentrated in vacuo to obtain crude product. The
crude was purified by flash column chromatography (silica gel 1.2
kg, eluting with ethyl acetate in Hexane (0-50%, 2 L each) to give
10.7 g of 88b as yellow semisolid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.05 (s, 1H, exchangeable), 8.41 (s, 1H,
exchangeable), 8.07 (s, 1H), 7.49-7.20 (m, 16H), 5.66 (s, 1H), 4.76
(s, 2H), 4.72-4.45 (m, 4H), 4.19 (s, 1H), 4.09-3.98 (m, 1H), 3.86
(d, 8.9, 1H), 3.76 (s, 3H), 3.75-3.68 (m, 1H), 1.09 (s, 3H); MS
(ES.sup.+): 609.1. c. To a solution of 88b (8.5 g, 14 mmol) in
methanol (140 mL) was added THF (140 mL) and 1 N NaOH (140 mL). The
reaction was heated with stirring at 40.degree. C. for 1.5 h. The
reaction mixture was concentrated in vacuo to remove methanol and
THF. The pH was adjusted to 6 using 2.5N HCl and the aqueous layer
was extracted twice with ethyl acetate (500 mL and 200 mL). The
organic layers were combined, dried and concentrated in vacuo to
furnish crude product. The crude was purified by flash column
chromatography (silica gel 200 g, eluting with 0-50% CMA 80 in
chloroform) to furnish 88c (9.5 g, 100%) as a light yellow solid;
MP 164.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
13.37-12.95 (bs, 1H), 9.42 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H),
7.35 (dd, J=13.6, 23.4 Hz, 15H), 5.66 (s, 1H), 4.68 (d, J=42.2 Hz,
6H), 4.18 (s, 1H), 4.01 (d, J=8.4 Hz, 1H), 3.83 (s, 2H), 3.33 (s,
1H), 1.07 (s, 3H); MS (ES.sup.+): 595.0. d. To a solution of 88c (2
g, 3.36 mmol) in benzene (30 mL) was added triethylamine (0.54 mL,
3.87 mmol) and diphenyl phosphoryl azide (0.82 mL, 97%, 3.68 mmol)
and heated at reflux for 14 h. The reaction mixture was cooled to
room temperature and quenched with 1M NaHCO.sub.3 (100 mL). The
reaction mixture was extracted with EtOAc (2.times.200 mL). The
combined organic extracts were washed with brine (150 mL), dried,
filtered and concentrated in vacuo. The residue obtained was
purified by flash column chromatography (silica gel,
chloroform/methanol, 1:0 to 20:1) to give 88d (1.42 g, 71%) as a
brown solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): 11.17 (s, 1H),
10.55 (s, 1H), 7.72 (s, 1H), 7.40-7.20 (m, 15H), 6.11 (s, 1H), 5.41
(s, 1H), 4.70-4.52 (m, 6H), 4.18-4.10 (m, 1H), 3.96 (d, J=7.7 Hz,
1H), 3.77-3.60 (m, 2H), 1.12 (s, 3H); MS (ES.sup.+): 592.1.
##STR00143##
Example 4
Synthesis of 89c
[0346] To a solution of tricyclic product 89b (0.165 g, 0.43 mmol)
in methanol (5 mL) was added aqueous 1 N HCl (5 mL) and stirred at
room temperature overnight. The reaction mixture was concentrated
in vacuo to dryness. The residue obtained was purified by flash
column chromatography (silica gel 12 g, eluting with 0-100% CMA 80
in chloroform) to give 89c (0.014 g, 9%) as a yellow solid; mp
169.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.00-7.91 (m, 1H), 7.23-7.15 (m, 1H), 6.91-6.85 (m, 1H), 5.32-5.27
(m, 1H), 5.03-4.93 (m, 1H), 4.86-4.79 (m, 2H), 3.89-3.70 (m, 3H),
3.65-3.55 (m, 2H), 2.00-1.93 (m, 3H), 0.87-0.79 (m, 3H); MS
(ES.sup.-) 344.8.
