U.S. patent application number 13/430341 was filed with the patent office on 2013-03-28 for hepatitis c therapies.
The applicant listed for this patent is Yarlagadda S. Babu, Pooran Chand, Yahya El-Kattan, Ajit K. Ghosh, Pravin L. Kotian, V. Satish Kumar, Tsu-Hsing Lin, Minwan Wu. Invention is credited to Yarlagadda S. Babu, Pooran Chand, Yahya El-Kattan, Ajit K. Ghosh, Pravin L. Kotian, V. Satish Kumar, Tsu-Hsing Lin, Minwan Wu.
Application Number | 20130078218 13/430341 |
Document ID | / |
Family ID | 36698901 |
Filed Date | 2013-03-28 |
United States Patent
Application |
20130078218 |
Kind Code |
A1 |
Babu; Yarlagadda S. ; et
al. |
March 28, 2013 |
HEPATITIS C THERAPIES
Abstract
The invention provides methods for treating hepatitis C viral
infections and related viral infections, as well as compounds and
compositions that are useful for treating such infections.
Inventors: |
Babu; Yarlagadda S.;
(Birmingham, AL) ; Chand; Pooran; (Birmingham,
AL) ; Wu; Minwan; (Vestavia Hills, AL) ;
Kotian; Pravin L.; (Hoover, AL) ; Kumar; V.
Satish; (Birmingham, AL) ; Lin; Tsu-Hsing;
(Vestavia Hills, AL) ; El-Kattan; Yahya; (Vestavia
Hills, AL) ; Ghosh; Ajit K.; (Birmingham,
AL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Babu; Yarlagadda S.
Chand; Pooran
Wu; Minwan
Kotian; Pravin L.
Kumar; V. Satish
Lin; Tsu-Hsing
El-Kattan; Yahya
Ghosh; Ajit K. |
Birmingham
Birmingham
Vestavia Hills
Hoover
Birmingham
Vestavia Hills
Vestavia Hills
Birmingham |
AL
AL
AL
AL
AL
AL
AL
AL |
US
US
US
US
US
US
US
US |
|
|
Family ID: |
36698901 |
Appl. No.: |
13/430341 |
Filed: |
March 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12399521 |
Mar 6, 2009 |
8163703 |
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13430341 |
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11388060 |
Mar 23, 2006 |
7514410 |
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12399521 |
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60665832 |
Mar 29, 2005 |
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60692572 |
Jun 22, 2005 |
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Current U.S.
Class: |
424/85.7 ;
435/184; 514/12.9; 514/23; 514/43; 536/53; 536/54; 536/55 |
Current CPC
Class: |
A61K 38/2292 20130101;
Y02A 50/393 20180101; A61K 45/06 20130101; A61K 31/7056 20130101;
A61K 31/7068 20130101; A61K 38/212 20130101; A61K 31/7064 20130101;
A61P 31/16 20180101; C07H 7/06 20130101; A61P 31/20 20180101; Y02A
50/30 20180101; A61P 43/00 20180101; C07H 19/22 20130101; A61P
31/12 20180101; C07H 11/04 20130101; Y02A 50/465 20180101; A61P
31/14 20180101 |
Class at
Publication: |
424/85.7 ;
536/53; 536/55; 514/23; 536/54; 514/43; 514/12.9; 435/184 |
International
Class: |
A61K 31/7064 20060101
A61K031/7064; A61K 31/7068 20060101 A61K031/7068; A61K 45/06
20060101 A61K045/06; A61K 31/7056 20060101 A61K031/7056; A61K 38/22
20060101 A61K038/22; A61K 38/21 20060101 A61K038/21; C07H 7/06
20060101 C07H007/06; C07H 11/04 20060101 C07H011/04 |
Claims
1. A compound of the formula: ##STR00059## wherein: R is OR.sub.a,
SR.sub.a, NR.sub.eR.sub.f, NR.sub.aNR.sub.bR.sub.c, alkyl, alkenyl,
alkynyl, aryl, (CH.sub.2).sub.nNR.sub.aR.sub.b,
(CH.sub.2).sub.nOR.sub.a, C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.a)CO.sub.2R.sub.b,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.a, CONR.sub.aR.sub.b, NHC(.dbd.NR.sub.a)NHR.sub.b,
NR.sub.aOR.sub.b, NR.sub.aNO, NHCONHR.sub.a,
NR.sub.aN.dbd.NR.sub.b, NR.sub.aN.dbd.CHR.sub.b,
NR.sub.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
NR.sub.aC(O)OR.sub.b, CH.dbd.N--OR.sub.a,
NR.sub.aC(.dbd.NH)NR.sub.bR.sub.c,
NR.sub.aC(O)NR.sub.bNR.sub.CR.sub.d, O--C(O)R.sub.a,
OC(O)--OR.sub.a, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.aR.sub.b,
SNR.sub.aR.sub.b, S--ONR.sub.aR.sub.b, or SO.sub.2NR.sub.aR.sub.b;
n is 0, 1, 2, 3, 4, or 5; 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 H and R.sup.3 is OH; or R.sup.2 is OH and R.sup.3 is H; R.sup.4
is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--; R.sup.5 is OH, alkyl-O--, alkylC(.dbd.O)O,
alkyl-S--, or alkylC(.dbd.O)--S-- R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl 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, pyrrolino, 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, pyrrolino, or thiomorpholino ring; R.sub.e
is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl or NO; and R.sub.f is H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl and NO; or
R.sub.e and R.sub.f together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, piperazino, azetidino,
morpholino, pyrrolino, or thiomorpholino ring; which ring is
optionally substituted with one or more halo, hydroxyl, alkyl,
alkenyl, or alkynyl; wherein any alkyl, cycloalkyl, alkenyl,
alkynyl, or acyl is optionally substituted with 1 to 3 substituents
selected from the group consisting of alkoxy, acyl, acylamino,
acyloxy, oxyacyl, amino, substituted amino, aminoacyl, aryl,
aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic; and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl,
acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic; or a pharmaceutically acceptable salt or prodrug
thereof.
2. The compound of claim 1 wherein R is OR.sub.a, Cl, SR.sub.a,
NR.sub.eR.sub.f, aryl or NR.sub.aNR.sub.bR.sub.c.
3. The compound of claim 1 wherein R is hydroxy, chloro, methoxy,
mercapto, methylthio, methylamino, isopropylamino, propylamino,
ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino,
1-(2-hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino,
azetidino, pyrrolidino, imidazolylpropylamino, pyrrolino,
morpholino, piperazino, hydroxyethylamino, bis-hydroxyethylamino,
hydroxypropylamino, hydroxyethylpyrrolidino, or
1-methyl-2-hydroxyethylamino.
4. The compound of claim 1 wherein R is NR.sub.eR.sub.f.
5. The compound of claim 1 which is
4-methylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Ethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Isopropylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Dimethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-n-Propylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-3-pyrrolino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(2-hydroxymethylpyrrolidino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyri-
midine;
4-(3-N-imidazolyl-n-propylamino)-7-.beta.-(D-ribofuranosyl)-furo[3-
,2-d]pyrimidine;
4-N-morpholino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-N-piperazino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-bis-hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimid-
ine;
4-(3-hydroxypropylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimi-
dine; or
4-(2-hydroxy-1-methyl-ethylamino)-7-.beta.-(D-ribofuranosyl)-furo-
[3,2-d]pyrimidine; or a pharmaceutically acceptable salt or prodrug
thereof.
6. The compound of claim 1 which is a prodrug.
7. The compound of claim 1 that comprises one or more mono-, di-,
or tri-phosphate groups.
8. The compound of claim 1 that comprises one or more
mono-phosphate groups.
9. The compound of claim 7 wherein the compound is a prodrug.
10. The compound of claim 7 wherein one or more phosphorous atoms
of the one or more pendent mono-, di-, or tri-phosphate groups is
bonded to one or more alkoxy or aryloxy groups.
11. The compound of claim 7 wherein one or more phosphorous atoms
of the pendent mono-, di-, or tri-phosphate groups is bonded to one
or more groups 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 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).
12. The compound of claim 7 wherein one or more phosphorous atoms
of the one or more pendent mono-, di-, or tri-phosphate groups is
bonded to one or more groups R.sub.z--N--; wherein each R.sub.z is
a residue of an amino acid.
13. The compound of claim 12 wherein the amino acid is a natural
amino acid.
14. The compound of claim 7 which comprises one or more groups of
formula: ##STR00060## wherein: R.sub.15 is H, alkyl, aryl,
cycloalkyl, heteroaryl, heterocyclic, or an amino acid; R.sub.16 is
H, aryl, or 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; R.sub.18 and R.sub.19 are each independently H,
alkyl, aryl, aralkyl, aryl, or 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, aralkyl, aryl or heteroaryl; R.sub.20 is alkyl, aryl, or
arylalkyl; R.sub.21 is H, alkyl, aryl, or arylalkyl; R.sub.22 is H
or lower acyl; p is an integer from 2-3; wherein any alkyl,
cycloalkyl, alkenyl, alkynyl, or acyl is optionally substituted
with 1 to 3 substituents selected from the group consisting of
alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted
amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro,
N.sub.3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,
thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl,
heteroaryl, and heterocyclic; and wherein any aryl, heteroaryl, or
heterocycle is optionally substituted with 1 to 3 substituents
selected from the group consisting of alkyl, alkenyl, alkynyl,
alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted
amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro,
N.sub.3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,
thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl,
heteroaryl, and heterocyclic.
15. The compound of claim 1 which is a prodrug wherein one or more
of R.sup.2, R.sup.3, and R.sup.4 is acyloxy, acylamino or R--O;
wherein R is a carboxy-linked amino acid.
16. A pharmaceutical composition comprising a compound as described
in claim 1, or a pharmaceutically acceptable salt or prodrug
thereof; and a pharmaceutically acceptable carrier.
17. The composition of claim 16 which further comprises one or more
additional anti-viral agents, immune modulators, or interferon
inducers.
18. The composition of claim 17 wherein the one or more anti-viral
agents are selected from ribavirin, levovirin, viramidine, thymosin
alpha-1, an inhibitor of a serine proteases, an inhibitor of
inosine monophosphatedehydrognease, interferon-.alpha., and
pegylated interferon-.alpha. (peginterferon-.alpha.).
19. The composition of claim 16 which further comprises one or more
additional HCV polymerase inhibitors.
20. The composition of claim 16 which further comprises one or more
protease inhibitors.
21. The composition of claim 16 which further comprises
ribavirin.
22. The composition of claim 16 which further comprises
interferon-.alpha. or pegylated interferon-.alpha.
(peginterferon-.alpha.).
23. A method for treating a viral infection selected from hepatitis
B, hepatitis C, Polio, Coxsackie A and B, Rhino, Echo, small pox,
Ebola, and West Nile in an animal, comprising administering to the
animal an effective amount of a compound of formula I: ##STR00061##
wherein: X.dbd.N or CH; Y.dbd.O, S or N--R.sup.4; R is OR.sub.3,
SR.sub.3, NR.sub.3R.sub.4, NR.sub.3NR.sub.4R.sub.5, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl,
(CH.sub.2).sub.nNR.sub.aR.sub.b, (CH.sub.2).sub.nOR.sub.a,
C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.3)CO.sub.2R.sub.4,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.3, CONR.sub.3R.sub.4, NHC(.dbd.NR.sub.3)NHR.sub.4,
NR.sub.3OR.sub.4, NR.sub.3NO, NHCONHR.sub.3,
NR.sub.3N.dbd.NR.sub.4, NR.sub.3N.dbd.CHR.sub.4,
NR.sub.3C(O)NR.sub.4R.sub.5, NR.sub.3C(S)NR.sub.4R.sub.5,
NR.sub.3C(O)OR.sub.4, CH.dbd.N--OR.sub.3,
NR.sub.3C(.dbd.NH)NR.sub.4R.sub.5,
NR.sub.3C(O)NR.sub.4NR.sub.5R.sub.6, O--C(O)R.sub.3,
OC(O)--OR.sub.3, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.3R.sub.4,
SNR.sub.3R.sub.4, S--ONR.sub.3R.sub.4, or SO.sub.2NR.sub.3R.sub.4;
n is 0, 1, 2, 3,4, or 5; R.sup.1 is H, NR.sub.3R.sub.4, Cl, F,
OR.sub.3, SR.sub.3, NHCOR.sub.3, NHSO.sub.2R.sub.3, NHCONHR.sub.3,
CN, alkyl, aryl, ONR.sub.3R.sub.4, or NR.sub.3C(O)OR.sub.4; R.sup.2
is ribose, 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; R.sup.3 is H,
alkyl, aryl, F, Cl, CN, CO.sub.2H or NH.sub.2; and R.sup.4 is H,
OH, alkyl, aryl, --COO-alkyl, CONH.sub.2, CONH-alkyl,
O--C(O)-alkyl, O--C(O)-aryl or alkoxy; R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 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 OH, --COO-alkyl,
CONH.sub.2, CONH-alkyl, O--C(O)-alkyl, O--C(O)-aryl alkoxy and NO;
or R.sub.3 and R.sub.4 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, piperazino, azetidino,
morpholino, pyrrolino, or thiomorpholino ring; or R.sub.4 and
R.sub.5 together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; wherein any ring formed by
R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 is optionally
substituted with one or more hydroxyl, halo, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted
alkynyl; and R.sub.a, R.sub.b, and R.sub.c are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl 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, pyrrolino, 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,
pyrrolino, or thiomorpholino ring; or a pharmaceutically acceptable
salt or prodrug thereof.