[0347] The intermediate 89b was prepared as follows:
a. To a solution of 40m, (2 g, 4.5 mmol) in DMF (20 mL) was added
copper iodide (17 mg, 0.9 mmol), methyl methacrylate (9.5 ml, 90
mmol), triethylamine (1.25 mL, 9 mmol) and
tetrakis(triphenylphosphine)Palladium (0.5 g, 0.45 mmol) and heated
with stirring at 70.degree. C. for 68 h. The reaction was diluted
with water (60 mL) and extracted with ethyl acetate (3.times.25
mL). The organic layers were combined washed with water (25 mL),
brine (25 mL), dried, filtered, and concentrated in vacuo to
dryness. The residue obtained was purified by flash column
chromatography (silica gel 40 g, eluting with 0-100% [9:1] of
EtOAc: MeOH in hexane) to give 89a (0.615 g, 33%) as a brown solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.93 (s, 1H), 7.84 (s,
1H), 7.35 (s, 2H), 6.86 (s, 114), 5.56 (s, 1H), 5.00 (t, J=5.8 Hz,
1H), 4.39 (d, J=2.4 Hz, 1H), 4.10-4.00 (m, 1H), 3.73 (d, J=4.6 Hz,
3H), 3.59 (t, J=5.4 Hz, 2H), 2.07 (d, J=1.2 Hz, 3H), 1.56 (s, 3H),
1.34 (s, 3H), 1.14 (s, 3H). b. To a freshly prepared solution of
sodium methoxide (1.57 mL, 0.1 M) in methanol (14 mL) was added 89a
(0.657 g, 1.57 mmol) and heated with stirring at reflux temperature
overnight. The reaction mixture was neutralized with glacial acetic
acid (0.3 mL) and concentrated in vacuo to dryness. The residue
obtained was purified by flash column chromatography (silica gel 12
g, eluting with 0-100% [9:1] of EtOAc: MeOH in hexane) to give 89b
(0.165 g, 27%) as a yellow solid.
##STR00144##
Example 5
Synthesis of 90c
[0348] To a solution of 90b (0.050 g, 0.13 mmol) in methanol (0.5
mL) was added aqueous 1 N HCl (0.5 mL) and stirred at room
temperature for 48 h. The reaction mixture was concentrated in
vacuo to dryness. The solid obtained was triturated with ether,
collected by filtration, washed with ether and dried in vacuo at
acetone reflux temperature to furnish 90c (0.008 g, 18%) as an off
white solid; mp 234.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.33-10.90 (m, 1H), 8.05 (s, 1H), 7.13 (s, 1H), 5.80 (d,
J=1.2 Hz, 1H), 5.34 (s, 1H), 4.99 (s, 3H), 3.83-3.70 (m, 3H), 3.61
(dd, J=4.2, 12.5 Hz, 1H), 2.20 (d, J=1.1 Hz, 3H), 0.84 (s, 3H); MS
(ES) 344.9.
[0349] Intermediate 90b was prepared as follows:
a. To a solution of 40m (1.3 g, 3 mmol) in DMF (25 mL) was added
copper iodide (110 mg, 0.6 mmol), methyl crotonate (6.36 ml, 60
mmol), triethylamine (0.84 mL, 6 mmol) and
tetrakis(triphenylphosphine) palladium (0.350 g, 0.3 mmol) and
heated at 70.degree. C. for 48 h. The reaction was diluted with
water (75 mL) and extracted with ethyl acetate (2.times.25 mL). The
organic layers were combined, washed with water (2.times.25 mL),
brine (25 mL), dried, filtered, and concentrated in vacuo to
dryness. The residue obtained was purified by flash column
chromatography (silica gel 40 g, eluting with 0-100% [9:1] of
EtOAc: MeOH in hexane) to give 90a (0.565 g, 46%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.95 (d, J=2.8 Hz, 2H), 6.87 (s, 1H),
5.78 (d, J=1.3 Hz, 1H), 5.56 (s, 114), 4.98 (t, J=5.8 Hz, 1H), 4.39
(d, J=2.5 Hz, 1H), 4.07-3.98 (m, 1H), 3.65 (s, 3H), 3.59 (t, J=5.4
Hz, 2H), 3.33 (s, 1H), 2.55 (d, J=1.1 Hz, 3H), 1.56 (s, 3H), 1.34
(s, 3H), 1.15 (s, 3H). b. To a freshly prepared solution of sodium
methoxide (0.67 mL, 0.1 M) in methanol (6 mL) was added 90a (0.280
g, 0.67 mmol) and heated with stirring at reflux overnight. The
reaction mixture was concentrated in vacuo and the residue obtained
was purified by flash column chromatography (silica gel 4 g,
eluting with 0-100% CMA 80 in chloroform) to give 90b (0.100 g,
39%) as a yellow solid; mp 152.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.14 (s, 1H), 8.06 (s, 1H), 6.97 (s, 1H),
5.82 (s, 1H), 5.47 (s, 1H), 5.01 (t, J=5.9 Hz, 1H), 4.41 (d, J=2.5
Hz, 1H), 4.11-4.01 (m, 1H), 3.62 (t, J=5.3 Hz, 2H), 2.22 (d, J=1.1
Hz, 3H), 1.56 (s, 3H), 1.34 (s, 3H), 1.12 (s, 3H); MS (ES)
384.9.
##STR00145##
Example 6
Synthesis of 91b
[0350] To a solution of tricyclic product 91a (20 mg, 0.05 mmol) in
methanol (0.5 mL) was added aqueous 1 N HCl (0.5 mL) and stirred at
room temperature overnight. The reaction mixture was concentrated
in vacuo to dryness to furnish 91b (19 mg, 100%) as a white solid;
mp 59-64.degree. C. NMR (300 MHz, DMSO-d.sub.6) .delta. 8.73-8.30
(m, 21-1), 8.02 (s, 1H), 6.79 (s, 1H), 5.32 (s, 1H), 4.06-3.84 (m,
3H), 3.75 (d, J=11.7 Hz, 31-1), 3.63 (d, J=8.8 Hz, 2H), 3.14 (d,
J=7.3 Hz, 211), 0.77 (s, 3H); MS (ES) 332.9.
[0351] Intermediate 91a was prepared as follows.
[0352] To a solution of tricyclic product 40o (100 mg, 0.27 mmol)
in methanol (100 mL) was added platinum oxide (50 mg) and
hydrogenated at 50 psi for 3 days. The catalyst was removed by
filtration through a pad of Celite and the filtrate concentrated in
vacuo to give crude product.
The crude residue was purified by flash column chromatography
(silica gel 4 g, eluting with CHCl.sub.3/CMA-80, 0-100%) to furnish
crude 91a (64 mgs). The crude material was recrystallized from
methanol (2 mL) to furnish pure 91a (25 mg, 25%) as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.02 (s, 1H), 8.17 (s,
1H), 6.78 (s, 1H), 5.58 (s, 1H), 5.00 (s, 1H), 4.40 (s, 1H), 4.05
(s, 1H), 3.58 (s, 2H), 3.02 (s, 2H), 2.91 (s, 2H), 1.56 (s, 3H),
1.34 (s, 3H), 1.14 (s, 3H); MS (ES.sup.+) 375.0, (ES) 373.3.
##STR00146##
Example 7
Synthesis of 92c
[0353] To a solution of tricyclic product 92b (220 mg, 0.59 mmol)
in methanol (4 mL) was added aqueous 1 N HCl (4 mL) and stirred at
room temperature overnight. The reaction mixture was concentrated
in vacuo to dryness. The residue obtained was triturated with ether
and the solid obtained was collected by filtration, washed with
ether and dried in vacuo at acetone reflux temperature to furnish
92c (145 mg, 74%) as a mustard solid; mp 152-159.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 12.60 (s, 1H), 9.76 (s, 1H),
9.27 (s, 1H), 8.02 (s, 1H), 7.55 (d, J=11.6 Hz, 1H), 7.13 (s, 1H),
6.39 (d, J=11.6 Hz, 1H), 5.23 (s, 1H), 4.99-4.20 (m, 3H), 3.77 (d,
J=10.1 Hz, 2H), 3.70-3.57 (m, 2H), 0.87 (s, 3H); MS (ES.sup.+)
332.0, (ES) 329.9.