24. The method of claim 23 wherein the compound of formula I is a
compound of the following formula: ##STR00062## wherein: Y is O or
S; R is OR.sub.3, SR.sub.3, NR.sub.3R.sub.4,
NR.sub.3NR.sub.4R.sub.5, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, (CH.sub.2).sub.n--CH(NHR.sub.3)CO.sub.2R.sub.4,
Cl, F, Br, I, CN, COOR.sub.3, CONR.sub.3R.sub.4,
NHC(.dbd.NR.sub.3)NHR.sub.4, NR.sub.3OR.sub.4, NR.sub.3NO,
NHCONHR.sub.3, NR.sub.3N.dbd.NR.sub.4, NR.sub.3N.dbd.CHR.sub.4,
NR.sub.3C(O)NR.sub.4R.sub.5, NR.sub.3C(S)NR.sub.4R.sub.5,
NR.sub.3C(O)OR.sub.4, CH.dbd.N--OR.sub.3,
NR.sub.3C(.dbd.NH)NR.sub.4R.sub.5,
NR.sub.3C(O)NR.sub.4NR.sub.5R.sub.6, O--C(O)R.sub.3,
OC(O)--OR.sub.3, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.3R.sub.4,
SNR.sub.3R.sub.4, S--ONR.sub.3R.sub.4, or SO.sub.2NR.sub.3R.sub.4;
n is 0-5; R.sup.1 is H, NR.sub.3R.sub.4, Cl, F, OR.sub.3, SR.sub.3,
NHCOR.sub.3, NHSO.sub.2R.sub.3, NHCONHR.sub.3, CN, alkyl, aryl,
ONR.sub.3R.sub.4, or NR.sub.3C(O)OR.sub.4; R.sup.2 is ribose,
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; and R.sub.3,
R.sub.4, R.sub.5, and R.sub.6 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 and NO; or R.sub.3 and R.sub.4 together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, or thiomorpholino ring; or
R.sub.4 and R.sub.5 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, piperazino, azetidino,
morpholino, or thiomorpholino ring; or a pharmaceutically
acceptable salt or prodrug thereof.
25. The method of claim 23 wherein the compound has the formula:
##STR00063## wherein X.dbd.N or CH; Y.dbd.O, S or N--R.sup.4;
R.dbd.OR.sup.5, NHR.sup.4, NR.sup.4R.sup.5, NHNHR.sup.4,
NR.sup.4NHR.sup.5, SR.sup.5, alkyl, aryl, Cl, NR.sup.4OR.sup.5,
NR.sup.4NO, or NHCONHR.sup.4; R.sup.1.dbd.H, NHR.sup.4, Cl, F,
OR.sup.4, SR.sup.4, NHCOR.sup.4, NHSO.sub.2R.sup.4, NHCONHR.sup.4,
CN, alkyl, aryl, or NR.sup.4R.sup.5; R.sup.2=ribose, 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; R.sup.3.dbd.H, alkyl, aryl, F, Cl, CN,
CO.sub.2H or NH.sub.2; R.sup.4.dbd.H, OH, alkyl, aryl, --COO-alkyl,
CONH.sub.2, CONH-alkyl, O--C(O)-alkyl, O--C(O)-aryl or alkoxy;
R.sup.5=alkyl, aryl, OH or alkoxy; or a pharmaceutically acceptable
salt or prodrug thereof.
26. The method of claim 25, provided that when Y.dbd.NH or S and
R.dbd.NH.sub.2, OH, SH, alkylamino, alkyloxy, or alkylthio, R.sup.2
is not from ribose or 2-deoxyribose.
27. The method of claim 23 wherein the compound has the formula:
##STR00064## wherein: R is OR.sub.a, SR.sub.a, NR.sub.eR.sub.f,
NR.sub.aNR.sub.bR.sub.c, alkyl, alkenyl, alkynyl, aryl,
(CH.sub.2).sub.nNR.sub.aR.sub.b, (CH.sub.2).sub.nOR.sub.a,
C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.a)CO.sub.2R.sub.b,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.a, CONR.sub.aR.sub.b, NHC(.dbd.NR.sub.a)NHR.sub.b,
NR.sub.aOR.sub.b, NR.sub.aNO, NHCONHR.sub.a,
NR.sub.aN.dbd.NR.sub.b, NR.sub.aN.dbd.CHR.sub.b,
NR.sub.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
NR.sub.aC(O)OR.sub.b, CH.dbd.N--OR.sub.a,
NR.sub.aC(.dbd.NH)NR.sub.bR.sub.c,
NR.sub.aC(O)NR.sub.bNR.sub.cR.sub.d, O--C(O)R.sub.a,
OC(O)--OR.sub.a, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.aR.sub.b,
SNR.sub.aR.sub.b, S--ONR.sub.aR.sub.b, or SO.sub.2NR.sub.aR.sub.b;
n is 0, 1, 2, 3, 4, or 5; 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 H and R.sup.3 is OH; or R.sup.2 is OH and R.sup.3 is H; R.sup.4
is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--; R.sup.5 is OH, alkyl-O--, alkylC(.dbd.O)O,
alkyl-S--, or alkylC(.dbd.O)--S-- R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl 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, pyrrolino, 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, pyrrolino, or thiomorpholino ring; R.sub.e
is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl or NO; and R.sub.f is H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl and NO; or
R.sub.e and R.sub.f together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, piperazino, azetidino,
morpholino, pyrrolino, or thiomorpholino ring; which ring is
optionally substituted with one or more halo, hydroxyl, alkyl,
alkenyl, or alkynyl; wherein any alkyl, cycloalkyl, alkenyl,
alkynyl, or acyl is optionally substituted with 1 to 3 substituents
selected from the group consisting of alkoxy, acyl, acylamino,
acyloxy, oxyacyl, amino, substituted amino, aminoacyl, aryl,
aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic; and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl,
acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic; or a pharmaceutically acceptable salt or prodrug
thereof.
28. The method of claim 23 wherein the viral infection is hepatitis
C.
29. The method of claim 27 wherein R is OR.sub.a, Cl, SR.sub.a,
NR.sub.eR.sub.f, aryl or NR.sub.aNR.sub.bR.sub.C.
30. The method of claim 27 wherein R is hydroxy, chloro, methoxy,
mercapto, methylthio, methylamino, isopropylamino, propylamino,
ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino,
1-(2-hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino,
azetidino, pyrrolidino, imidazolylpropylamino, pyrrolino,
morpholino, piperazino, hydroxyethylamino, bis-hydroxyethylamino,
hydroxypropylamino, hydroxyethylpyrrolidino, or
1-methyl-2-hydroxyethylamino.
31. The method of claim 27 wherein R is NR.sub.eR.sub.f.
32. The method of claim 27 wherein the compound is
4-methylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Ethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Isopropylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Dimethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-n-Propylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-3-pyrrolino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(2-hydroxymethylpyrrolidino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyri-
midine;
4-(3-N-imidazolyl-n-propylamino)-7-.beta.-(D-ribofuranosyl)-furo[3-
,2-d]pyrimidine;
4-N-morpholino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-N-piperazino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-bis-hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimid-
ine;
4-(3-hydroxypropylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimi-
dine; or
4-(2-hydroxy-1-methyl-ethylamino)-7-.beta.-(D-ribofuranosyl)-furo-
[3,2-d]pyrimidine; or a pharmaceutically acceptable salt or prodrug
thereof.
33. The method of claim 23 wherein the compound is a prodrug.
34. The method of claim 23 wherein the compound of formula I
comprises one or more mono-, di-, or tri-phosphate groups.
35. The method of claim 23 wherein the compound of formula I
comprises one or more mono-phosphate groups.
36. The method of claim 34 wherein the compound is a prodrug.
37. The method of claim 34 wherein one or more phosphorous atoms of
the one or more pendent mono-, di-, or tri-phosphate groups is
bonded to one or more alkoxy or aryloxy groups.
38. The method of claim 34 wherein one or more phosphorous atoms of
the pendent mono-, di-, or tri-phosphate groups is bonded to one or
more groups 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 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).
39. The method of claim 34 wherein one or more phosphorous atoms of
the one or more pendent mono-, di-, or tri-phosphate groups is
bonded to one or more groups R.sub.z--N--; wherein each R.sub.z is
a residue of an amino acid.
40. The method of claim 39 wherein the amino acid is a natural
amino acid.
41. The method of claim 34 wherein the compound of formula I
comprises one or more groups of formula: ##STR00065## wherein:
R.sub.15 is H, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic,
or an amino acid; R.sub.16 is H, aryl, or 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; R.sub.18 and R.sub.19 are each independently H, alkyl, aryl,
aralkyl, aryl, or 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, aralkyl, aryl or heteroaryl; R.sub.20 is alkyl, aryl, or
arylalkyl; R.sub.21 is H, alkyl, aryl, or arylalkyl; R.sub.22 is H
or lower acyl; p is an integer from 2-3; wherein any alkyl,
cycloalkyl, alkenyl, alkynyl, or acyl is optionally substituted
with 1 to 3 substituents selected from the group consisting of
alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted
amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro,
N.sub.3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,
thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl,
heteroaryl, and heterocyclic; and wherein any aryl, heteroaryl, or
heterocycle is optionally substituted with 1 to 3 substituents
selected from the group consisting of alkyl, alkenyl, alkynyl,
alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted
amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro,
N.sub.3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,
thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl,
heteroaryl, and heterocyclic.
42. The method of claim 33 wherein the prodrug is a compound of
formula I wherein one or more of R.sup.2, R.sup.3, and R.sup.4 is
acyloxy, acylamino or R--O; wherein R is a carboxy-linked amino
acid.
43. The method of claim 23 which further comprises administering to
the animal one or more additional viral polymerase inhibitors.
44. The method claim 23 which further comprises administering to
the animal, one or more protease inhibitors.
45. The method of claim 23 which further comprises administering
ribavirin to the animal.
46. The method of claim 23 which further comprises administering
interferon-.alpha. or pegylated interferon-.alpha.
(peginterferon-.alpha.) to the animal.
47. The method of claim 27 wherein the virus is hepatitis C.
48. A method for inhibiting an HCV 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 as described in claim 23.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/399,521, filed Mar. 6, 2009, which is a continuation of U.S.
application Ser. No. 11/388,060, filed Mar. 23, 2006 and issued at
U.S. Pat. No. 7,514,410 on Apr. 7, 2009, and claims the benefit of
priority to International Application No. PCT/US2005/039072 filed
Oct. 28, 2005; and this application also claims the benefit of
priority of U.S. Provisional Application No. 60/665,832, filed Mar.
29, 2005 and the benefit of priority of U.S. Provisional
Application No. 60/692,572, filed Jun. 22, 2005; these applications
are incorporated herein by reference in their entirety.
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), hepacivirus (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. 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 single stranded 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] Viral diseases are one of the major causes of deaths and
economic losses in the world. Out of various viral diseases, HIV,
HBV and HCV infections are more important and responsible for a
large number of deaths. There are some drugs for HIV, only a few
for HBV but no good drug for HCV. Hepatitis C is a viral liver
disease, caused by infection with the hepatitis C virus (HCV).
There are approximately 170 million people worldwide with chronic
HCV infection, of which about 2.7 million are in the United States.
HCV is a leading cause of cirrhosis, a common cause of
hepatocellular carcinoma, and is the leading cause of liver
transplantation in the United States. Currently, .alpha.-interferon
monotherapy and .alpha.-interferon-ribavirin combination therapy
are the only approved treatments for HCV.
[0009] U.S. Pat. No. 4,584,369 is directed to certain compounds
that are reported to inhibit the growth of leukemia cells. In the
Background section of the patent it states that some beta-glycosyl
C-Nucleoside compounds appear to have some anti-viral activity.
There is no antiviral data reported in the patent for any compounds
and there is no disclosure regarding which viruses the
beta-glycosyl C-Nucleoside compounds may have activity against.