[0354] Intermediate 92b was prepared as follows.
a. To a solution of 40m (2.23 g, 4.99 mmol) in DMF (70 mL) was
added copper iodide (380 mg, 1.99 mmol), triethylamine (3 mL, 21.8
mmol) and tetrakis(triphenylphosphine) palladium (1.15 g, 1 mmol).
To the suspension was added acrylonitrile (14.3 ml, 217 mmol) in 4
portions over a period of 3 h and heated with stirring at
70.degree. C. for 3 days. The reaction was diluted with water (210
mL) and extracted with ethyl acetate (3.times.70 mL). The organic
layers were combined, washed with water (70 mL), brine (70 mL)
dried, filtered, and concentrated in vacuo to dryness. The residue
obtained was purified by flash column chromatography (silica gel,
110 g, eluting with 0-100% [9:1] of EtOAc: MeOH in hexane) to give
92a (619 mg, 33%) as a mustard-colored solid; mp 238.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.15 (d, J=15.9 Hz,
1H), 7.74 (s, 2H), 7.42 (s, 1H), 7.20 (s, 1H), 6.19 (d, J=15.7 Hz,
1H), 5.51 (s, 1H), 4.96 (t, J=5.8 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H),
4.03 (d, J=2.4 Hz, 1H), 3.66-3.55 (m, 2H), 1.55 (s, 3H), 1.33 (s,
3H), 1.12 (s, 3H); IR (KBr) 2209 cm.sup.-1; MS (ES) 370.1.8.
[0355] To a freshly prepared solution of sodium methoxide (36 mg
sodium in 1.6 ml methanol, 0.1 M) was added 92a (0.58 g, 1.56 mmol)
and heated with stirring at reflux for 4 h and then at room
temperature overnight. The reaction mixture was neutralized with
glacial acetic acid (0.094 mL) and concentrated in vacuo to
dryness. The residue obtained was purified by flash column
chromatography (silica gel 12 g, eluting with CHCl.sub.3/CMA-80,
0-100%) to furnish 92b (265 mg, 44%) as a rust solid; mp
112-114.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.05
(s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 6.99 (d, J=11.4 Hz, 1H), 6.60
(s, 1H), 5.73 (d, J=11.5 Hz, 1H), 5.34 (s, 1H), 4.98 (t, J=5.7 Hz,
1H), 4.37 (d, J=2.4 Hz, 1H), 4.03-3.98 (m, 1H), 3.64-3.48 (m, 2H),
1.52 (s, 3H), 1.33 (s, 3H), 1.12 (s, 3H); MS (ES.sup.+) 372.1, (ES)
369.9.
##STR00147## ##STR00148##
Example 8
Synthesis of 93f
[0356] To a suspension of 93e (310 mg, 0.54 mmol) in MeOH was added
1N aqueous HCl (1.8 mL) Pd/C (10%, 100 mg) and hydrogenated at 60
psi for 25 h. The reaction mixture was filtered and the filtrate
was concentrated in vacuo. The residue obtained was purified by
flash column chromatography (silica gel, 30 g, eluting with
chloroform/CMA80, 1:0 to 1:1) to furnish 93f (137 mg, 83%) as a
white solid; mp: 254.2.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.96 (s, 1H), 7.78 (s, 1H), 6.50 (s, 1H),
5.28 (s, 1H), 4.92 (d, J=6.7 Hz, 1H), 4.76 (t, J=5.4 Hz, 1H), 4.71
(s, 1H), 3.80-3.67 (m, 3H), 3.65-3.50 (m, 314), 2.95-2.85 (m, 2H),
0.83 (s, 3H); MS (ES.sup.+): 307.1.
[0357] Intermediate 93e was prepared as follows.
a. To a solution of 42a (27.85 g, 44.23 mmol) in pyridine (400 mL)
was added 4-methoxytriphenylmethyl chloride (56.74 g, 178.24 mmol)
and heated with stirring at 70.degree. C. for 16 h. The reaction
mixture was diluted with EtOAc (1.5 L), washed with water
(2.times.700 mL) and brine (500 mL), dried, filtered, and
concentrated. The residue was purified by flash column
chromatography (silica gel eluting with hexanes/EtOAc, 1:0 to 4:1)
to give 93a (28.38 g, 71%) as a light yellow solid; mp 78.6.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.91 (s, 1H), 7.63
(s, 1H), 7.45-7.12 (m, 27H), 6.96 (s, 1H), 6.87 (d, J=8.9 Hz, 2H),
5.56 (s, 1H), 4.74-4.50 (m, 6H), 4.20-4.12 (m, 1H), 4.02 (d, J=8.5
Hz, 1H), 3.87-3.64 (m, 2H), 3.71 (s, 3H), 1.05 (s, 3H). b. To a
solution of 93a, (26.1 g, 28.94 mmol) in DME (500 mL) was added
potassium vinyltrifluoroborate (7.2 g, 53.75 mmol), NaHCO.sub.3
(7.2 g, 85.70 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (1.4 g, 98%, 1.99
mmol), H.sub.2O (65 mL) and refluxed for 6 h. The reaction mixture
was diluted with water (500 mL) and extracted with EtOAc (1.8 L and
0.5 L). The organic layers were combined and washed with brine (500
mL), dried, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel eluting with
hexanes/EtOAc, 1:0 to 6:1) to furnish 93b (18.3 g, 74%) as a light
yellow solid; mp 79.7.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.56 (s, 1H), 7.44-7.12 (m, 28H), 7.01 (dd,
J=17.2, 11.0 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J=8.8 Hz, 2H), 5.57
(s, 1H), 5.31 (d, J=17.2 Hz, 1H), 5.16 (d, J=11.0 Hz, 1H),
4.76-4.52 (m, 6H), 4.22-4.13 (m, 1H), 4.04 (d, J=8.4 Hz, 1H),
3.88-3.70 (m, 2H), 3.71 (s, 3H), 1.05 (s, 3H); MS (ES): 847.6. c.
To a cold (ice water bath) solution of 93b (20.5 g, 24.15 mmol) in
THF (90 mL) was added dropwise borane dimethyl sulfide solution (2M
in THF, 9.5 mL) and stirred at room temperature for 4 h. The
reaction mixture was quenched with ethanol (19 mL), aqueous 3N NaOH
(6.0 mL), and cooled with ice/water. To the cold reaction mixture
was added hydrogen peroxide (30% in water, 6 mL) and heated at
reflux for 1 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate (1L), washed with water
(2.times.500 mL), brine (300 ml), dried and concentrated in vacuo.