SUMMARY OF THE INVENTION
[0010] It has been found that certain compounds inhibit a viral
polymerase from the Flaviviridae family of viruses, HCV viral
polymerase. Accordingly, the invention relates to certain fused
furan, thiophene and pyrrole compounds and particularly to fused
furan, thiophene and pyrrole compounds that are useful as
inhibitors of hepatitis B, hepatitis C, Polio, Coxsackie A and B,
Rhino, Echo, small pox, Ebola, and West Nile virus polymerases.
[0011] In one embodiment the invention provides a method for
treating a viral infection selected from hepatitis B, hepatitis C,
Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West
Nile in an animal (e.g. a human), comprising administering to the
animal an effective amount of a compound of formula I:
##STR00001##
wherein:
[0012] X.dbd.N or CH;
[0013] Y.dbd.O, S or N--R.sup.4;
[0014] R is OR.sub.3, SR.sub.3, NR.sub.3R.sub.4,
NR.sub.3NR.sub.4R.sub.5, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, (CH.sub.2).sub.nNR.sub.aR.sub.b,
(CH.sub.2).sub.nOR.sub.a, C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.3)CO.sub.2R.sub.4,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.3, CONR.sub.3R.sub.4, NHC(.dbd.NR.sub.3)NHR.sub.4,
NR.sub.3OR.sub.4, NR.sub.3NO, NHCONHR.sub.3,
NR.sub.3N.dbd.NR.sub.4, NR.sub.3N.dbd.CHR.sub.4,
NR.sub.3C(O)NR.sub.4R.sub.5, NR.sub.3C(S)NR.sub.4R.sub.5,
NR.sub.3C(O)OR.sub.4, CH.dbd.N--OR.sub.3,
NR.sub.3C(.dbd.NH)NR.sub.4R.sub.5,
NR.sub.3C(O)NR.sub.4NR.sub.5R.sub.6, O--C(O)R.sub.3,
OC(O)--OR.sub.3, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.3R.sub.4,
SNR.sub.3R.sub.4, S--ONR.sub.3R.sub.4, or
SO.sub.2NR.sub.3R.sub.4;
[0015] n is 0, 1, 2, 3, 4, or 5;
[0016] R.sup.1 is H, NR.sub.3R.sub.4, Cl, F, OR.sub.3, SR.sub.3,
NHCOR.sub.3, NHSO.sub.2R.sub.3, NHCONHR.sub.3, CN, alkyl, aryl,
ONR.sub.3R.sub.4, or NR.sub.3C(O)OR.sub.4;
[0017] R.sup.2 is ribose, 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;
[0018] R.sup.3 is H, alkyl, aryl, F, Cl, CN, CO.sub.2H or NH.sub.2;
and
[0019] R.sup.4 is H, OH, alkyl, aryl, --COO-alkyl, CONH.sub.2,
CONH-alkyl, O--C(O)-alkyl, O--C(O)-aryl or alkoxy;
[0020] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 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 OH, --COO-alkyl, CONH.sub.2, CONH-alkyl,
O--C(O)-alkyl, O--C(O)-aryl alkoxy and NO; or R.sub.3 and R.sub.4
together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; or R.sub.4 and R.sub.5 together
with the nitrogen to which they are attached form a pyrrolidino,
piperidino, piperazino, azetidino, morpholino, pyrrolino, or
thiomorpholino ring; wherein any ring formed by R.sub.3 and R.sub.4
or R.sub.4 and R.sub.5 is optionally substituted with one or more
hydroxyl, halo, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, or substituted alkynyl; and
[0021] R.sub.a, R.sub.b, and R.sub.c are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl 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, pyrrolino, 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,
pyrrolino, or thiomorpholino ring;
[0022] or a pharmaceutically acceptable salt or prodrug
thereof.
[0023] Certain compounds of formula I are novel. Accordingly, the
invention also provides novel compounds of formula I as described
herein as well as pharmaceutically acceptable salts and prodrugs
thereof. For example, in one embodiment, the invention provides a
compound of the formula:
##STR00002##
wherein:
[0024] R is OR.sub.a, SR.sub.a, NR.sub.eR.sub.f,
NR.sub.aNR.sub.bR.sub.c, alkyl, alkenyl, alkynyl, aryl,
(CH.sub.2).sub.nNR.sub.aR.sub.b, (CH.sub.2).sub.nOR.sub.a,
C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.a)CO.sub.2R.sub.b,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.a, CONR.sub.aR.sub.b, NHC(.dbd.NR.sub.a)NHR.sub.b,
NR.sub.aOR.sub.b, NR.sub.aNO, NHCONHR.sub.a,
NR.sub.aN.dbd.NR.sub.b, NR.sub.aN.dbd.CHR.sub.b,
NR.sub.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
NR.sub.aC(O)OR.sub.b, CH.dbd.N--OR.sub.a,
NR.sub.aC(.dbd.NH)NR.sub.bR.sub.c,
NR.sub.aC(O)NR.sub.bNR.sub.CR.sub.d, O--C(O)R.sub.a,
OC(O)--OR.sub.a, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.aR.sub.b,
SNR.sub.aR.sub.b, S--ONR.sub.aR.sub.b, or
SO.sub.2NR.sub.aR.sub.b;
[0025] n is 0, 1, 2, 3, 4, or 5;
[0026] 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;
[0027] R.sup.2 is H and R.sup.3 is OH; or R.sup.2 is OH and R.sup.3
is H;
[0028] R.sup.4 is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--;
[0029] R.sup.5 is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--
[0030] R.sub.a, R.sub.b, R.sub.c, and R.sub.d are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl 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, pyrrolino, 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,
pyrrolino, or thiomorpholino ring;
[0031] R.sub.e is alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic, aryl, acyl, SO.sub.2-alkyl or NO; and R.sub.f is H,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl and NO; or R.sub.e and R.sub.f together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino
ring; which ring is optionally substituted with one or more halo,
hydroxyl, alkyl, alkenyl, or alkynyl;
[0032] wherein any alkyl, cycloalkyl, alkenyl, alkynyl, or acyl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkoxy, acyl, acylamino, acyloxy, oxyacyl,
amino, substituted amino, aminoacyl, aryl, aryloxy, cyano, halogen,
hydroxyl, nitro, N.sub.3, carboxyl, carboxyl esters, thiol,
thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl,
thioheterocyclic, cycloalkyl, heteroaryl, and heterocyclic;
[0033] and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl,
acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic;
[0034] or a pharmaceutically acceptable salt or prodrug
thereof.
[0035] In another embodiment the invention provides a method for
inhibiting an HCV 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.
[0036] In another embodiment the invention 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 agents, immune
modulators, or interferon inducers.
[0037] In another embodiment the invention provides a method for
treating hepatitis C 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.
[0038] In another embodiment the invention provides a method for
inhibiting an HCV 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.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0039] 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, glycollic, 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] The term "alkoxy" refers to the group alkyl-O--.
[0047] 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).
[0048] 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, alkenyl, and alkynyl.
[0049] The term "acyloxy" as used herein refers to the groups
alkyl-C(O)O--, alkenyl-C(O)O--, alkynyl-C(O)O--, aryl-C(O)O--,
cycloalkyl-C(O)O--, heteroaryl-C(O)O--, and
heterocyclic-C(O)O--.
[0050] The term "oxyacyl" as used herein refers to the groups
alkyl-OC(O) alkenyl-OC(O)--, alkynyl-OC(O) aryl-OC(O)--,
cycloalkyl-OC(O)--, heteroaryl-OC(O)--, and
heterocyclic-OC(O)--.
[0051] The term "amino" as used herein refers to the group
--NH.sub.2.
[0052] 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.
[0053] The term "aminoacyl" as used herein refers to the groups
--NZ.sub.3C(O)alkyl, --NZ.sub.3C(O)cycloalkyl,
--NZ.sub.3C(O)alkenyl, --NZ.sub.3C(O)alkynyl, --NZ.sub.3C(O)aryl,
--NZ.sub.3C(O)heteroaryl, and --NZ.sub.3C(O)heterocyclic, where
Z.sub.3 is hydrogen or alkyl.
[0054] 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.
[0055] 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.
[0056] The term "carboxyl" as used herein refers to --COOH or salts
thereof.
[0057] The term "carboxyl esters" as used herein refers to the
groups-C(O)O-alkyl, and --C(O)O-aryl.
[0058] 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.
[0059] The term "cycloalkoxy" as used herein refers to
--O-cycloalkyl groups.
[0060] The term "formyl" as used herein refers to HC(O)--.
[0061] The term "halogen" as used herein refers to fluoro, chloro,
bromo and iodo.
[0062] The term "heteroaryl" as used herein refers to an aromatic
group of from 5 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.
[0063] The term "heteroaryloxy" as used herein refers to the group
--O-heteroaryl.
[0064] The term "heterocycle" or "heterocyclic" refers to a
saturated or unsaturated group (but not heteroaryl) having a single
ring or multiple condensed rings, from 3 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 atoms may also be
present in their oxidized forms.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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, 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.
[0069] 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.
[0070] 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.
[0071] The term "substituted alkoxy" as used herein refers to the
group substituted alkyl-O--.
[0072] 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)--.
[0073] 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.
[0074] The term "substituted aryloxy" as used herein refers to
substituted aryl-O-groups.
[0075] 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.
[0076] The term "substituted cycloalkoxy" as used herein refers to
--O-substituted cycloalkyl groups.
[0077] 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.
[0078] The term "substituted heteroaryloxy" as used herein refers
to the group --O-substituted heteroaryl.
[0079] 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.
[0080] The term "thiol" as used herein refers to the group
--SH.
[0081] The term "thioalkyl" or "alkylthioether" or "thioalkoxy"
refers to the group-S-alkyl.
[0082] The term "thiocycloalkyl" as used herein refers to the group
--S-cycloalkyl.
[0083] The term "thioaryl" as used herein refers to the group
--S-aryl.
[0084] The term "thioheteroaryl" as used herein refers to the group
--S-heteroaryl.
[0085] The term "thioheterocyclic" as used herein refers to the
group --S-heterocyclic.
[0086] 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, 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 one of the twenty
naturally occurring L amino acids.
[0087] Sugars described herein may either be in D or L
configuration.
[0088] Specific values listed below for radicals, substituents, and
ranges, are for illustration only; they do not exclude other
defined values or other values within defined ranges for the
radicals and substituents
[0089] A specific value for R is OR.sub.a, Cl, SR.sub.a,
NR.sub.eR.sub.f, aryl or NR.sub.aNR.sub.bR.sub.c; wherein R.sub.a,
R.sub.b, R.sub.c, and R.sub.d are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic, aryl, acyl, SO.sub.2-alkyl and NO; or R.sub.b and
R.sub.c together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; R.sub.e is alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl or
NO; and R.sub.f is H, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic, aryl, acyl, SO.sub.2-alkyl and NO; or R.sub.e and
R.sub.f together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; which ring is optionally
substituted with one or more halo, hydroxyl, alkyl, alkenyl, or
alkynyl.
[0090] A specific value for R is hydroxy, chloro, methoxy,
mercapto, methylthio, methylamino, isopropylamino, propylamino,
ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino,
1-(2-hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino,
azetidino, pyrrolidino, imidazolylpropylamino, pyrrolino,
morpholino, piperazino, hydroxyethylamino, bis-hydroxyethylamino,
hydroxypropylamino, hydroxyethylpyrrolidino, or
1-methyl-2-hydroxyethylamino.
[0091] A specific value for R.sup.1 is NR.sub.eR.sub.f.
[0092] A specific compound is
4-methylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Ethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Isopropylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-Dimethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-n-Propylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-3-pyrrolino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(2-hydroxymethylpyrrolidino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyri-
midine;
4-(3-N-imidazolyl-n-propylamino)-7-.beta.-(D-ribofuranosyl)-furo[3-
,2-d]pyrimidine;
4-N-morpholino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-N-piperazino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine;
4-(N-bis-hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimid-
ine;
4-(3-hydroxypropylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimi-
dine; or
4-(2-hydroxy-1-methyl-ethylamino)-7-.beta.-(D-ribofuranosyl)-furo-
[3,2-d]pyrimidine;
or a pharmaceutically acceptable salt or prodrug thereof.
[0093] In one embodiment, the invention excludes compounds of
formula I wherein Y is S; when R is --NH.sub.2, --OH, --SH, or
--SCH.sub.3; R.sup.1 is hydrogen; and R.sup.2 is non-phosphorylated
ribose; as well as compounds of formula I wherein Y is O; when R is
--NH.sub.2; R.sup.1 is hydrogen; and R.sup.2 is non-phosphorylated
ribose.
[0094] In another embodiment the invention excludes compounds of
formula I wherein Y is S; R is --NH.sub.2, --OH, --SH, or
--SCH.sub.3; R.sup.1 is hydrogen; and R.sup.2 is ribose; as well as
compounds of formula I wherein Y is O; R is --NH.sub.2; R.sup.1 is
hydrogen; and R.sup.2 is ribose. In another embodiment, the
invention excludes compounds of formula I wherein R is --SH, --OH,
--S-alkyl, --O-alkyl, or NR.sub.3R.sub.4; R.sub.3 and R.sub.4 are
each H or alkyl; and R.sup.2 has the following formula:
##STR00003##
wherein: one of R.sup.300 and R.sup.304 is H and the other is H or
OH; R.sup.302 is OH, alkyl-O--, alkylC(.dbd.O)O--, alkyl-S--, or
alkylC(.dbd.O)--S--; R.sup.303 is H; and Z.sup.300 is OH,
alkyl-O--, alkylC(.dbd.O)O--, alkyl-S--, or
alkylC(.dbd.O)--S--.
[0095] In another embodiment, the invention excludes compounds of
formula I wherein R.sup.2 has the following formula:
##STR00004##
wherein: one of R.sup.300 and R.sup.304 is H and the other is H or
OH; R.sup.302 is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--; R.sup.303 is H; and Z.sup.300 is OH,
alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or alkylC(.dbd.O)--S--.
[0096] In one embodiment of the invention R.sup.2 is:
##STR00005##
[0097] In one embodiment of the invention R.sup.2 is:
##STR00006##
[0098] In one embodiment of the invention R.sup.2 is:
##STR00007##
[0099] In one embodiment of the invention R.sup.3 is H.
[0100] In one embodiment of the invention the compound of formula I
has the following formula:
##STR00008##
wherein:
[0101] Y is O or S;
[0102] R is OR.sub.3, SR.sub.3, NR.sub.3R.sub.4,
NR.sub.3NR.sub.4R.sub.5, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, (CH.sub.2).sub.n--CH(NHR.sub.3)CO.sub.2R.sub.4,
Cl, F, Br, I, CN, COOR.sub.3, CONR.sub.3R.sub.4,
NHC(.dbd.NR.sub.3)NHR.sub.4, NR.sub.3OR.sub.4, NR.sub.3NO,
NHCONHR.sub.3, NR.sub.3N.dbd.NR.sub.4, NR.sub.3N.dbd.CHR.sub.4,
NR.sub.3C(O)NR.sub.4R.sub.5, NR.sub.3C(S)NR.sub.4R.sub.5,
NR.sub.3C(O)OR.sub.4, CH.dbd.N--OR.sub.3,
NR.sub.3C(.dbd.NH)NR.sub.4R.sub.5,
NR.sub.3C(O)NR.sub.4NR.sub.5R.sub.6, O--C(O)R.sub.3,
OC(O)--OR.sub.3, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.3R.sub.4,
SNR.sub.3R.sub.4, S--ONR.sub.3R.sub.4, or
SO.sub.2NR.sub.3R.sub.4;
[0103] n is 0-5;
[0104] R.sup.1 is H, NR.sub.3R.sub.4, Cl, F, OR.sub.3, SR.sub.3,
NHCOR.sub.3, NHSO.sub.2R.sub.3, NHCONHR.sub.3, CN, alkyl, aryl,
ONR.sub.3R.sub.4, or NR.sub.3C(O)OR.sub.4;
[0105] R.sup.2 is ribose, 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; and
[0106] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 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 and NO; or R.sub.3 and R.sub.4 together with
the nitrogen to which they are attached form a pyrrolidino,
piperidino, piperazino, azetidino, morpholino, or thiomorpholino
ring; or R.sub.4 and R.sub.5 together with the nitrogen to which
they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, or thiomorpholino ring;
[0107] or a pharmaceutically acceptable salt or prodrug
thereof.
[0108] In one embodiment of the invention the compound of formula I
has the
##STR00009##
wherein [0109] X.dbd.N or CH; [0110] Y.dbd.O, S or N--R.sup.4;
[0111] R.dbd.OR.sup.5, NHR.sup.4, NR.sup.4R.sup.5, NHNHR.sup.4,
NR.sup.4NHR.sup.5, SR.sup.5, alkyl, aryl, Cl, NR.sup.4OR.sup.5,
NR.sup.4NO, or NHCONHR.sup.4; [0112] R.sup.1.dbd.H, NHR.sup.4, Cl,
F, OR.sup.4, SR.sup.4, NHCOR.sup.4, NHSO.sub.2R.sup.4,
NHCONHR.sup.4, CN, alkyl, aryl, or NR.sup.4R.sup.5; [0113]
R.sup.2=ribose, 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; [0114]
R.sup.3.dbd.H, alkyl, aryl, F, Cl, CN, CO.sub.2H or NH.sub.2;
[0115] R.sup.4.dbd.H, OH, alkyl, aryl, --COO-alkyl, CONH.sub.2,
CONH-alkyl, O--C(O)-alkyl, O--C(O)-aryl or alkoxy; [0116]
R.sup.5=alkyl, aryl, OH or alkoxy.
[0117] In one embodiment of the invention the compound of formula I
has the formula:
##STR00010##
wherein:
[0118] R is OR.sub.a, SR.sub.a, NR.sub.eR.sub.f,
NR.sub.aNR.sub.bR.sub.c, alkyl, alkenyl, alkynyl, aryl,
(CH.sub.2).sub.nNR.sub.aR.sub.b, (CH.sub.2).sub.nOR.sub.a,
C(.dbd.NR.sub.a)NR.sub.bR.sub.c,
(CH.sub.2).sub.n--CH(NHR.sub.a)CO.sub.2R.sub.b,
(CH.sub.2).sub.n--S-alkyl, (CH.sub.2).sub.n--S-aryl, Cl, F, Br, I,
CN, COOR.sub.a, CONR.sub.aR.sub.b, NHC(.dbd.NR.sub.a)NHR.sub.b,
NR.sub.aOR.sub.b, NR.sub.aNO, NHCONHR.sub.a,
NR.sub.aN.dbd.NR.sub.b, NR.sub.aN.dbd.CHR.sub.b,
NR.sub.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
NR.sub.aC(O)OR.sub.b, CH.dbd.N--OR.sub.a,
NR.sub.aC(.dbd.NH)NR.sub.bR.sub.c,
NR.sub.aC(O)NR.sub.bNR.sub.cR.sub.d, O--C(O)R.sub.a,
OC(O)--OR.sub.a, ONH--C(O)O-alkyl, ONHC(O)O-aryl, ONR.sub.aR.sub.b,
SNR.sub.aR.sub.b, S--ONR.sub.aR.sub.b, or
SO.sub.2NR.sub.aR.sub.b;
[0119] n is 0, 1, 2, 3, 4, or 5;
[0120] 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;
[0121] R.sup.2 is H and R.sup.3 is OH; or R.sup.2 is OH and R.sup.3
is H;
[0122] R.sup.4 is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--;
[0123] R.sup.5 is OH, alkyl-O--, alkylC(.dbd.O)O, alkyl-S--, or
alkylC(.dbd.O)--S--
[0124] R.sub.a, R.sub.b, R.sub.c, and R.sub.d are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO.sub.2-alkyl 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, pyrrolino, 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,
pyrrolino, or thiomorpholino ring;
[0125] R.sub.e is alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic, aryl, acyl, SO.sub.2-alkyl or NO; and R.sub.f is H,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl,
SO.sub.2-alkyl and NO; or R.sub.e and R.sub.f together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino
ring; which ring is optionally substituted with one or more halo,
hydroxyl, alkyl, alkenyl, or alkynyl;
[0126] wherein any alkyl, cycloalkyl, alkenyl, alkynyl, or acyl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkoxy, acyl, acylamino, acyloxy, oxyacyl,
amino, substituted amino, aminoacyl, aryl, aryloxy, cyano, halogen,
hydroxyl, nitro, N.sub.3, carboxyl, carboxyl esters, thiol,
thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl,
thioheterocyclic, cycloalkyl, heteroaryl, and heterocyclic;
[0127] and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl,
acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic. Representative compounds of this formula were found
to be particularly useful for treating HCV.
Prodrugs
[0128] 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, or aryloxy group.
[0129] 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-linked amino acid.
[0130] 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).
[0131] 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.z--N--; 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.
[0132] In another embodiment the prodrug comprises one of more
groups of formula:
##STR00011##
wherein:
[0133] R.sub.15 is H, alkyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, and an amino acid;
[0134] R.sub.16 is H, monocyclic aryl, or 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;
[0135] R.sub.18 and R.sub.19 are each independently H, alkyl, aryl,
aralkyl, monocyclic aryl or 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, aralkyl, monocyclic aryl or monocyclic heteroaryl;
and
[0136] R.sub.20 is alkyl, aryl, or arylalkyl;
[0137] R.sub.21 is H, alkyl, aryl, or arylalkyl;
[0138] R.sub.22 is H or lower acyl;
[0139] p is an integer from 2-3;
[0140] wherein any alkyl, cycloalkyl, alkenyl, alkynyl, or acyl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkoxy, acyl, acylamino, acyloxy, oxyacyl,
amino, substituted amino, aminoacyl, aryl, aryloxy, cyano, halogen,
hydroxyl, nitro, N.sub.3, carboxyl, carboxyl esters, thiol,
thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl,
thioheterocyclic, cycloalkyl, heteroaryl, and heterocyclic;
[0141] and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl,
acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N.sub.3, carboxyl,
carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic.
[0142] 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, alkyl, aryl, alkenyl, alkynyl,
heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl
or cycloalkenyl groups as defined earlier. [0143] (a) Carboxamides,
represented as --NHC(O)R.sub.p [0144] (b) Carbamates, represented
as --NHC(O)OR.sub.p [0145] (c) (Acyloxy)alkyl Carbamates,
represented as NHC(O)OROC(O)R.sub.p [0146] (d) Enamines,
represented as --NHCR(.dbd.CHCO.sub.2R.sub.p) or
--NHCR(.dbd.CHCONR.sub.pR.sub.p) [0147] (e) Schiff Bases,
represented as --N.dbd.CR.sub.pR.sub.p [0148] (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).
[0149] Prodrug forms of carboxyl-bearing compounds include
esters
[0150] (--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.
##STR00012##
Synthetic Processes
[0151] Processes for preparing compounds of formula I, or
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.
[0152] 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.
[0153] 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.
Isomers and Physical Forms
[0154] 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 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.
[0155] It will be appreciated that sugars can exist in .alpha.- and
.beta.-forms. The invention includes compounds of formula I
comprising sugars in both .alpha.- and .beta.-forms. In one
embodiment, the sugars are in the C-1 .beta.-form.
[0156] For example, it would be known in the field of chemistry
that a compound of the following formula:
##STR00013##
wherein R is OH would form a tautomer of the following formula:
##STR00014##
Accordingly, the invention includes all tautometric forms of the
compounds of formulae I.
Pharmaceutical Compositions, Modes of Administration and Methods of
Treatment
[0157] The present disclosure provides compounds of the general
formula (I) as detailed above which are inhibitors of HCV DNA
and/or RNA polymerases. Various forms of DNA and RNA viral
polymerases are inhibited by the compounds disclosed, such as but
not limited to HCV RdRps. The compounds of the present disclosure
therefore have utility in treating and/or preventing HCV infections
in a host and in treatment and/or preventing a variety of disease
states and/or conditions caused by or related to HCV infections. In
one embodiment, the compounds are useful in the above mentioned
treating and/or preventing by inhibiting a HCV RNA and DNA
polymerases.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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. 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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).
[0172] 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.
[0173] 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.
[0174] 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.
[0175] Useful embodiments of pharmaceutical dosage forms for
administration of the compounds according to the present invention
can be illustrated as follows.
[0176] 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.
[0177] 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.
[0178] 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. Appropriate aqueous and non-aqueous coatings may be
applied to increase palatability, improve elegance and stability or
delay absorption.
[0179] 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.
[0180] 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.
[0181] 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 HCV infection or treating a
disease state and/or condition caused by or related to such
infection. Such treatment need not be complete to be useful.
[0182] The methods of treating HCV infection or a disease state
and/or condition caused by or related to said infection may further
comprise administering a therapeutically effective amount of a
compound of the present invention in combination with a
therapeutically effective amount of an immune modulator, an
interferon inducer (see Kurimoto et. al. Bioorganic and Med. Chem.,
2003, 11, 5501-5508; and Hirota et. al. gJ. Med. Chem. 2002, 45,
5419-5422), or 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
monophosphate-dehydrognease, 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-.alpha.2b, a consensus interferon, and a purified
interferon-.alpha. product.
[0183] The ability of a compound to inhibit an HCV polymeras 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
[0184] Antiviral activity of the test compounds can be 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 are added to dividing cultures once daily for
three days. Media is changed with each addition of compound.
Cultures generally started the assay at 30-50% confluence and reach
confluence during the last day of treatment. Intracellular HCV RNA
levels and cytotoxicity are assessed 24 hours after the last dose
of compound.
[0185] Triplicate cultures for HCV RNA levels (on 48-well and
96-well plates) and cytotoxicity (on 96-well plates) are used. A
total of six untreated control cultures, and triplicate cultures
treated with .alpha.-interferon and ribavirin can serve as positive
antiviral and toxicity controls.
[0186] Intracellular HCV RNA levels can be 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 is
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. Representative compounds of the invention that
were tested in the above assay typically demonstrated an IC.sub.50
of less than about 100 .mu.m.
Compound Synthesis
[0187] 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 identified in the Schemes and Examples herein. The
following abbreviations are used herein.
Tr: trityl Bn: benzyl TBDPS: tert-butyldiphenylsilyl m-CPBA:
3-chloroperoxybenzoic acid TFA: trifluoroacetic acid TBDMSCl:
tert-butyldimethylsilyl chloride DMF: dimethylformamide THF:
tetrahydrofuran LDA: lithium diisopropylamine TEAB:
triethylammonium bicarbonate mMTrCl: monomethoxytrityl chloride
DMAP: dimethylaminopyridine DEAE: diethylaminoethyl-sepharose
CMA-80: Chloroform 80:MeOH 18:NH.sub.4OH:2
CMA-50: Chloroform 50:MeOH 40:NH.sub.4OH:10
[0188] Bz: benzoyl BnBr: benzyl bromide LiHMDS: lithium
hexamethyldisalazane TBDPSCl: tert-butyldiphenylsilyl chloride
DMSO: dimethylsulfoxide RMgBr: alkyl magnesium bromide DIBAL:
diisobutylaluminum hydride DBN: 1,5-diazabicyclo[4.3.0]non-5-ene
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene MeMgBr: methylmagnesium
bromide
[0189] Representative compounds can be prepared using the synthetic
procedures illustrated in Schemes 1-9 below.
##STR00015##
##STR00016##
##STR00017##
##STR00018##
##STR00019##
##STR00020##
##STR00021##
##STR00022##
##STR00023##
Cl is converted to the groups described in Scheme 8.
[0190] Appropriately protected starting materials 2 or 3 (Scheme
1), are either commercially available or can be prepared from the
known literature procedures. The description of synthetic schemes
1-9 follows.
Scheme 1, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.NH, R.dbd.NH.sub.2, R.sup.1.dbd.H, R.sup.2=any Group
Described, and R.sup.3.dbd.H:
[0191] Compound 3 (prepared from literature procedures or from 2 by
the reaction of NCCH.sub.2P(O)(OEt).sub.2 and sodium hydride), is
reacted with Brederick's reagent
[tert-butoxybis(dimethylamino)methane] to give 4, which on acidic
hydrolysis with acetic acid or trifluoroacetic acid generates
compound 5. Compound 5 is further reacted with amino acetonitrile
to give 6, where NH is protected with methoxycarbonyl and cyclized
in the presence of a base, such as DBU, and then NH is deprotected
with sodium carbonate in methanol to give desired cyclized product
7. The isomers of the cyclized product are separated by
chromatography or crystallization. Further cyclization of desired 7
with formamidine acetate and deprotection of the hydroxyl or amino
functionalities in R.sup.2 produces the desired targets 8.
Scheme 2, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.NH, R.dbd.OH, R.sup.1.dbd.H, R.sup.2=any Group Described, and
R.sup.3.dbd.H:
[0192] Compound 5 is reacted with
NH.sub.2CH.sub.2CO.sub.2C.sub.2H.sub.5 to give 9, which is then
cyclized with a base, such as DBU to give compound 10. The isomers
of the cyclized product are separated by chromatography or
crystallization. Further cyclization of desired 10 with formamidine
acetate followed by deprotection of the hydroxyl or amino
functionalities in R.sup.2 produces the desired target 11.
Scheme 3, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.S, R.dbd.NH.sub.2, R.sup.1.dbd.H, R.sup.2=any Group
Described, and R.sup.3.dbd.H:
[0193] Compound 5 is treated with methanesulfonyl chloride in the
presence of base and then reacted with acetylthioacetonitrile and
sodium carbonate to give compound 12, which on heating cyclizes to
13. The isomers of the cyclized product are separated by
chromatography or crystallization. Further cyclization of desired
13 with formamidine acetate followed by deprotection of the
hydroxyl or amino functionalities in R.sup.2 produces the desired
target 14.
Scheme 4, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.O, R.dbd.NH.sub.2, R.sup.1.dbd.H, R.sup.2=any Group
Described, and R.sup.3.dbd.H:
[0194] Compound 5 is treated with chloroacetonitrile in the
presence of potassium fluoride and 18-crown-6 to generate 15, which
on treatment with LDA cyclizes to desired 16. The isomers of the
cyclized product are separated by chromatography or
crystallization. Further cyclization of desired 16 with formamidine
acetate followed by deprotection of the hydroxyl or amino
functionalities in R.sup.2 produces the desired target 17.
Scheme 5, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.O, R.dbd.Cl, SH or S-alkyl, R.sup.1.dbd.H, R.sup.2=any Group
Described, and R.sup.3.dbd.H:
[0195] Compound 16 is treated with H.sub.2S gas to produce
thioamide 18, which on cyclization with formamidine acetate gives
compound 19. Further treatment of 19 with POCl.sub.3 generates
protected 20, which is a common intermediate for various
R-substituted compounds. Compounds 19 and 20, if deprotected
produces the targets 20, with R.dbd.SH and Cl. Compound 19 on
treating with alkyl halides may produce S-alkyl compounds also.
Scheme 6, Preparation of Compounds of Formula I wherein X.dbd.N,
Y.dbd.O, R.dbd.Cl, R.sup.1.dbd.H, R.sup.2=any Group Described, and
R.sup.3.dbd.H:
[0196] Compound 20 alternatively is produced through this Scheme.
The reaction of the sodium salt of compound 5 with bromo or
chlorodiethylmalonate generates 21, which on base treatment
cyclizes to give 22. The isomers of the cyclized product are
separated by chromatography or crystallization. Further cyclization
of desired 22 with formamidine acetate gives 23, which on treatment
with POCl.sub.3 generates protected 20, which is a common
intermediate for various R-substituted compounds. Compound 23, if
deprotected produces the targets, with R.dbd.OH. Compound 23 on
treating with alkyl halides may produce O-alkyl compounds also.
Scheme 7, Preparation of Compounds of formula I wherein X.dbd.N;
Y.dbd.O, S or NH; R.dbd.OH; R.sup.1.dbd.NH.sub.2, R.sup.2=any Group
Described, and R.sup.3.dbd.H:
[0197] Compound 24 is treated with
N,N'-bis-methoxycarbonyl-5-methylthiourea in the presence of
mercury (II) chloride to generate 25, which on treatment with base
for cyclization followed by deprotection of the hydroxyl or amino
functionalities in R.sup.2 produces the desired target 26.
Scheme 8, Preparation of Compounds of Formula I wherein X.dbd.N;
Y.dbd.O, S or NH; R.dbd.NHR.sup.4/NR.sup.4R.sup.5, Ar,
NR.sup.4OR.sup.5, NR.sup.4NHR.sup.5, NHNHR.sup.4, SR.sup.5 or
OR.sup.5; R.sup.1.dbd.H, R.sup.2=any Group Described, and
R.sup.3.dbd.H:
[0198] Compound 20, when Y.dbd.O is prepared as described in Scheme
5 and 6. When Y.dbd.S or NH, these are prepared from the
corresponding 13, 7 and 18 by the same methods used in Schemes 5
and 6. Compound 20 on treatment with i) amines, R.sup.4NH.sub.2 or
R.sup.4R.sup.5NH produces 28; ii) aryl boronic acids under Suzuki
coupling conditions generates 27; iii) alkoxyamines,
HNR.sup.4OR.sup.5 gives 33; iv) di-substituted hydrazines,
HNR.sup.4NHR.sup.5 produces 32; v) mono-substituted hydrazines,
NH.sub.2NHR.sup.4 gives 31; vi) thioalkoxide, R.sup.5SNa generates
30; and vii) alkoxides, R.sup.5ONa produces 29. The hydroxyl or
amino functionalities in R.sup.2 of these compounds are deprotected
under suitable conditions to afford the appropriate targets.
Scheme 9, Preparation of Compounds of Formula I wherein X.dbd.CH,
Y.dbd.O, NH or S, R.dbd.Cl or the Substituents as Described in
Scheme 8, R.sup.1.dbd.H, R.sup.2=any Group Described, and
R.sup.3.dbd.H:
[0199] Compound 34, when Y.dbd.O is the same compound as 18 in
Scheme 5. Compound 34 when Y.dbd.NH and S, are prepared from 7 and
13 by treatment with H.sub.2S gas. Compound 34 is converted to 35
by treating with (CH.sub.3).sub.2CH(CH.sub.2).sub.2ONO and
diiodomethane and iodo group of 35 is displaced with acetylenic
group to generate 36 by the reaction of trimethylsilylacetylene and
(PhCN).sub.2PdCl.sub.2 catalyst followed by acidic treatment.
Cyclization of 36 to 37 is achieved through dimethylamine treatment
in ethanol followed by aqueous acetic acid. Thio functionality in
37 is converted to chloro with POCl.sub.3 to give 38, a common
intermediate. Further treatment of 38 with the reagents described
in Scheme 8 followed by deprotection of amino and hydroxyl groups
in R.sup.2 yields the desired targets 38, where Cl is replaced by
different groups.
[0200] Comopunds can also be prepared as illustrated in the
following Schemes A-1 to D-2.
[0201] Preparation of R.sub.2--CH.sub.2CN Compounds:
##STR00024##
Preparation of Compounds of the Invention from R.sub.2CH.sub.2CN
Intermediates
[0202] In the following schemes, R.sub.2 is a sugar group bearing
one or more protecting groups.
##STR00025##
##STR00026##
##STR00027##
##STR00028##
##STR00029##
##STR00030##
Preparation of Monophosphates and Triphosphates of Nucleosides
(Represented by Example C-1)
[0203] The following Schemes illustrate the preparation of
compounds of formula I that have one or more phosphate groups. In
these Schemes, B represents the furopyrimidine base of formula I,
and B(P) represents the furopyrimidine base of formula I, bearing
one or more protecting groups.
##STR00031##
##STR00032##
Preparation of Prodrugs
[0204] The following Schemes illustrate the preparation of prodrugs
of the invention.
##STR00033##
##STR00034##
[0205] The invention will now be illustrated by the following
non-limiting Examples.
Example A-1
##STR00035##
[0206]
2-(3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-tetrahydrofuran-2-yl)acet-
onitrile (Scheme A-1)
[0207] Step 1: To a solution of D-ribose (61 g, 406.66 mmol) in
methanol (1 L) was added conc. sulfuric acid (6.1 mL) and stirred
at 4.degree. C. for 16 h. The reaction mixture was neutralized
using triethylamine (40 mL), concentrated to dryness and
co-distilled twice with 200 mL of toluene to remove trace amount of
water. This furnished 72 g of crude O-methyl-D-ribofuranose, which
was used as such for next step.
[0208] Step 2: To a slurry of NaH (65 g, 60%, 1.626 mol) in DMF
(200 mL) was added crude compound from Step 1 (72 g, 406.66 mmol)
in DMF (800 mL) over a period of 0.5 h, maintaining the temperature
below 5.degree. C. The anion formed was stirred at room temperature
for 30 min. Benzyl bromide (219.1 g, 1280.9 mmol) was added
dropwise over a period of 1 h maintaining temperature between
0-5.degree. C. The reaction was stirred at room temperature for 12
h (TLC analysis in 30% ethyl acetate/hexane showed complete
disappearance of starting material), was diluted with water (500
mL) and extracted with ethyl acetate (2.times.1 L). The combined
organic extracts were washed twice with water (1 L), brine (500
mL), and dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under vacuum to furnish crude residue. The crude
residue was purified by flash chromatography (silica gel 1 kg),
eluting with ethyl acetate in hexanes to furnish 112 g (63.3%) of
desired product as an oil. .sup.1H NMR (DMSO-d.sub.6): .delta.
7.36-7.27 (m, 15H), 4.92 (s, 1H), 4.66-4.44 (m, 6H), 4.12-4.07 (m,
1H), 3.97 (dd, J=6.78 and 4.5 Hz, 1H), 3.91 (d, J=4.5 Hz, 1H), 3.55
(dd, J=10.73 and 3.4 Hz, 1H), 3.42 (dd, J=10.7 and 6.0 Hz, 1H),
3.21 (s, 3H).
[0209] Step 3: To a solution of product from Step 2 (114 g, 262.35
mmol) in dioxane (250 mL) was added 4 N HCl (250 mL) and heated at
reflux for 4 h. The reaction mixture was allowed to attain room
temperature and diluted with ethyl acetate (1.5 L). The aqueous
layer was separated and extracted with ethyl acetate (3.times.1 L).
The organic layers were combined, washed with water (2.times.500
mL), saturated aqueous NaHCO.sub.3 (250 mL), water (500 mL), and
brine (250 mL), and dried over MgSO.sub.4 and filtered. The
filtrate was concentrated under vacuum to furnish crude product.
The crude product was purified by flash chromatography (silica gel
1.5 kg, eluting with ethyl acetate in hexanes 0 to 30%) to furnish
starting material (9.9 g), and 85.3 g (45%) of desired product
(mixture of isomers) as an oil. .sup.1H NMR (DMSO-d.sub.6): .delta.
7.32-7.25 (m, 15H), 6.57 (d, J=4.8 Hz, 0.7H, D.sub.2O
exchangeable), 5.82 (d, J=7.7 Hz, 0.3H), 5.26 (dd, J=7.7, 3.5 Hz,
0.3H), 5.21 (dd, J=4.8, 1.3 Hz, 0.7H), 4.70-4.43 (m, 6H), 4.16 (q,
J=4.1 Hz, 0.3H), 4.06-3.96 (m, 1.3H), 3.93-3.87 (m, 0.7H), 3.80
(dd, J=4.3, 1.5 Hz, 0.7H), 3.58-3.41 (m, 2H);
[0210] Step 4: To a stirred solution of product from Step 3 (15 g,
35.67 mmol) in THF (150 mL) was added diethyl
(cyanomethyl)phosphonate (6.95 g, 39.23 mmol) at room temperature
followed by lithium bis(trimethylsilyl)amide (39.2 mL, 1M solution
in THF) addition at -78.degree. C. The reaction mixture was stirred
at -78.degree. C. for about 20 min and at 0.degree. C. for 1.5 h
and then was quenched by adding water (50 mL). The reaction was
extracted with ether (2.times.200 mL), washed with water
(2.times.50 mL), brine (1.times.50 mL), and dried over Mg SO.sub.4.
After filtration, the filtrate was concentrated and purified by
flash chromatography using 0 to 30% ethyl acetate in hexanes to
give 10.79 g (68.2%) of desired compound as a mixture of isomers as
an oil. MS (ES.sup.+) 444.33 (M+1).
Example B-1
##STR00036##
[0211]
7-.beta.-(2',3',5'-Tri-O-benzyl-D-ribofuranosyl)-furo[3,2-d]pyrimid-
in-4(3H)-one (Scheme B-1)
[0212] Step 1: To a stirred solution of compound from Step 4 of
example A-1,
(3S,4R,5R)-(3,4-bis-benzyloxy-5-benzyloxymethyl-tetrahydro-furan-2-y-
l)-acetonitrile (10.7 g, 24.12 mmol) in DMF (150 mL) was added
tert-butoxybis(dimethylamino)methane (21.02 g, 120.62 mmol) at room
temperature and stirred for 12 h. The reaction mixture was diluted
with toluene (700 mL) and washed with water (2.times.250 mL), brine
(1.times.50 mL) and dried (MgSO.sub.4). After filtration, the
filtrate was concentrated to give (13.8 g) of desired product,
which was used as such for next step.
[0213] Step 2: The compound from Step 1 (13.8 g, 24.12 mmol) was
dissolved in chloroform (250 mL), trifluoroacetic acid (4.59 g,
40.29 mmol) and water (137 mL) at room temperature and stirred for
18 h. The organic layer was separated and the aqueous layer was
extracted with chloroform (2.times.200 mL). The combined organic
extracts were washed with water (2.times.200 mL), brine
(1.times.100 mL), and dried (MgSO.sub.4). After filtration, the
filtrate was concentrated to afford 12.59 g of desired product. A
small amount was taken out and purified on silica gel column using
ethyl acetate and hexanes. MS (ES.sup.+) 494.20 (M+23), (ES.sup.-)
470.28 (M-1); Anal. Calcd for C.sub.29H.sub.29NO.sub.5.0.75;
H.sub.2O: C, 71.80; H, 6.33; N, 2.88. Found: C, 71.95; H, 6.04; N,
2.88.
[0214] Step 3: To a stirred solution of product from Step 2, (186.5
g, 395.4 mmol) in DMF (1500 mL) was added sodium hydride (19.7 g,
60%, 494.3 mmol) in four portions at 0.degree. C. over a period of
1.5 h followed by 2-bromodiethylmalonate (118.1 g, 494.3 mmol) over
a period of 30 min at 0.degree. C. and stirred at room temperature
for 12 h. After diluting with water (1000 mL), the reaction mixture
was extracted with ethyl acetate (3.times.2000 mL). The combined
organic extracts were washed with water (2.times.1000 mL), brine
(1.times.200 mL), and dried (MgSO.sub.4). After filtration, the
filtrate was concentrated to give 296 g of crude desired product,
which was used in the next reaction without further
purification.
[0215] Step 4: To a compound from Step 3 (296 g, crude) in EtOH
(1000 mL) was added 1,5-diazabicyclo[4.3.0]non-5-ene (58.9 g,
474.48 mmol) at room temperature and stirred for 18 h. The reaction
mixture was concentrated and the residue was dissolved in ethyl
acetate (4000 mL), washed with water (2.times.1000 mL), brine
(2.times.500 mL), and dried (MgSO.sub.4). After filtration, the
filtrate was concentrated and the crude residue was purified by
flash chromatography on silica gel using ethyl acetate and hexanes
to afford 29 g, (13.1%) of the desired product as light brown
oil.
[0216] Step 5: To a stirred solution of compound from Step 4 (29.0
g, 52.04 mmol) in EtOH (600 mL) was added formamidine acetate (135
g, 1301 mmol) at room temperature and heated at reflux for four
days and the solid material was removed by filtration and filtrate
was concentrated. The residue was dissolved in chloroform (400 mL),
washed with water (2.times.100 mL), brine (1.times.100 mL), and
dried (MgSO.sub.4). The crude residue was purified by flash
chromatography on silica gel using CMA-80 in chloroform (0 to 20%)
to afford 12 g (42.8%) of the desired product (12 g, 42.8%) as a
colorless crystalline solid; mp 88-100.degree. C. .sup.1H NMR
(DMSO-d.sub.6): .delta. 12.66 (bs, 1H, D.sub.2O exchangeable), 8.11
(s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.33-7.25 (m, 15H), 5.11 (d, J=4.8
Hz, 1H), 4.61 (s, 2H), 4.58-4.48 (m, 4H), 4.4 (t, J=4.7 Hz, 1H),
4.19-4.12 (m, 2H), 3.63 (ddd, J=23.3, 10.7. 3.2 Hz, 2H); MS
(ES.sup.+) 539.43 (M+1), 561.42 (M+23), (ES.sup.-) 537.44 (M-1);
Anal. Calcd for C.sub.32H.sub.30N.sub.2O.sub.6: C, 71.36; H, 5.61;
N, 5.20. Found: C, 71.30; H, 5.54; N, 5.10.
Example B-2
##STR00037##
[0217]
4-Chloro-7-.beta.-(2',3',5'-tri-O-benzyl-D-ribofuranosyl)-furo[3,2--
d]pyrimidine (Scheme B-2)
[0218] To a stirred solution of compound from Example B-1, Step 5,
(6.26 g, 11.62 mmol), benzyltriethylammonium chloride (5.29 g,
23.24 mmol), N,N-dimethylaniline (2.12 g, 17.43 mmol) in
acetonitrile (50 mL) was added phosphorous oxychloride (10.69 g,
69.74 mmol) at 80.degree. C. and further stirred at 80.degree. C.
for 30 min. Then the reaction was concentrated to dryness,
dissolved in chloroform (100 mL) and quenched with water (50 mL).
The organic layer was separated and aqueous layer was further
extracted with chloroform (2.times.50 mL). The combined chloroform
extracts were washed with water (2.times.100 mL), sat. NaHCO.sub.3
(1.times.50 mL), water (1.times.100 mL), and brine (1.times.50 mL),
and dried (MgSO.sub.4). After filtration, the filtrate was
concentrated and the residue was purified by flash chromatography
on silica gel column using ethyl acetate in hexanes (0 to 25%) to
afford 5.62 g (86.8%) of desired product as a colorless crystalline
solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.87 (s, 1H), 8.54 (s,
1H), 7.33-7.19 (m, 15H), 5.21 (d, J=5.1 Hz, 1H), 4.66-4.47 (m, 7H),
4.24-4.18 (m, 2H), 3.66 (ddd, J=23.1, 10.5. 3.5 Hz, 2H); Anal.
Calcd for C.sub.32H.sub.29Cl N.sub.2O.sub.5: C, 68.99; H, 5.24; Cl,
6.36; N, 5.02. Found: C, 69.12; H, 5.19; Cl, 6.30; N, 5.04.
General Method of Preparation of Compounds in Examples B-3 to
B-19
[0219] Step 1: A solution of chloro compound from example B-2 (1
equiv.), appropriate amine (6 equiv.), and triethylamine (20
equiv.) in ethanol was heated at 35 to 45.degree. C. for 5 h to 15
h. After concentration, the residue was partitioned between
chloroform or ethyl acetate and water. The organic layer was washed
with water and brine, dried over MgSO.sub.4. After filtration the
residue was purified by crystallization or on silica gel column
using appropriate solvent system.
[0220] Step 2: A solution of product from step 1 (1 equiv.) in
dichloromethane was treated with 1M solution of BCl.sub.3 in
dichloromethane (2 to 10 equiv.) at 0 to -78.degree. C. and stirred
for 1-3 h. The reaction mixture was quenched with methanol and
concentrated to dryness. The residue was co-evaporated with HCl and
ethanol mixture two times and with ethanol two times. The residue
was purified by re-crystallization or silica gel column using
appropriate solvent system.
Example B-3
##STR00038##
[0221]
4-Methylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0222] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.30 (s, 1H), 8.21 (s,
1H), 7.93 (d, J=4.7 Hz, 1H, D.sub.2O exchangeable), 5.80 (dd,
J=9.4, 3.3 Hz, 1H, D.sub.2O exchangeable), 5.05 (d, J=6.4 Hz, 1H,
D.sub.2O exchangeable), 4.88 (d, J=4.3 Hz, 1H), 4.77 (d, J=7.3, Hz,
1H, D.sub.2O exchangeable), 4.35-4.29 (m, 1H), 1.04-4.00 (m, 1H),
3.89 (dd, J=5.4, 2.6 Hz, 1H), 3.63 (td, J=12.0, 3.0 Hz, 1H),
3.52-3.44 (m, 1H), 2.97 (d, J=4.5 Hz, 3H); MS (ES.sup.+) 282.51
(M+1)
Example B-4
##STR00039##
[0223]
4-Ethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0224] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.21 (s,
1H), 8.00 (t, J=5.8 Hz, 1H, D.sub.2O exchangeable), 5.81 (d, J=10.1
Hz, 1H, D.sub.2O exchangeable), 5.04 (d, J=7.62 Hz, 1H, D.sub.2O
exchangeable), 4.68 (d, J=6.2 Hz, 1H, D.sub.2O exchangeable), 4.76
(d, J=7.3 Hz, 1H), 4.35-4.29 (m, 1H), 4.04-4.00 (m, 1H), 3.89 (dd,
J=5.4, 2.8 Hz, 1H), 3.63 (d, J=13.1 Hz, 1H), 3.54-3.46 (m, 3H),
1.18 (t, J=7.15 Hz, 3H); MS (ES.sup.+) 296.52 (M+1).
Example B-5
##STR00040##
[0225]
4-Isopropylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0226] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.21 (s,
1H), 7.84 (d, J=8.1 Hz, 1H, D.sub.2O exchangeable), 5.83 (bs, 1H,
D.sub.2O exchangeable), 5.03 (d, J=6.4 Hz, 1H, D.sub.2O
exchangeable), 4.88 (d, J=4.3 Hz, 1H, D.sub.2O exchangeable), 4.76
(d, J=7.3 Hz, 1H), 4.45-4.29 (m, 2H), 4.04-4.00 (m, 1H), 3.89 (dd,
J=5.2, 2.6 Hz, 1H), 3.63 (dd, J=12.0, 2.6 Hz, 1H), 3.53-3.44 (m,
1H), 1.21 (d, J=6.5 Hz, 6H); MS (ES) 308 (M-1).
Example B-6
##STR00041##
[0227]
4-Dimethylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0228] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (s, 1H), 8.24 (s,
1H), 5.76 (dd, J=9.4, 3.4 Hz, 1H, D.sub.2O exchangeable), 5.05 (d,
J=6.2 Hz, 1H, D.sub.2O exchangeable), 4.88 (d, J=4.5 Hz, 1H,
D.sub.2O exchangeable), 4.78 (d, J=7.3 Hz, 1H), 4.35-4.29 (m, 1H),
4.04-4.00 (m, 1H), 3.89 (dd, J=5.8, 3.0 Hz, 1H), 3.63 (dd, J=12.4,
3.4 Hz, 1H), 3.52-3.44 (m, 1H), 3.33 (s, 6H); MS (ES.sup.+) 296.51
(M+1).
Example B-7
##STR00042##
[0229]
4-n-Propylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-c]pyrimidine
(Scheme B-3)
[0230] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.21 (s,
1H), 8.03 (bs, 1H, D.sub.2O exchangeable), 5.81 (dd, J=9.8, 3.4 Hz,
1H, D.sub.2O exchangeable), 5.04 (d, J=6.4 Hz, 1H, D.sub.2O
exchangeable), 4.88 (d, J=4.3 Hz, 1H, D.sub.2O exchangeable), 4.76
(d, J=7.3 Hz, 1H), 4.36-4.29 (m, 1H), 4.04-4.00 (m, 1H), 3.89 (dd,
J=5.4, 2.6 Hz, 1H), 3.65-3.60 (m, 1H), 3.52-3.40 (m, 3H), 1.65-1.54
(m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS (ES.sup.+) 310 (M+1),
(ES.sup.-) 308.48 (M-1).
Example B-8
##STR00043##
[0231]
4-Cyclopropylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0232] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.31 (s, 1H), 8.23 (s,
1H), 8.14 (d, J=3.5 Hz, 1H, D.sub.2O exchangeable), 5.77 (dd,
J=9.4, 3.4 Hz, 1H, D.sub.2O exchangeable), 5.05 (d, J=6.4 Hz, 1H,
D.sub.2O exchangeable), 4.88 (d, J=4.3 Hz, 1H, D.sub.2O
exchangeable), 4.77 (d, J=7.3 Hz, 1H), 4.36-4.29 (m, 1H), 4.04-4.00
(m, 1H), 3.89 (dd, J=5.8, 3.2 Hz, 1H), 3.63-3.44 (m, 2H), 3.01-2.92
(m, 1H), 0.79-0.73 (m, 2H), 0.62-0.57 (m, 2H); MS (ES.sup.+) 08.52
(M+1), (ES) 306.46 (M-1).
Example B-9
##STR00044##
[0233] 4-Azetidino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0234] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (s, 1H), 8.23 (s,
1H), 5.72 (dd, J=9.2, 3.2 Hz, 1H, D.sub.2O exchangeable), 5.04 (d,
J=6.4 Hz, 1H, D.sub.2O exchangeable), 4.88 (d, J=4.5 Hz, 1H,
D.sub.2O exchangeable), 4.77 (d, J=7.3 Hz, 1H), 4.35-4.28 (m, 5H),
4.03-3.99 (m, 1H), 3.88 (dd, J=5.8, 3.0 Hz, 1H), 3.65-3.44 (m, 2H),
2.49-2.40 (m, 2H); MS (ES) 308.52 (M+1).
Example B-10
##STR00045##
[0235]
4-Pyrrolidino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0236] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.33 (s, 1H), 8.29 (s,
1H), 5.91 (bs, 1H, D.sub.2O exchangeable), 5.11 (d, J=6.2 Hz, 1H,
D.sub.2O exchangeable), 4.95 (d, J=4.3 Hz, 1H, D.sub.2O
exchangeable), 4.84 (d, J=7.3 Hz, 1H), 4.41-4.35 (m, 1H), 4.10-4.01
(m, 1H), 3.96 (dd, J=5.8, 3.0 Hz, 1H), 3.94-3.67 (m, 5H), 3.58-3.51
(m, 1H), 2.07-1.97 (bs, 4H); MS (ES.sup.+) 322.54 (M+1).
Example B-11
##STR00046##
[0237]
4-(N-3-Pyrrolino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0238] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.74 (s, 1H), 8.54 (s,
1H), 6.10 (br, 2H, olefinic protons), 4.91 (d, J=6.5 Hz, 1H), 4.84
(br, 2H), 4.55 (br, 2H), 4.01-4.10 (m, 2H), 3.88-3.96 (m, 1H),
3.62-3.64 (m, 2H); MS (ES.sup.+) 342.33 (M+Na) and (ES.sup.-) 318
(M-1).
Example B-12
##STR00047##
[0239]
4-(2-Hydroxymethylpyrrolidino)-7-.beta.-(D-ribofuranosyl)-furo[3,2--
d]pyrimidine (Scheme B-3)
[0240] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.72 (s, 1H), 8.55 (s,
1H), 4.91 (d, J=6.0 Hz, 1H), 4.46-4.72 (m, 1H), 3.74-4.10 (m, 5H),
3.42-3.69 (m, 4H), 1.88-2.32 (m, 4H); MS (ES.sup.+) 374.34 (M+Na)
and (ES.sup.-) 350.35 (M-1).
Example B-13
##STR00048##
[0241]
4-(3-N-Imidazolyl-n-propylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,-
2-d]pyrimidine (Scheme B-3)
[0242] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.29 (s, 1H), 8.23 (s,
1H), 8.09 (br, 1H), 7.66 (br, 1H), 7.21 (br, 1H), 6.89 (br, 1H),
5.80 (m, 1H), 5.05 (d, J=6.4 Hz, 1H), 4.90 (d, J=4.33 Hz, 1H), 4.77
(d, J=7.34 Hz, 1H), 4.29-4.35 (m, 1H), 4.0 (m, 3H), 3.87-3.90 (m,
1H), 3.60-3.66 (m, 1H), 3.4-3.53 (m, 3H), 1.98-2.03 (m, 2H); MS
(ES.sup.+) 376.36 (M+1).
Example B-14
##STR00049##
[0243]
4-N-Morpholino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0244] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.71 (s, 1H), 8.53 (s,
1H), 4.91 (d, J=6.5 Hz, 1H), 4.0-4.15 (m, 6H), 3.91-3.94 (m, 1H),
3.76-3.81 (m, 4H), 3.66 (dd, J=12 and 3 Hz 1H), 3.60 (dd, J=12 and
3 Hz, 1H); MS (ES.sup.+) 338.38 (M+1) and (ES.sup.-) 336.38
(M-1).
Example B-15
##STR00050##
[0245]
4-N-piperazino-7-.beta.(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0246] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.30 (s, 1H), 8.24 (s,
1H), 5.70 (m, 1H), 5.06 (br, 1H), 4.89 (br, 1H), 4.78 (d, J=7.15
Hz, 1H), 4.28-4.36 (m, 1H), 4.0 (br, 1H), 3.83-3.91 (m, 6H),
3.59-3.67 (m, 1H), 3.4-3.52 (m, 1H), 2.8 (m, 4H); MS (ES.sup.+)
337.4 (M+1) and (ES.sup.-) 335.38 (M-1).
Example B-16
##STR00051##
[0247]
4-(Hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimid-
ine (Scheme B-3)
[0248] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.22 (s,
1H), 7.94 (br, 1H), 5.8 (m, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.89 (d,
J=4.14 Hz, 1H), 4.78 (m, 1H), 4.76 (d, J=7.34 Hz, 1H), 4.29-4.36
(m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.4-3.66 (m, 6H); MS (ES.sup.+)
334.36 (M+Na) and (ES.sup.-) 310.38 (M-1).
Example B-17
##STR00052##
[0249]
4-(N-Bis-hydroxyethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]p-
yrimidine (Scheme B-3)
[0250] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.22 (s,
1H), 5.78 (m, 1H), 5.04 (d, J=6.21 Hz, 1H), 4.83-4.88 (m, 3H), 4.78
(d, J=7.34 Hz, 1H), 4.3-4.36 (m, 1H), 4.0 (m, 1H), 3.8-3.9 (m, 5H),
3.56-3.69 (m, 5H), 3.44-3.52 (m, 1H); MS (ES.sup.+) 356.38 (M+1)
and (ES.sup.-) 354.35 (M-1).
Example B-18
##STR00053##
[0251]
4-(3-Hydroxypropylamino)-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyri-
midine (Scheme B-3)
[0252] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.27 (s, 1H), 8.21 (s,
1H), 7.97 (br, 1H), 5.80 (m, 1H), 5.04 (d, J=6.4 Hz, 1H), 4.88 (d,
J=4.3 Hz, 1H), 4.76 (d, J=7.3 Hz, 1H), 4.52 (t, J=5.08 Hz, 1H),
4.29-4.36 (m, 1H), 4.0 (m, 1H), 3.88-3.90 (m, 1H), 3.60-3.66 (m,
1H), 3.42-3.56 (m, 5H), 1.74 (m, 2H); MS (ES.sup.+) 326.41 (M+1)
and (ES.sup.-) 324.41 (M-1).
Example B-19
##STR00054##
[0253]
4-(2-Hydroxy-1-methyl-ethylamino)-7-.beta.-(D-ribofuranosyl)-furo[3-
,2-d]pyrimidine (Scheme B-3)
[0254] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.26 (s, 1H), 8.22 (s,
1H), 7.68 (d, J=8.2 Hz, 1H), 5.80 (m, 1H), 5.04 (dd, J=6.4 and 1.5
Hz, 1H), 4.88 (d, J=4.3 Hz, 1H), 4.78 (m, 1H), 4.76 (d, J=7.3 Hz,
1H), 4.27-4.36 (m, 2H), 4.0 (m, 1H), 3.89 (m, 1H), 3.58-3.66 (m,
1H), 3.36-3.54 (m, 3H), 1.18 (d, J=6.78 Hz, 3H); MS (ES.sup.+)
348.37 (M+Na) and (ES.sup.-) 324.40 (M-1).
Example B-20
##STR00055##
[0255] 4-Phenyl-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0256] Step 1: To a suspension of 10% Pd--C (100 mg) in methanol
(50 mL) was added the product from example B-1 (3.0 g, 5.57 mmol)
and conc. HCl (0.5 mL) and the mixture was hydrogenated at 70 psi
for 16 h. The catalyst was removed by filtration and the filtrate
was concentrated to give
7-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-3H-furo[3,2--
d]pyrimidin-4-one (1.66 g), which was used as such for the next
step. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.24 (s, 1H), 8.12 (s,
1H), 5.03-4.07 (br, 3H, D.sub.2O exchangeable), 4.76 (d, J=6.4 Hz,
1H), 4.23 (dd, J=6.6, 5.1 Hz, 1H), 3.98 (t, J=3.9 Hz, 1H), 3.83
(dd, J=7.3, 3.5 Hz, 1H), 3.60 (dd, J=12.0, 3.5 Hz, 1H), 3.47 (dd,
J=12.0, 3.9 Hz, 1H); MS (ES.sup.+) 269.47 (M+1), MS (ES.sup.-)
267.43 (M-1).
[0257] Step 2: To a stirred solution of the product from step 1
(1.66 g) in pyridine (20 mL) was added benzoyl chloride (5.22 g,
37.16 mmol) at 0.degree. C. and the reaction mixture was brought to
RT and stirred for 16 h. After concentration, the residue was
dissolved in ethyl acetate (50 mL), washed with water (2.times.20
mL), brine (1.times.20 mL), dried (MgSO.sub.4), filtered and the
filtrate was concentrated. The crude residue was purified by flash
chromatography using ethyl acetate in hexanes (0 to 100%) to give
benzoylated product (2.77 g, 77.0%) as a colorless solid. .sup.1H
NMR (DMSO-d.sub.6): .delta. 12.7 (s, 1H, D.sub.2O exchangeable),
8.39 (s, 1H), 8.04-8.00 (m, 2H), 7.90-7.85 (m, 5H), 7.69-7.61 (m,
3H), 7.54-7.42 (m, 6H), 6.09 (t, J=5.8 Hz, 1H), 5.97 (t, J=5.5 Hz,
1H), 5.47 (d, J=5.6 Hz, 1H), 4.74-4.69 (m, 2H), 4.60 (dd, J=12.9,
5.4 Hz, 1H); MS (ES.sup.+) 581.37 (M+1), MS (ES.sup.-) 579.34
(M-1).
[0258] Step 3: To a stirred solution of product from step 2 (2.70
g, 4.65 mmol), benzyltriethylammonium chloride (2.07 g, 9.31 mmol),
and N,N-dimethylaniline (0.85 g, 6.98 mmol) in acetonitrile (20 mL)
was added phosphorous oxychloride (4.28 g, 27.93 mmol) at
80.degree. C. and the mixture was further stirred at 80.degree. C.
for 30 min. After concentration, the residue was dissolved in
chloroform (100 mL) and washed with water. The organic layer was
separated and aqueous layer was further extracted with chloroform
(2.times.30 mL). The combined chloroform extracts were washed with
water (2.times.50 mL), sat. NaHCO.sub.3 (50 mL), water (50 mL), and
brine (25 mL), and dried (MgSO.sub.4). After filtration, the
filtrate was concentrated and the residue was purified by flash
chromatography on silica gel column using ethyl acetate in hexanes
(0 to 25%) to afford chloro compound 2.58 g (92.5%) as a colorless
crystalline solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.81 (s,
1H), 8.74 (s, 1H), 8.03-8.01 (m, 2H), 7.92-7.87 (m, 4H), 7.69-7.61
(m, 3H), 7.54-7.42 (m, 6H), 6.15 (t, J=5.8 Hz, 1H), 6.04 (t, J=5.4
Hz, 1H), 5.60 (d, J=5.8 Hz, 1H), 4.80-4.73 (m, 2H), 4.62 (dd,
J=12.6, 4.8 Hz, 1H); MS (ES.sup.+) 599.36 (M+1), 621.32 (M+Na).
[0259] Step 4: To a stirred mixture of chloro compound from step 3
(0.50 g, 0.83 mmol), phenylboronic acid (0.30 g, 2.50 mmol), and
sodium bicarbonate (0.32 g, 5.01 mmol) in ethyleneglycol dimethyl
ether (10 mL) and water (1 mL) was bubbled nitrogen for 15 min.
Dichloro bis triphenylphosphine palladium(II) (58 mg) was added and
the mixture was heated to 80.degree. C. for 16 h. The reaction was
diluted with water (50 mL) and extracted with ethyl acetate
(2.times.100 mL). The combined organic extracts were washed with
water (2.times.50 mL), brine (25 mL) and dried (MgSO.sub.4). After
filtration, the filtrate was concentrated and the residue was
purified by flash chromatography on silica gel column using ethyl
acetate in hexanes (0 to 30%) to afford 449 mg (83.9%) of desired
compound as a colorless crystalline solid. .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.96 (s, 1H), 8.80 (s, 1H), 8.43-8.40 (m,
2H), 8.07-8.04 (m, 2H), 7.93-7.88 (m, 4H), 7.68-7.61 (m, 6H),
7.54-7.42 (m, 6H), 6.26 (t, J=5.8 Hz, 1H), 6.09 (t, J=5.27 Hz, 1H),
5.64 (d, J=5.8 Hz, 1H), 4.81-4.75 (m, 2H), 4.64 (dd, J=12.9, 5.3
Hz, 1H); MS (ES) 641.43 (M+1).
[0260] Step 5: To a stirred solution of product from Step 4 (0.43
g, 0.67 mmol) in methanol (10 mL) was added ammonia saturated in
methanol (15 mL) and sealed the reaction mixture in a steel bomb.
After stirring for 15 h at RT, the reaction mixture was
concentrated to dryness and the residue was purified by flash
chromatography on silica gel using CMA-80 in chloroform (0 to 100%)
which afforded 110 mg (49.9%) of the desired product as a colorless
crystalline solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 9.13 (s,
1H), 8.67 (s, 1H), 8.47-8.44 (m, 2H), 7.69-7.63 (m, 3H), 5.14 (d,
J=5.8 Hz, 1H, D.sub.2O exchangeable), 5.09 (dd, J=7.3, 4.5 Hz, 1H,
D.sub.2O exchangeable), 4.97 (d, J=5.1 Hz, 1H, D.sub.2O
exchangeable), 4.94 (d, J=6.4 Hz, 1H), 4.39 (dd, J=10.9, 6.02 Hz,
1H), 4.06 (dd, J=9.2, 4.7 Hz, 1H), 3.89 (dd, J=8.1, 4.1 Hz, 1H),
3.71-3.64 (m, 1H), 3.57-3.49 (m, 1H); MS (ES.sup.+) 329.43 (M+1),
351.41 (M+Na), MS (ES.sup.-) 327.41 (M-1), 363.35 (M+Cl).
Example B-21
##STR00056##
[0261]
4-Methylthio-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
(Scheme B-3)
[0262] The stirred mixture of,
2-(4-chloro-furo[3,2-d]pyrimidin-7-yl)-5-benzoyloxymethyl-tetrahydro-fura-
n-3,4-dibenzoate, product from step-3 of example B-20 (0.35 g,
0.585 mmol) in tetrahydrofuran (15 mL) was treated with sodium
thiomethoxide (0.41 g, 5.85 mmol) at RT. After stirring for 16 h at
RT, the reaction mixture was concentrated to dryness and the
residue was purified on a column of silica gel to afford 0.12 g
(68.7%) of the desired product, as a colorless crystalline solid.
.sup.1HNMR (DMSO-d.sub.6): .delta. 8.87 (s, 1H), 8.47 (s, 1H),
5.12-5.07 (m, 2H, 1H, D.sub.2O exchangeable), 4.95 (d, J=5.1 Hz,
1H, D.sub.2O exchangeable), 4.86 (d, J=6.6 Hz, 1H, D.sub.2O
exchangeable), 4.31 (dd, J=11.1, 6.2 Hz, 1H), 4.03 (dd, J=9.4, 4.8
Hz, 1H), 3.87 (q, J=3.7 Hz, 1H), 3.68-3.61 (m, 1H), 3.54-3.46 (m,
1H); MS (ES.sup.+): 299.40 (M+1), 321.35 (M+Na), (ES) 297.38
(M-1).
Example B-22
##STR00057##
[0263]
2-Amino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidin-4(3H)-one
(Scheme B-4)
[0264] Step 1: To a solution of product from step 4 of example B-1
(0.49 g, 0.88 mmol) in pyridine (10 mL) was added triethylamine
(0.62 mL, 4.4 mmol), mercury (II) chloride (0.48 g, 1.76 mmol), 1,3
dicarbomethoxy-2-methyl-2-thiopsuedourea (0.37 g, 1.76 mmol) and
the reaction mixture was stirred at 50.degree. C. overnight.
Reaction was not complete so the same amounts of the reagents were
added again and heated at 50.degree. C. for 48 h. Solvent was
removed under vacuum and the residue was triturated with ethyl
acetate (100 mL) and filtered through a pad of Celite.RTM. to
remove insoluble impurities. The filtrate was concentrated under
vacuum and the residue obtained was purified by column
chromatography (silica gel 40 g, eluting with 0-75% ethyl acetate
in hexanes) to furnish the desired product as yellow oil. It was
used as such for the next step
[0265] Step 2: To a solution of product from Step 1 (0.2 g, 0.28
mmol) in methanol (3 mL) was added sodium methoxide (5.4M solution
in methanol, 0.052 mL) and stirred at room temperature overnight.
The reaction was quenched with glacial acetic acid (0.04 mL, 1.5
mmol) and concentrated under vacuum to dryness. The residue
obtained was purified by column chromatography (silica gel 10 g,
eluting with 0-25% CMA-80 in chloroform) to furnish 63 mg (37%) of
desired product,
2-methoxycarbonylamino-7-(3,4-bis-benzyloxy-5-benzyloxymethyl-tetrahydrof-
uran-2-yl)-3H-furo[3,2-d]pyrimidin-4-one, as yellow oil.
[0266] Step 3: To the product from Step 2 (60 mg, 0.1 mmol) in
methanol (1.0 mL) was added 1N NaOH (0.25 mL, 0.25 mmol) and heated
at RT overnight. Again 1N NaOH (0.75 mL) was added and heated at
50.degree. C. for 4 h. The reaction mixture was cooled to room
temperature and pH adjusted to 6 using glacial acetic acid. The
reaction mixture was concentrated under vacuum to remove methanol
and the residue was purified on a column of silica gel to give 41
mg of desired product.
[0267] Step 4: A mixture of the product from step 3 (40 mg), 10%
Pd/C (40 mg) in methanol (2 mL) and 1N HCl (0.7 mL) was
hydrogenated at 50 psi for 6 h. The catalyst was removed by
filtration through Celite and the residue was dried to give 25 mg
of the product. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.11 (s, 1H),
4.69 (d, J=6.9 Hz, 1H), 4.05-4.01 (m, 1H), 3.97-3.95 (m, 1H),
3.89-3.86 (m, 1H), 3.80-3.63 (m, 2H); MS (ES.sup.-) 282.34
(M-1).
Example C-1
##STR00058##
[0268] Triphosphate of
4-methylamino-7-.beta.-(D-ribofuranosyl)-furo[3,2-d]pyrimidine
[0269] Step 1: A mixture of compound from example B-3 (66 mg, 0.23
mmol), MMTrCl (87 mg, 98%, 0.28 mmol), DMAP (5 mg, 0.04 mmol), and
pyridine (2.25 mL) in DMF (1.5 mL) was stirred at room temperature
for 22 h. Additional three portions of MMTrCl (87 mg, 180 mg, 180
mg) were added and the reaction mixture was stirred for 15 h, 23 h,
and 45 h, respectively after each addition of MMTrCl. The reaction
mixture was then treated with triethylamine (1.7 mL, 12.2 mmol),
DMAP (14 mg, 0.11 mmol), and 4-nitrobenzoyl chloride (0.87 g, 98%,
4.59 mmol) and stirred at room temperature for 67 h followed by
dilution with ethyl acetate (100 mL). After washing with water
(2.times.50 mL) and brine (50 mL), the organic phase was dried over
MgSO.sub.4, filtered and the filtrate was concentrated. The residue
was purified on a silica gel column using hexanes/EtOAc (1:0 to
1:1) as eluent to give crude product (269 mg), which was use as
such for the next step.
[0270] Step 2: A solution of the above product from step 1 (260 mg)
in acetonitrile (8 mL) was treated with 0.2 N HCl (0.4 mL) and
stirred at room temperature for 3 h. The reaction mixture was
brought to pH 5 with 0.5 N aq. NaOH followed by dilution with water
(20 mL) and concentration to remove most of acetonitrile. The
aqueous mixture was extracted with EtOAc (2.times.25 mL) and
chloroform (2.times.50 mL). The combined extracts were dried over
MgSO.sub.4. After filtration and concentration, the residue was
purified twice on a silica gel column using hexanes/EtOAc/MeOH
(1:0:0 to 1:1:0.1) as eluent to give product (47 mg, .about.90%
pure) which was used as such for next step. MS (ES.sup.-): 727.65
(M-1).
[0271] Step 3: A suspension of the above product from step 2 (45
mg) in a mixture of pyridine (70 .mu.L) and 1,4-dioxane (210 .mu.L)
was treated with a freshly prepared solution of
chloro-4H-1,3,2-benzodioxaphosphorin-4-one (1M in 1,4-dioxane, 75
.mu.L). The reaction mixture was stirred at room temperature for 20
min followed by treatment with a solution of tributylammonium
pyrophosphate, 1.6 Bu.sub.3N.1.0 H.sub.4P.sub.2O.sub.7 (47 mg, 0.10
mmol) in DMF (205 .mu.L) and tri-n-butylamine (65 .mu.L),
simultaneously. The clear solution formed was stirred at room
temperature for 30 min followed by treatment with 2.6 mL of 1%
I.sub.2 in Py/H.sub.2O (98/2). Excess iodine was reduced by 5%
aqueous sodium thiosulphate (215 .mu.L) and the resulting solution
was concentred to dryness. The residue was treated with conc.
NH.sub.4OH (20 mL). The reaction mixture was stirred at room
temperature overnight followed by concentration to dryness. The
residue was dissolved in H.sub.2O (20 mL) and washed with
CH.sub.2Cl.sub.2 (2.times.15 mL). The aqueous phase was
concentrated under vacuum for a short period of time to remove the
trace amounts 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, 250 mL/250 mL, 0:1 to 1:0). The
fractions containing the desired nucleotide was combined and
concentrated. The residue was redissolved in H.sub.2O and purified
further by HPLC (CH.sub.3CN/0.1 M TEAB buffer, pH=8.0, 0-20 min,
0-35% CH.sub.3CN; 20-28 min, 35-100% CH.sub.3CN, monitoring at 260
nm) to give desired triphosphate (t.sub.R=15.3 min). .sup.1H NMR
(D.sub.2O): .delta. 8.17 (s, 1H), 8.04 (s, 1H), 5.00 (d, J=6.0 Hz,
1H), 4.40-4.00 (m, 5H), 2.94 (s, 3H); .sup.31P NMR (D.sub.2O):
.delta. -6.28 (1P), -9.70 (1P), -20.47 (1P); MS (ES.sup.-): 520.14
(M-1).
Example D-1
[0272] 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 1.0N 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 01N 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
The above formulations may be obtained by conventional procedures
well known in the pharmaceutical art.
[0273] 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.
* * * * *