The residue obtained was purified by flash column chromatography
(silica gel, eluting with ethyl acetate in hexane 1:0 to 2:1) to
give 93c (11.17 g, 53%) as a yellow solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.95 (s, 1H), 7.45 (s, 1H), 7.42-7.22 (m,
27H), 6.81 (d, J=9.0 Hz, 2H), 6.62 (s, 1H), 5.57 (s, 1H), 5.51 (t,
J=3.7 Hz, 1H), 4.76-4.48 (m, 6H), 4.20-4.10 (m, 1H), 4.04 (d, J=8.4
Hz, 1H), 3.91-3.66 (m, 2H), 3.71 (s, 3H), 3.58-3.46 (m, 2H),
2.97-2.86 (s, 2H), 1.03 (s, 3H). d. To a solution of 93c (1.0 g,
1.15 mmol) and triphenylphosphine (610 mg, 2.30 mmol) in
1,4-dioxane (15 mL) was added dropwise a solution of DIAD (0.5 mL,
95%, 2.41 mmol) in 1,4-dioxane (2.5 mL) and stirred at room
temperature for 16 h. The reaction mixture was concentrated in
vacuo and the residue obtained was purified by flash column
chromatography (silica gel 50 g, eluting with ethyl acetate in
hexane 1:0 to 4:1) to give 93d (730 mg, 75%) as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.68 (s, 1H),
7.49-7.15 (m, 27H), 6.86 (d, J=9.0 Hz, 2H), 6.59 (s, 1H), 5.53 (s,
1H), 4.80-4.45 (m, 6H), 4.22-4.10 (m, 1H), 4.02 (d, J=7.9 Hz, 1H),
3.86-3.64 (m, 2H), 3.72 (s, 3H), 3.60-3.34 (m, 2H), 3.18-2.92 (m,
2H), 1.08 (s, 3H); MS (ES.sup.+): 671.1 (M+Na). e. To a solution of
93d (618 mg, 0.73 mmol) in acetonitrile (35 mL) was added aqueous
1N HCl (3.5 mL) and stirred at room temperature for 17 h. The
reaction mixture was neutralized with aqueous 0.5 N NaOH, diluted
with water (50 mL), and concentrated in vacuo to remove
acetonitrile. The aqueous layer was extracted with CHCl.sub.3/MeOH
(5:1, 100 mL and 50 mL). The combined organic extracts were dried,
filtered and concentrated in vacuo. The residue obtained was
purified by flash column chromatography (silica gel 30 g, eluting
with hexane/ethyl acetate/methanol, 1:1:0 to 1:1:0.1) to give 93e
(362 mg, 86%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.01 (s, 1H), 7.81 (s, 1H), 7.41-7.27 (m, 15H), 6.53 (s,
1H), 5.55 (s, 1H), 4.77-4.49 (m, 6H), 4.26-4.12 (m, 1H), 4.04 (d,
J=8.1 Hz, 114), 3.85-3.65 (m, 2H), 3.60-3.48 (m, 2H), 2.83 (t,
J=6.5 Hz, 2H), 1.10 (s, 3H); MS (ES.sup.+): 577.1.
##STR00149##
Example 9
Synthesis of 94
[0358] To a suspension of 40p (33 mg, 0.1 mmol) in
trimethylphosphate (1 mL) at 0.degree. C. was added phosphorus
oxychloride (19 .mu.L, 0.21 mmol) and stirred at 0.degree. C. for 1
h. The reaction mixture was treated with n-tributylamine (70 .mu.L,
0.29 mmol), acetonitrile (100 .mu.L), tributylammonium
pyrophosphate (H.sub.4P.sub.2O.sub.7.1.6 n-Bu.sub.3N, 190 mg, 0.40
mmol) and stirred at room temperature for 0.5 h. The reaction
mixture was quenched with 1M TEAB buffer (5 mL, pre-cooled with
ice/water, pH=8.0), diluted with water (20 mL), and washed with
dichloromethane (2.times.15 mL). The aqueous solution was
concentrated in vacuo to remove traces of CH.sub.2Cl.sub.2 and
purified by DEAE ion exchange column chromatography with a linear
gradient of TEAB buffer (1M TEAB buffer, pH=8.0/H.sub.2O, 0:1 to
1:0, total volume: 500 mL). The fractions containing the desired
triphosphate were combined and concentrated. The residue was
re-dissolved in H.sub.2O and purified by HPLC(CH.sub.3CN/0.1 M TEAB
buffer, pH=8.0, 0-30 min; 0-35% CH.sub.3CN; monitoring at 238 nM)
to give 94 (t.sub.R=18.7 min). Fractions containing 94 were
concentrated and re-dissolved in 2 mL of H.sub.2O and the
concentration of 94 was measured to be 0.34 mM (yield: 0.7%) by UV
(240 nm, .epsilon.=58,000 M.sup.-1 cm.sup.-1). .sup.1H NMR (300
MHz, D.sub.2O) .delta. 7.79 (s, 1H), 7.19 (d, J=12.0 Hz, 1H), 7.02
(s, 1H), 5.78 (d, J=12.0 Hz, 1H), 5.46 (s, 1H), 4.04 (s, 2H),
4.50-3.50 (m, 2H), 0.91 (s, 3H). .sup.31P NMR (121 MHz, D.sub.2O):
.delta. -8.8 (1P), -11.0 (1P), -22.3 (1P), MS (ES): 570.9
(M-1).
##STR00150##
Example 10
Synthesis of 95
[0359] To a suspension of 95e (64 mg, 0.2 mmol) in
trimethylphosphate (2 mL) at 0.degree. C. was added phosphorus
oxychloride (37 .mu.L, 0.4 mmol) and stirred at 0.degree. C. for 1
h. The reaction mixture was treated with n-tributylamine (150
.mu.L, 0.62 mmol), acetonitrile (200 .mu.L), tributylammonium
pyrophosphate (H.sub.4P.sub.2O.sub.7.1.6 n-Bu.sub.3N, 380 mg, 0.8
mmol) and stirred at room temperature for 0.5 h. The reaction
mixture was quenched with 1M TEAB buffer (10 mL, pre-cooled with
ice water, pH=8.0), diluted with water (20 mL), and washed with
dichloromethane (2.times.15 mL). The aqueous phase was concentrated
in vacuo to remove the trace of CH.sub.2Cl.sub.2 and purified by
DEAE ion exchange column chromatography with a linear gradient of
TEAB buffer (1M TEAB buffer, pH=8.0/H.sub.2O, 0:1 to 1:0, total:
500 mL). The fractions containing the desired triphosphate were
combined and concentrated. The residue was re-dissolved in H.sub.2O
and purified by HPLC(CH.sub.3CN/0.1 M TEAB buffer, pH=8.0, 0-40
min, 0-35% CH.sub.3CN; monitoring at 244 nm) to give 95
(t.sub.R=17.2 min). Fractions containing 95 were concentrated and
re-dissolved in 2 mL of H.sub.2O and the concentration of 95 was
measured to be 9.8 mM (yield: 10%) by UV (280 nm, .epsilon.=6,400
M.sup.-1 cm.sup.-1). .sup.1H NMR (300 MHz, D.sub.2O) .delta. 7.53
(s, 1H), 6.40 (s, 1H), 5.31 (s, 1H), 4.32-4.00 (m, 4H), 0.93 (s,
3H); .sup.31P NMR (D.sub.2O) .delta. -10.69 (d, J=19.4 Hz, 1P),
-11.26 (d, J=20.6 Hz, 1P), -23.24 (t, J=19.4 Hz, 1P). MS (ES):
560.1 (M-1).
Example 11
[0360] The following illustrate representative pharmaceutical
dosage forms, containing a compound of Formula I, or a
pharmaceutically acceptable salt or prodrug thereof (`Compound X`),
for therapeutic or prophylactic use in humans.
TABLE-US-00001 (i) Tablet 1 mg/tablet Compound X = 100.0 Lactose
77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline
cellulose 92.5 Magnesium stearate 3.0 300.0
TABLE-US-00002 (ii) Tablet 2 mg/tablet Compound X = 20.0
Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch
glycolate 15.0 Magnesium stearate 5.0 500.0
TABLE-US-00003 (iii) Capsule mg/capsule Compound X = 10.0 Colloidal
silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0
Magnesium stearate 3.0 600.0
TABLE-US-00004 (iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free
acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium
phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1
mL
TABLE-US-00005 (v) Injection 2 (10 mg/ml) mg/ml Compound X = (free
acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium
phosphate 1.1 Polyethylene glycol 400 200.0 01 N Sodium hydroxide
solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s.
ad 1 mL
TABLE-US-00006 (vi) Aerosol mg/can Compound X = 20.0 Oleic acid
10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane
10,000.0 Dichlorotetrafluoroethane 5,000.0
[0361] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art.
[0362] All publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *