U.S. patent application number 10/631577 was filed with the patent office on 2004-02-12 for heterocycle carboxamides as antiviral agents.
Invention is credited to Anderson, David John, Beauchamp, Thomas J., Bundy, Gordon L., Ciske, Fred L., Farrell, John R., Genin, Michael J., Graber, David R., Judge, Thomas M., Moon, Malcolm Wilson, Schnute, Mark E., Strohbach, Joseph Walter, Thaisrivongs, Suvit, Thorarensen, Atli, Turner, Steven Ronald, Vaillancourt, Valerie A., Wolf, Allison J..
Application Number | 20040029879 10/631577 |
Document ID | / |
Family ID | 26912046 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040029879 |
Kind Code |
A1 |
Anderson, David John ; et
al. |
February 12, 2004 |
Heterocycle carboxamides as antiviral agents
Abstract
The present invention provides a compound of formula I 1 which
is useful as antiviral agents, in particular, as agents against
viruses of the herpes family.
Inventors: |
Anderson, David John;
(Kalamazoo, MI) ; Beauchamp, Thomas J.; (Portage,
MI) ; Bundy, Gordon L.; (Kalamazoo, MI) ;
Ciske, Fred L.; (Lawton, MI) ; Farrell, John R.;
(Kalamazoo, MI) ; Graber, David R.; (Kalamazoo,
MI) ; Genin, Michael J.; (Paw Paw, MI) ;
Judge, Thomas M.; (St. Otsego, MI) ; Moon, Malcolm
Wilson; (Kalamazoo, MI) ; Schnute, Mark E.;
(Kalamazoo, MI) ; Strohbach, Joseph Walter;
(Mendon, MI) ; Thaisrivongs, Suvit; (Kalamazoo,
MI) ; Thorarensen, Atli; (Portage, MI) ;
Turner, Steven Ronald; (Kalamazoo, MI) ;
Vaillancourt, Valerie A.; (Kalamazoo, MI) ; Wolf,
Allison J.; (Kalamazoo, MI) |
Correspondence
Address: |
Lucy X. Yang
Pharmacia & Upjohn Company
Global Intellectual Property
301 Henrietta Street
Kalamazoo
MI
49001
US
|
Family ID: |
26912046 |
Appl. No.: |
10/631577 |
Filed: |
July 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10631577 |
Jul 31, 2003 |
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09887578 |
Jun 22, 2001 |
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6624159 |
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60217559 |
Jul 12, 2000 |
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60272143 |
Feb 28, 2001 |
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Current U.S.
Class: |
514/233.2 ;
514/246; 514/267; 514/296; 544/115; 544/118; 544/125; 544/180;
544/252; 546/94 |
Current CPC
Class: |
C07D 471/06 20130101;
A61P 31/12 20180101; A61P 31/22 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/233.2 ;
514/246; 514/267; 514/296; 544/118; 544/115; 544/125; 544/180;
544/252; 546/94 |
International
Class: |
A61K 031/5377; A61K
031/53; A61K 031/519; A61K 031/4745; C07D 487/14 |
Claims
What is claimed is:
1. A compound of formula I, 103wherein, X is Cl, Br, F, CN or
NO.sub.2; G is (a) C.sub.1-4alkyl which is fully saturated or
partially unsaturated and is substituted by hydroxy, or (b)
C.sub.1-4alkyl substituted by NR.sup.1R.sup.2 or 4-tetrahydropyran;
R.sup.1 is C.sub.2-7alkyl substituted by hydroxy, C.sub.1-4alkoxy,
or aryl; R.sup.2 is hydrogen or C.sub.1-7alkyl; or R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached form
(a) a morpholine which may be optionally substituted by aryl or
C.sub.1-7alkyl; or (b) a pyrrolidine ring substituted by hydroxy; W
is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7 or W8 104A
is CR.sup.4 or nitrogen; B is CR.sup.5 or nitrogen; D is (a)
--(CR.sup.13R.sup.14).sub.a--, where a is 2 or 3 (b)
--(CR.sup.15R.sup.16).sub.4--, (c)
--Y--CR.sup.13R.sup.14--CR.sup.13R.sup- .14--, (d)
--CR.sup.13R.sup.14--Y--CR.sup.13R.sup.14--, (e)
--Y--CR.sup.13R.sup.14--Y--, (f)
--CR.sup.13R.sup.14--CR.sup.13R.sup.14--- Y--, (g)
--Y--(CR.sup.15R.sup.16).sub.n--, (h) --Y--CR.sup.15.dbd.CR.sup.1-
5--, (i) --Y--CR.sup.15.dbd.N--, (j)
--CR.sup.15.dbd.CR.sup.15--N--, (k) --N.dbd.CR.sup.15--Y--, (l)
--(CR.sup.15R.sup.16).sub.b--N.dbd.CR.sup.15-- -, where b is 0 or 1
(m) --CR.sup.15.dbd.N--(CR.sup.15R.sup.16).sub.b--, where b is 0 or
1 (n) --N.dbd.N--, (o) --N.dbd.CR.sup.15--(CR.sup.15R.sup-
.16).sub.b--, where b is 0 or 1 (p) --CR.sup.15.dbd.CR.sup.15--,
(q) --N.dbd.N--Y--, (r) --Y--N.dbd.N--, (s) --Y--N.dbd.CR.sup.15--,
or (t)
--CR.sup.15R.sup.16--Y--CR.sup.15R.sup.16--CR.sup.15R.sup.16--; E
is CR.sup.8 or nitrogen; J is CR.sup.15 or nitrogen; K is (a)
--(CR.sup.15R.sup.16).sub.a--, where a is 2 or 3, or (b)
--CR.sup.15.dbd.CR.sup.15--; L is (a)
--(CR.sup.15R.sup.16).sub.a--, where a is 2 or 3, or (b)
--Y--(CR.sup.15R.sup.16)--(CR.sup.15R.sup.16)--- ; Y is oxygen,
S(O).sub.m, or NR.sup.7; with the provisos that: when W is of
formula W1; G is C.sub.1-4alkyl which is fully saturated and is
substituted by hydroxy or morpholinyl, in which morpholinyl is
attached through nitrogen; A is CR.sup.4; B is CR.sup.5; and
R.sup.8 is hydrogen then at least one of R.sup.13, R.sup.14, or
R.sup.7 is not hydrogen or C.sub.1-7alkyl; when W is of formula W1,
A is CR.sup.4, B is CR.sup.5, D is
--Y--CR.sup.13R.sup.14--CR.sup.13R.sup.14--, and R.sup.8 is
hydrogen then Y is not oxygen; when W is of formula W1, A is
CR.sup.4, and B is CR.sup.5 then D is not
--CR.sup.15.dbd.CR.sup.15--; R.sup.4 is H, halogen, or
C.sub.1-4alkyl optionally substituted by one to three halogens;
R.sup.5 is (a) H, (b) halo, (c) OR.sup.12, (d) SR.sup.12, (e)
C.sub.1-7alkyl which may be partially unsaturated and optionally
substituted by one or more substituents selected from OR.sup.12,
SR.sup.12, NR.sup.10R.sup.11, or halo, (f) C.sub.3-8cycloalkyl
which may be partially unsaturated and is optionally substituted by
one or more substituents selected from halogen, OR.sup.12,
SR.sup.12, or NR.sup.10R.sup.11, (g) (C.dbd.O)R.sup.9, (h)
S(O).sub.mR.sup.9, (i) (C.dbd.O)OR.sup.2, (j) NHSO.sub.2R.sup.9,
(k) nitro, or (l) cyano; R.sup.7 is (a) H, (b) C.sub.1-7alkyl which
may be partially unsaturated and optionally substituted by one or
more substituents selected from OR.sup.12, SR.sup.12,
NR.sup.10R.sup.11, or halo, (c) C.sub.3-8cycloalkyl which may be
partially unsaturated and is optionally substituted by one or more
substituents selected from halogen, OR.sup.12, SR.sup.12, or
NR.sup.10R.sup.11, (d) aryl, (e) het, (f) (C.dbd.O)R.sup.9, or (g)
S(O).sub.mR.sup.9; R.sup.8 is (a) H, (b) C.sub.1-7alkyl which may
be partially unsaturated and optionally substituted by one or more
substituents selected from OR.sup.12, SR.sup.12, NR.sup.10R.sup.11,
or halo, (c) OR.sup.12, or (d) SR.sup.12; R.sup.9 is (a)
C.sub.1-7alkyl optionally substituted by OR.sup.12 or
NR.sup.2R.sup.2, (b) C.sub.3-8cycloalkyl optionally substituted by
OR.sup.12 or NR.sup.2R.sup.2, (c) NR.sup.10R.sup.11, (d) aryl, or
(e) het, wherein said het is bound through a carbon atom; R.sup.10
and R.sup.11 are independently (a) H, (b) aryl, (c) C.sub.1-7alkyl
which may be partially unsaturated and is optionally substituted by
one or more substituents selected from CONR.sup.2R.sup.2,
CO.sub.2R.sup.2, het, aryl, cyano, or halo, (d) C.sub.2-7alkyl
which may be partially unsaturated and is substituted by one or
more substituents selected from NR.sup.2R.sup.2, OR.sup.2, or
SR.sup.2, (e) C.sub.3-8cycloalkyl which may be partially
unsaturated and is optionally substituted by one or more
substituents selected from halogen, OR.sup.2, SR.sup.2, or
NR.sup.2R.sup.2, or (f) R.sup.10 and R.sup.11 together with the
nitrogen to which they are attached form a het; R.sup.12 is (a) H,
(b) aryl, (c) het (d) C.sub.1-7alkyl optionally substituted by
aryl, or halogen, (e) C.sub.2-7alkyl substituted by OR.sup.2,
SR.sup.2, or NR.sup.2R.sup.2, or (f) C.sub.3-8cycloalkyl which may
be partially unsaturated and is optionally substituted by one or
more substituents selected from halogen, OR.sup.2, SR.sup.2, or
NR.sup.2R.sup.2; R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are
independently (a) H (b) C.sub.1-7alkyl which may be partially
unsaturated and optionally substituted by one or more OR.sup.12,
SR.sup.12, NR.sup.10R.sup.11, or halo groups, (c)
C.sub.3-8cycloalkyl which may be partially unsaturated and is
optionally substituted by one or more substituents selected from
halogen, OR.sup.12, SR.sup.12, or NR.sup.10R.sup.11, (d) aryl, (e)
het, wherein said het is bound through a carbon atom, (f)
OR.sup.12, (g) SR.sup.12, (h) NR.sup.10R.sup.11; (i)
(C.dbd.O)OR.sup.2, or (j) R.sup.13 and R.sup.14 or R.sup.15 and
R.sup.16 together with the carbon to which they are attached form
(C.dbd.O); each m is independently 0, 1 or 2; each n is
independently 1 or 3; aryl is a phenyl radical or an ortho-fused
bicyclic carbocyclic radical wherein at least one ring is aromatic,
and aryl may be optionally substituted with one or more
substituents selected from halo, OH, cyano, NR.sup.2R.sup.2,
CO.sub.2R.sup.2, CF.sub.3, C.sub.1-6alkoxy, and C.sub.1-6 alkyl
which maybe further substituted by one to three SR.sup.2,
NR.sup.2R.sup.2, OR.sup.2, or CO.sub.2R.sup.2 groups; het is a
four- (4), five- (5), six- (6), or seven- (7) membered saturated or
unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms
selected from oxygen, sulfur, or nitrogen, which is optionally
fused to a benzene ring, or any bicyclic heterocycle group, and het
may be optionally substituted with one or more substituents
selected from halo, OH, cyano, phenyl, CO.sub.2R.sup.2, CF.sub.3,
C.sub.1-6alkoxy, oxo, oxime, and C.sub.1-6 alkyl which may be
further substituted by one to three SR.sup.2, NR.sup.2R.sup.2,
OR.sup.2, or CO.sub.2R.sup.2 groups; halo or halogen is F, Cl, Br,
I; 1 represents the point of attachment between W and G; 2
represents the point of attachment between W and the carbonyl group
of Formula (I); and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 wherein W is of the formula W1.
3. A compound of claim 2 wherein W is of the formula W1.1.
4. A compound of claim 2 wherein W is of the formula W1.3.
5. A compound of claim 2 wherein W is of the formula W1.5.
6. A compound of claim 2 wherein W is of the formula W1.6.
7. A compound of claim 2 wherein W is of the formula W1.7.
8. A compound of claim 2 wherein W is of the formula W1.8.
9. A compound of claim 2 wherein W is of the formula W1.9.
10. A compound of claim 2 wherein W is of the formula W1.10.
11. A compound of claim 2 wherein W is of the formula W1.11.
12. A compound of claim 2 wherein W is of the formula W1.14.
13. A compound of claim 2 wherein W is of the formula W1.15.
14. A compound of claim 2 wherein W is of the formula W1.17.
15. A compound of claim 2 wherein W is of the formula W1.18.
16. A compound of claim 2 wherein W is of the formula W1.19.
17. A compound of claim 2 wherein W is of the formula W1.20.
18. A compound of claim 2 wherein W is of the formula W1.23.
19. A compound of claim 2 wherein W is of the formula W1.24.
20. A compound of claim 2 wherein W is of the formula W1.25.
21. A compound of claim 2 wherein W is of the formula W1.26.
22. A compound of claim 2 wherein W is of the formula W1.52.
23. A compound of claim 1 wherein W is of the formula W2.
24. A compound of claim 1 wherein W is of the formula W3.
25. A compound of claim 24 wherein W is of the formula W3.1.
26. A compound of claim 1 wherein W is of the formula W4.
27. A compound of claim 26 wherein W is of the formula W4.1.
28. A compound of claim 1 wherein W is of the formula W5.
29. A compound of claim 1 wherein W is of the formula W6.
30. A compound of claim 1 wherein W is of the formula W7.
31. A compound of claim 1 wherein W is of the formula W8.
32. The compound according to claim 1, wherein X is Cl.
33. The compound according to claim 1 wherein G is
4-morpholinylmethyl.
34. The compound according to claim 1 wherein G is
3-hydroxypropyl.
35. The compound according to claim 1 wherein G is
3-hydroxy-1-propynyl.
36. The compound according to claim 1 wherein G is
tetrahydro-2H-pyran-4-y- lmethyl.
37. A compound of claim 2 where R.sup.8 is hydrogen.
38. A compound of claim 37 where A is CR.sup.4 and B is
CR.sup.5.
39. A compound of claim 38 where R.sup.4 is hydrogen and R.sup.5 is
hydrogen.
40. The compound according to claim 1 which is selected from the
group consisting of
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-imidazo-
[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxy-1-propy-
nyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-6H-imidazo[4,5,1-ij]quinolin-
e-5-carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-
-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-1,2-dihydro-6H-pyrro-
lo-[3,2,1-ij]quinoline-5-carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(4-morp-
holinylmethyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxami-
de;
N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,-
2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydr-
o-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-
-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]-
quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-
-oxo-2,3-dihydro-7H-[1,3,4]-oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H--
[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran4-ylmethyl)-7-oxo-2,3-d-
ihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihydro-7H-
-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-
-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,3-
,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenz-
yl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4--
ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-p-
yran-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinolin-
e-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-ox-
o-7H-[1,4]thiazino-[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[-
1,4]-thiazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hy-
droxypropyl)-3-methyl-7-oxo-7H-[1,4]thiazino[2,3,4-ij]-quinoline-6-carboxa-
mide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]t-
hiazino [2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(morpholin-
-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4]thiazino-[2,3,4-ij]quinoline-6-c-
arboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,-
7H-[1,3]oxazino-[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-
-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-car-
boxamide;
N-(4-chlorobenzyl)-7-oxo-3-phenyl-9-(tetrahydro-2H-pyran-4-ylmet-
hyl)-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxaz-
ino-[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-p-
ropynyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxa-
line-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo--
3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-oxo-3-ph-
enyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-3-phenyl-2,3-di-
hydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,3,7-trioxo-2,3-dihydro-1H,7-
H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydro-
xypropyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido-[1,2,3-de]quinoxaline-6-ca-
rboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,3,7-trioxo-2,3-dih-
ydro-1H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1H,7H-p-
yrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-
propyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxam-
ide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-2,3-dihydro-1H,-
7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hyd-
roxypropyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carb-
oxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro--
1H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4--
morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido-[1,2,3-de]quinoxalin-
e-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7--
dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-2,3-d-
ihydro-1H,7H-[1,2,4]triazino[5,6, 1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-2,3-dihydr-
o-1H,7H-[1,2,4]triazino[5,6, 1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-2,3-di-
hydro-1H,7H-[1,2,4]triazino[5,6, 1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-
-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,
1-ij]quinoline-6-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydr-
o-1H,7H-pyrido[3,2, 1-ij]cinnoline-8-carboxamide;
1-benzyl-N-(4-chlorobenz-
yl)-5-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnol-
ine-8-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-2,7-
-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-2,7-dioxo--
2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihydro-1H-
,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydro-
xy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino-[5,4,3-ij]quinoline-6-ca-
rboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,-
3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahy-
dro-2H-pyran-4-ylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quino-
line-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phe-
nyl-1H,7H-[1,3]thiazino-[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydr-
o-1H,7H-pyrido[3,2, 1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-methyl-7-oxo-3-phenyl-2,3-d-
ihydro-1H,7H-pyrido[3,2, 1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2-methyl-7-oxo-3-phenyl-2,3-di-
hydro-1H,7H-pyrido[3,2, 1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-2-methyl-7-oxo-3-ph-
enyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,-
7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)--
9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinaz-
oline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-(4-morp-
holinyl)-7-oxo-7H-[1,3,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-(4-morpholinyl)-7-oxo-7H-[1,3,4]-
-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-2-(4-mor-
pholinyl)-9-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]-thiadiazino[6,5,4-ij]qu-
inoline-6-carboxamide;
N-(4-chlorobenzyl)-2-(4-morpholinyl)-7-oxo-9-(tetra-
hydro-2H-pyran-4-ylmethyl)-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carb-
oxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-1H,7H-py-
razino[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4--
morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino-[3,2,1-ij][1,7]naphthy-
ridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,-
3-dihydro-1H,7H-pyrazino-[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino-
[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpho-
linylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino-[2,3,4-ij][1,7]naphthyridi-
ne-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-di-
hydro-7H-[1,4]thiazino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxa-
zino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-m-
orpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino-[2,3,4-ij][1,7]naphthy-
ridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dih-
ydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]-q-
uinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7--
dioxo-3H,7H-pyrido[1,2,3-de]-quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-d-
e]-quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-
-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxa-
mide;
2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,-
7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-10-(3-hy-
droxypropyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]-diazepino[3,2,1-ij]q-
uinoline-7-carboxamide;
N-(4-chlorobenzyl)-10-(3-hydroxy-1-propynyl)-2,4,8-
-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxam-
ide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,4,8-trioxo-1,2,3,4-tetr-
ahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro--
8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imida-
zo-[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxy-1-pr-
opynyl)-2,6-dioxo-1,2-dihydro-6H-imidazo-[4,5,1-ij]quinoline-5-carboxamide-
;
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[-
4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(4-morpholinylmethy-
l)-2,6-dioxo-1-[2-(1-piperidinyl)ethyl]-1,2-dihydro-6H-imidazo[4,5,1-ij]qu-
inoline-5-carboxamide;
N-(4-chlorobenzyl)-1-[2-(4-methyl-1-piperazinyl)eth-
yl]-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quin-
oline-5-carboxamide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-
-dihydro-2H,8H-[1,4]-oxazepino[2,3,4-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]oxazin-
o-[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(-
tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,4]-oxazino[2,3,4-ij]quinoline-6-carb-
oxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]oxa-
zino[2,3,4-ij]-quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypro-
p-1-ynyl)-3-methyl-7-oxo-7H-[1,4]oxazino
[2,3,4-ij]quinoline-6-carboxamide- ;
N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4-
]oxazino-[2,3,4-ij]quinoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-10-
-(4-morpholinylmethyl)-3,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,-
1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-4,7-d-
ioxo-1,2-dihydro-4H,7H-imidazo-[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-4,7-dioxo-1,2-dihydro-4H,7H-im-
idazo-[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
N-(4-chlorobenzyl)-5-(3--
hydroxy-1-propynyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naph-
thyridine-8-carboxamide;
N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-3-oxo--
9,10-dihydro-3H,8H-pyrido [3,2,1-ij]quinoline-2-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-
-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; and
pharmaceutically acceptable salts thereof.
41. The compound according to claim 40 which is selected from the
group consisting of
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihyd-
ro-2H,8H-[1,4]-oxazepino [2,3,4-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imida-
zo-[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylm-
ethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxam-
ide;
N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl)--
7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-d-
ihydro-6H-pyrrolo[3,2, 1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydr-
o-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-6-(morph-
olin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido-[3,2,1-ij]quinoline-2-car-
boxamide;
N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,-
3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide
hydrobromide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro--
8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,7H-py-
rido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy--
1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxali-
ne-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-ox-
o-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-
-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenz-
yl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepin-
o[6,7,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1--
ynyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-
-carboxamide;
N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2-
,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; and
pharmaceutically acceptable salts thereof.
42. The compound according to claim 41 which is selected from the
group consisting of
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihyd-
ro-2H,8H-[1,4]-oxazepino [2,3,4-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-py-
rido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(4-
-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxalin-
e-6-carboxamide hydrobromide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)--
2,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,
1-ij]quinoline-7-carboxamide;
2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-mor-
pholinylmethyl)-7-oxo-3H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydr-
o-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; and
pharmaceutically acceptable salts thereof.
43. The compound according to claim 42 which is selected from the
group consisting of
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-di-
hydro-1H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-
-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; and
pharmaceutically acceptable salts thereof.
44. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
45. A method of treating or preventing a viral infection,
comprising administering to a mammal in need of such treatment, a
compound of claim 1.
46. The method according to claim 45 wherein said viral infection
is a herpes virus infection.
47. The method according to claim 45 wherein said mammal is a
human.
48. The method according to claim 45 wherein said mammal is a
livestock or companion animal.
49. The method according to claim 47 wherein the infection is
herpes simplex virus type 1 or 2, human herpes virus type, 6, 7, or
8, varicella zoster virus, human cytomegalovirus, or Epstein-Barr
virus.
50. The method according to claim 47 wherein the infection is
herpes simplex virus type 1 or 2, human herpes virus type 8,
varicella zoster virus, human cytomegalovirus, or Epstein-Barr
virus.
51. The method according to claim 45 wherein the amount
administered is from about 0.1 to about 300 mg/kg of body
weight.
52. The method according to claim 51 wherein the amount
administered is from about 1 to about 30 mg/kg of body weight.
53. The method according to claim 45 wherein the compound is
administered parenterally, topically, intravaginally, orally, or
rectally.
54. A method for inhibiting a viral DNA polymerase, comprising
contacting the polymerase with an effective inhibitory amount of a
compound of claim 1.
55. The method of claim 54 wherein the polymerase and the compound
are contacted in vitro.
56. The method of claim 54 wherein the polymerase and the compound
are contacted in vivo.
57. The compound of any one of claim 1 for use in medical
treatment.
58. The compound of claim 57 wherein the treatment is the treatment
or prevention of a herpes viral infection.
59. The use of a compound or composition of any one of claim 1 to
prepare a medicament for treating or preventing a herpes viral
infection in a mammal.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the following
provisional applications: U.S. Serial No. 60/217,559, filed Jul.
12, 2000, and U.S. Serial No. 60/272,143, filed Feb. 28, 2001,
under 35 USC 119(e)(i).
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention provides heterocycle carboxamide
derivatives. These compounds are useful as antiviral agents, in
particular, as agents against viruses of the herpes family.
[0004] 2. Technology Description
[0005] The herpesviruses comprise a large family of double stranded
DNA viruses. They are also a source of the most common viral
illnesses in man. Eight of the herpes viruses, herpes simplex virus
types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV),
human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human
herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been
shown to infect humans.
[0006] HSV-1 and HSV-2 cause herpetic lesions on the lips and
genitals, respectively. They also occasionally cause infections of
the eye and encephalitis. HCMV causes birth defects in infants and
a variety of diseases in immunocompromised patients such as
retinitis, pneumonia, and gastrointestinal disease. VZV is the
causative agent of chicken pox and shingles. EBV causes infectious
mononucleosis. It can also cause lymphomas in immunocompromised
patients and has been associated with Burkitt's lymphoma,
nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the
causative agent of roseola and may be associated with multiple
sclerosis and chronic fatigue syndrome. HHV-7 disease association
is unclear, but it may be involved in some cases of roseola. HHV-8
has been associated with Karposi's sarcoma, body cavity based
lymphomas, and multiple myeloma.
[0007] U.S. Pat. No. 5,792,774 discloses specific quinoline
derivatives that are alleged to have therapeutic utility via
inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis
factor activity.
[0008] Despite the above teachings, there still exists a need in
the art for novel compounds that demonstrate desirable antiviral
activity.
BRIEF SUMMARY OF THE INVENTION
[0009] In accordance with the present invention, novel compounds
which demonstrate antiviral activity are provided. More
specifically, the compounds are specific heterocycle carboxamide
derivatives which are useful as antiviral agents, particularly
against herpes viruses.
[0010] Even more specifically, the present invention provides a
compound of formula I, 2
[0011] wherein,
[0012] X is Cl, Br, F, CN or NO.sub.2;
[0013] G is
[0014] (a) C.sub.1-4alkyl which is fully saturated or partially
unsaturated and is substituted by hydroxy, or
[0015] (b) C.sub.1-4alkyl substituted by NR.sup.1R.sup.2 or
4-tetrahydropyran;
[0016] R.sup.1 is C.sub.2-7alkyl substituted by hydroxy,
C.sub.1-4alkoxy, aryl, or heteroaryl;
[0017] R.sup.2 is hydrogen or C.sub.1-7alkyl;
[0018] or R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached form (a) a morpholine which may be optionally
substituted by aryl or C.sub.1-7alkyl; or (b) a pyrrolidine ring
substituted by hydroxy;
[0019] W is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7 or
W8 3
[0020] A is CR.sup.4 or nitrogen;
[0021] B is CR.sup.5 or nitrogen;
[0022] D is
[0023] (a) --(CR.sup.13R.sup.14).sub.a--, where a is 2 or 3
[0024] (b) --(CR.sup.15R.sup.16).sub.4--,
[0025] (c) --Y--CR.sup.13R.sup.14--CR.sup.13R.sup.14--,
[0026] (d) --CR.sup.13R.sup.14--Y--CR.sup.13R.sup.14--,
[0027] (e) --Y--CR.sup.13R.sup.14--Y--,
[0028] (f) --CR.sup.13R.sup.14--CR.sup.13R.sup.14--Y--,
[0029] (g) --Y--(CR.sup.15R.sup.16).sub.n--,
[0030] (h) --Y--CR.sup.15.dbd.CR.sup.15--,
[0031] (i) --Y--CR.sup.15.dbd.N--,
[0032] (j) --CR.sup.15.dbd.CR.sup.15--Y--,
[0033] (k) --N.dbd.CR.sup.15--Y--,
[0034] (l) --(CR.sup.15R.sup.16).sub.b--N.dbd.CR.sup.15--, where b
is 0 or 1
[0035] (m) --CR.sup.15.dbd.N--(CR.sup.15R.sup.16).sub.b--, where b
is 0 or 1
[0036] (n) --N.dbd.N--,
[0037] (o)--N.dbd.CR.sup.15--(CR.sup.15R.sup.16).sub.b--, where b
is 0 or 1
[0038] (p) --CR.sup.15.dbd.CR.sup.15--,
[0039] (q) --N.dbd.N--Y--,
[0040] (r) --Y--N.dbd.N--,
[0041] (s) --Y--N.dbd.CR.sup.15--, or
[0042] (t)
--CR.sup.15R.sup.16--Y--CR.sup.15R.sup.16--CR.sup.15R.sup.16--;
[0043] E is CR.sup.8 or nitrogen;
[0044] J is CR.sup.15 or nitrogen;
[0045] K is
[0046] (a) --(CR.sup.15R.sup.16).sub.a--, where a is 2 or 3, or
[0047] (b) --CR.sup.15.dbd.CR.sup.15--,
[0048] L is
[0049] (a) --(CR.sup.15R.sup.16).sub.a--, where a is 2 or 3, or
[0050] (b) --Y--(CR.sup.5R.sup.16) --(CR.sup.15R.sup.16)--;
[0051] Y is oxygen, S(O).sub.m, or NR.sup.7;
[0052] with the provisos that:
[0053] when W is of formula W1; G is C.sub.1-4alkyl which is fully
saturated and is substituted by hydroxy or morpholinyl, in which
morpholinyl is attached through nitrogen; A is CR.sup.4; B is
CR.sup.5; and R.sup.8 is hydrogen then at least one of R.sup.13,
R.sup.14, or R.sup.7 is not hydrogen or C.sub.1-7alkyl;
[0054] when W is of formula W1, A is CR.sup.4, B is CR.sup.5, D is
--Y--CR.sup.13R.sup.14--CR.sup.13R.sup.14--, and R.sup.8 is
hydrogen then Y is not oxygen;
[0055] when W is of formula W1, A is CR.sup.4, and B is CR.sup.5
then D is not --CR.sup.15.dbd.CR.sup.15--;
[0056] R.sup.4 is H, halogen, or C.sub.1-4alkyl optionally
substituted by one to three halogens;
[0057] R.sup.5 is
[0058] (a) H,
[0059] (b) halo,
[0060] (c) OR.sup.12,
[0061] (d) SR.sup.12,
[0062] (e) C.sub.1-7alkyl which may be partially unsaturated and
optionally substituted by one or more substituents selected from
OR.sup.12, SR.sup.12, NR.sup.10R.sup.11, or halo,
[0063] (f) C.sub.3-8cycloalkyl which may be partially unsaturated
and is optionally substituted by one or more substituents selected
from halogen, OR.sup.12, SR.sup.12, or NR.sup.10R.sup.11,
[0064] (g) (C.dbd.O)R.sup.9,
[0065] (h) S(O).sub.mR.sup.9,
[0066] (i) (C.dbd.O)OR.sup.2,
[0067] (j) NHSO.sub.2R.sup.9,
[0068] (k) nitro, or
[0069] (l) cyano;
[0070] R.sup.7 is
[0071] (a) H,
[0072] (b) C.sub.1-7alkyl which may be partially unsaturated and
optionally substituted by one or more substituents selected from
OR.sup.12, SR.sup.12, NR.sup.10R.sup.11, or halo,
[0073] (c) C.sub.3-8cycloalkyl which may be partially unsaturated
and is optionally substituted by one or more substituents selected
from halogen, OR.sup.12, SR.sup.12, or NR.sup.10R.sup.11,
[0074] (d) aryl,
[0075] (e) het,
[0076] (f) (C.dbd.O)R.sup.9, or
[0077] (g) S(O).sub.mR.sup.9;
[0078] R.sup.8 is
[0079] (a) H,
[0080] (b) C.sub.1-7alkyl which may be partially unsaturated and
optionally substituted by one or more substituents selected from
OR.sup.12, SR.sup.12, NR.sup.10R.sup.11, or halo,
[0081] (c) OR.sup.12, or
[0082] (d) SR.sup.12;
[0083] R.sup.9 is
[0084] (a) C.sub.1-7alkyl optionally substituted by OR.sup.12 or
NR.sup.2R.sup.2,
[0085] (b) C.sub.3-8cycloalkyl optionally substituted by OR.sup.12
or NR.sup.2R.sup.2,
[0086] (c) NR.sup.10R.sup.11,
[0087] (d) aryl, or
[0088] (e) het, wherein said het is bound through a carbon
atom;
[0089] R.sup.10 and R.sup.11 are independently
[0090] (a) H,
[0091] (b) aryl,
[0092] (c) C.sub.1-7alkyl which may be partially unsaturated and is
optionally substituted by one or more substituents selected from
CONR.sup.2R.sup.2, CO.sub.2R.sup.2, het, aryl, cyano, or halo,
[0093] (d) C.sub.2-7alkyl which may be partially unsaturated and is
substituted by one or more substituents selected from
NR.sup.2R.sup.2, OR.sup.2, or SR.sup.2,
[0094] (e) C.sub.3-8cycloalkyl which may be partially unsaturated
and is optionally substituted by one or more substituents selected
from halogen, OR.sup.2, SR.sup.2, or NR.sup.2R.sup.2, or
[0095] (f) R.sup.10 and R.sup.11 together with the nitrogen to
which they are attached form a het;
[0096] R.sup.12 is
[0097] (a) H,
[0098] (b) aryl,
[0099] (c) het
[0100] (d) C.sub.1-7alkyl optionally substituted by aryl, or
halogen,
[0101] (e) C.sub.2-7alkyl substituted by OR.sup.2, SR.sup.2, or
NR.sup.2R.sup.2, or
[0102] (f) C.sub.3-8cycloalkyl which may be partially unsaturated
and is optionally substituted by one or more substituents selected
from halogen, OR.sup.2, SR.sup.2, or NR.sup.2R.sup.2;
[0103] R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are
independently
[0104] (a) H
[0105] (b) C.sub.1-7alkyl which may be partially unsaturated and
optionally substituted by one or more OR.sup.12, SR.sup.12,
NR.sup.10R.sup.11, or halo groups,
[0106] (c) C.sub.3-8cycloalkyl which may be partially unsaturated
and is optionally substituted by one or more substituents selected
from halogen, OR.sup.12, SR.sup.12, or NR.sup.10R.sup.11,
[0107] (d) aryl,
[0108] (e) het, wherein said het is bound through a carbon
atom,
[0109] (f) OR.sup.12,
[0110] (g) SR.sup.12,
[0111] (h) NR.sup.10R.sup.11;
[0112] (i) (C.dbd.O)OR.sup.2, or
[0113] (j) R.sup.13 and R.sup.14 or R.sup.15 and R.sup.16 together
with the carbon to which they are attached form (C.dbd.O);
[0114] each m is independently 0, 1 or 2;
[0115] each n is independently 1 or 3;
[0116] aryl is a phenyl radical or an ortho-fused bicyclic
carbocyclic radical wherein at least one ring is aromatic, and aryl
may be optionally substituted with one or more substituents
selected from halo, OH, cyano, NR.sup.2R.sup.2, CO.sub.2R.sup.2,
CF.sub.3, C.sub.1-6alkoxy, and C.sub.1-6 alkyl which maybe further
substituted by one to three SR.sup.2, NR.sup.2R.sup.2, OR.sup.2, or
CO.sub.2R.sup.2 groups;
[0117] het is a four- (4), five- (5), six- (6), or seven- (7)
membered saturated or unsaturated heterocyclic ring having 1, 2, or
3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is
optionally fused to a benzene ring, or any bicyclic heterocycle
group, and het may be optionally substituted with one or more
substituents selected from halo, OH, cyano, phenyl,
CO.sub.2R.sup.2, CF.sub.3, C.sub.1-6alkoxy, oxo, oxime, and
C.sub.1-6 alkyl which may be further substituted by one to three
SR.sup.2, NR.sup.2R.sup.2, OR.sup.2, or CO.sub.2R.sup.2 groups;
[0118] halo or halogen is F, Cl, Br, I;
[0119] 1 represents the point of attachment between W and G;
[0120] 2 represents the point of attachment between W and the
carbonyl group of Formula (I);
[0121] and pharmaceutically acceptable salts thereof.
[0122] In particularly preferred embodiments, X is Cl and G is
4-morpholinylmethyl.
[0123] Another embodiment of the present invention provides a
pharmaceutical composition comprising a compound of formula (I) as
defined above, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. In preferred embodiments, the
composition preferably comprises a therapeutically effective amount
of the compound or salt.
[0124] Still another embodiment of the present invention provides a
method for treating a disease or condition in a mammal caused by a
viral infection, particularly a herpes viral infection, comprising
administering to the mammal a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
[0125] A further embodiment of the present invention comprises the
use of a compound of formula (I) or a pharmaceutically acceptable
salt thereof to prepare a medicament for treating or preventing
diseases or disorders caused by a viral infection, and particularly
a herpes viral infection.
[0126] A final embodiment of the present invention comprises a
method for inhibiting a viral DNA polymerase, comprising contacting
(in vitro or in vivo) the polymerase with an effective inhibitory
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
[0127] An object of the present invention is to provide novel
compounds having biological activity.
[0128] A further object of the present invention is to provide
novel pharmaceutical compositions.
[0129] Still another object of the present invention is to provide
a method for treating a disease or condition in a mammal caused by
a viral infection, particularly a herpes virus infection.
[0130] Another object of the present invention is to provide a
method for inhibiting a viral DNA polymerase.
[0131] These, and other objects, will readily be apparent to those
skilled in the art as reference is made to the detailed description
of the preferred embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0132] In describing the preferred embodiment, certain terminology
will be utilized for the sake of clarity. Such terminology is
intended to encompass the recited embodiment, as well as all
technical equivalents which operate in a similar manner for a
similar purpose to achieve a similar result.
[0133] 1. Terminology Definitions
[0134] The following definitions are used, unless otherwise
described: halo is fluoro, chloro, bromo, or iodo. Alkyl denotes
both straight and branched groups; but reference to an individual
radical such as "propyl" embraces only the straight chain radical,
a branched chain isomer such as "isopropyl" being specifically
referred to. When alkyl can be partially unsaturated, the alkyl
chain may comprise one or more (e.g., 1, 2, 3, or 4) double or
triple bonds in the chain.
[0135] Aryl denotes a phenyl radical or an ortho-fused bicyclic
carbocyclic radical wherein at least one ring is aromatic. Het is a
four- (4), five- (5), six- (6), or seven- (7) membered saturated or
unsaturated ring containing 1, 2 or 3 heteroatoms selected from the
group consisting of non-peroxide oxygen, sulfur, and nitrogen,
which is optionally fused to a benzene ring, or any bicyclic
heterocyclic group. Het includes "heteroaryl", which encompasses a
radical attached via a ring carbon of a monocyclic aromatic ring
containing five or six ring atoms consisting of carbon and 1, 2, 3,
or 4 heteroatoms each selected from the group consisting of
non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H,
O, C.sub.1-4alkyl, phenyl or benzyl.
[0136] 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 mixture thereof, of a
compound of the invention, which possesses 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 antiviral activity using the standard tests described
herein, or using other similar tests which are well known in the
art.
[0137] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating a lower and upper
number of carbon atoms in the moiety, i.e., the prefix C.sub.i-j
indicates a moiety of the integer "i" to the integer "j" carbon
atoms, inclusive. Thus, for example, C.sub.1-7alkyl refers to alkyl
of one to seven carbon atoms, inclusive.
[0138] The compounds of the present invention are generally named
according to the IUPAC or CAS nomenclature system. Abbreviations
which are well known to one of ordinary skill in the art may be
used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h"
for hour or hours and "rt" for room temperature).
[0139] Specific and preferred 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. The compounds of the invention
include compounds of formula (I) having any combination of the
values, specific values, more specific values, and preferred values
described herein.
[0140] Mammal denotes human and animals, specifically including
food animals and companion animals.
[0141] 2. The Invention
[0142] The present invention comprises compounds of formula (I) as
defined above, and their pharmaceutically acceptable salts.
[0143] For the compounds of formula (I), alkyl can be methyl,
ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl,
3-pentyl, hexyl, heptyl, etc.; C.sub.3-8cycloalkyl can be
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,
butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy,
1-methylhexyloxy, or heptyloxy; het can be azetidinyl,
3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino, morpholino,
thiomorpholino, or heteroaryl; and heteroaryl can be furyl,
imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl,
(or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,
isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
[0144] When alkyl is partially unsaturated, it can be vinyl, allyl,
1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.
[0145] Specific examples of W1 include, 4567891011121314
[0146] Specific examples of W2 include, 151617
[0147] Specific examples of W3 include: 18
[0148] Specific examples of W4 include, 1920
[0149] Specific examples of W5 include: 2122
[0150] Specific examples of W6 include: 2324
[0151] Specific examples of W7 include, 2526
[0152] Specific examples of W8 include: 27
[0153] Particularly preferred compounds are those where X is Cl and
G is 4-morpholinylmethyl.
[0154] Examples of the present invention include, but are not
limited to the following:
[0155]
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-imidazo[4,5,1-i-
j]quinoline-5-carboxamide;
[0156]
N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-6H-imidazo[4,5,1--
ij]quinoline-5-carboxamide;
[0157]
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-6H-imidazo[4,5,1-ij]qu-
inoline-5-carboxamide;
[0158]
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihyd-
ro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
[0159]
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-1,2-dihydro-6H-
-pyrrolo-[3,2,1-ij]quinoline-5-carboxamide;
[0160]
1-amino-N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-1,2-dihydr-
o-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
[0161]
N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-
-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
[0162]
N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2--
dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
[0163]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihy-
dro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0164]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7-
H-[1,3,4]-oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0165]
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihyd-
ro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0166]
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-ox-
o-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0167]
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihy-
dro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0168]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihy-
dro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0169]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7-
H-[1,3,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0170]
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihyd-
ro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0171]
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-ox-
o-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0172]
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]-
thiazino-[2,3,4-ij]quinoline-6-carboxamide;
[0173]
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl-
)-7H-[1,4]-thiazino[2,3,4-ij]quinoline-6-carboxamide;
[0174]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]thiaz-
ino[2,3,4-ij]-quinoline-6-carboxamide;
[0175]
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]-
thiazino [2,3,4-ij]quinoline-6-carboxamide;
[0176]
N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-
-[1,4]thiazino-[2,3,4-ij]quinoline-6-carboxamide;
[0177]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1-
,3]oxazino-[5,4,3-ij]quinoline-6-carboxamide;
[0178]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]ox-
azino[5,4,3-ij]quinoline-6-carboxamide;
[0179]
N-(4-chlorobenzyl)-7-oxo-3-phenyl-9-(tetrahydro-2H-pyran-4-ylmethyl-
)-1H,7H-[1,3]oxazino [5,4,3-ij]quinoline-6-carboxamide;
[0180]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,-
3]oxazino-[5,4,3-ij]quinoline-6-carboxamide;
[0181]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-3-phenyl-
-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0182]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-3-phenyl-2,3--
dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0183]
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-ox-
o-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0184]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-3-phenyl--
2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0185]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,3,7-trioxo-2,3-dihydr-
o-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0186]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,3,7-trioxo-2,3-dihydro-1H,-
7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0187]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,3,7-trioxo-2,3-dihydro-
-1H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0188]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1-
H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0189]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H--
pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0190]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-2,3-dihydro-1-
H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0191]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-2,3-dihydro-1H,7H--
pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0192]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0193]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0194]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3--
dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0195]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-
-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
[0196]
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-2,3--
dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
[0197]
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo--
2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
[0198]
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-me-
thyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxam-
ide;
[0199]
1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3--
dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
[0200]
1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-2,7-dioxo-2,3-dihyd-
ro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
[0201]
1-benzyl-N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-2,7-dioxo-2,3-d-
ihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
[0202]
1-benzyl-N-(4-chlorobenzyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-2,7--
dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
[0203]
N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihy-
dro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
[0204]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1-
,3]thiazino-[5,4,3-ij]quinoline-6-carboxamide;
[0205]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]th-
iazino[5,4,3-ij]quinoline-6-carboxamide;
[0206]
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-3-pheny-
l-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
[0207]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,-
3]thiazino-[5,4,3-ij]quinoline-6-carboxamide;
[0208]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-methyl-7-oxo-3-phenyl-2,3--
dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0209]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-methyl-7-oxo-3-phenyl-
-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0210]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2-methyl-7-oxo-3phenyl-2-
,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0211]
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-2-methyl-7-ox-
o-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0212]
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihyd-
ro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0213]
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-d-
ihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
[0214]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-(4-morpholinyl)-7-oxo-
-7H-[1,3,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0215]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-(4-morpholinyl)-7-oxo-7H-[-
1,3,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0216]
N-(4-chlorobenzyl)-2-(4-morpholinyl)-9-(4-morpholinylmethyl)-7-oxo--
7H-[1,3,4]-thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0217]
N-(4-chlorobenzyl)-2-(4-morpholinyl)-7-oxo-9-(tetrahydro-2H-pyran-4-
-ylmethyl)-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
[0218]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-1H,7H-pyra-
zino[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
[0219]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H--
pyrazino-[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
[0220]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-1H,7H-
-pyrazino-[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
[0221]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]th-
iazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0222]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,-
4]thiazino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0223]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1-
,4]thiazino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0224]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1-
,4]oxazino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0225]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,-
4]oxazino-[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0226]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]ox-
azino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
[0227]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-
-de]-quinoxaline-6-carboxamide;
[0228]
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-3H,7H-pyrido[-
1,2,3-de]-quinoxaline-6-carboxamide;
[0229]
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-3H,7H-pyrido[1-
,2,3-de]-quinoxaline-6-carboxamide;
[0230]
N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl-
)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
[0231] 2-(benzyl
amino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-
H,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide;
[0232]
N-(4-chlorobenzyl)-10-(3-hydroxypropyl)-2,4,8-trioxo-1,2,3,4-tetrah-
ydro-8H-[1,4]-diazepino[3,2,1-ij]quinoline-7-carboxamide;
[0233]
N-(4-chlorobenzyl)-10-(3-hydroxy-1-propynyl)-2,4,8-trioxo-1,2,3,4-t-
etrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
[0234]
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,4,8-trioxo-1,2,3,4-te-
trahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
[0235]
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetra-
hydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
[0236]
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-
-imidazo-[4,5,1-ij]quinoline-5-carboxamide;
[0237]
N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-2,6-dioxo-1,2-dihydro-6-
H-imidazo-[4,5,1-ij]quinoline-5-carboxamide;
[0238]
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-2,6-dioxo-1,2-dihydro-6H-imi-
dazo[4,5,1-ij]quinoline-5-carboxamide;
[0239]
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1-[2-(1-piperi-
dinyl)ethyl]-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
[0240]
N-(4-chlorobenzyl)-1-[2-(4-methyl-1-piperazinyl)ethyl]-8-(4-morphol-
inylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxam-
ide;
[0241]
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-
-[1,4]-oxazepino[2,3,4-ij]quinoline-7-carboxamide;
[0242]
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]-
oxazino-[2,3,4-ij]quinoline-6-carboxamide;
[0243]
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl-
)-7H-[1,4]-oxazino[2,3,4-ij]quinoline-6-carboxamide;
[0244]
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]oxazi-
no[2,3,4-ij]-quinoline-6-carboxamide;
[0245]
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]-
oxazino [2,3,4-ij]quinoline-6-carboxamide;
[0246]
N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-
-[1,4]oxazino-[2,3,4-ij]quinoline-6-carboxamide;
[0247]
2-benzyl-N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,-
3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide;
[0248]
N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-4,7-dioxo-1,2-dihydro-4H,7H--
imidazo-[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
[0249]
N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-4,7-dioxo-1,2-dihydro-4H-
,7H-imidazo-[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
[0250]
N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-4,7-dioxo-1,2-dihydro-4-
H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
[0251]
N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-3-oxo-9,10-dihydro-3H,8H-
-pyrido[3,2,1-ij]quinoline-2-carboxamide;
[0252]
N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-d-
ihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide
hydrobromide;
[0253] and pharmaceutically acceptable salts thereof.
[0254] Representative examples of the synthesis of compounds
falling within the scope of formulas W1-W8 are as follows.
[0255] The following Charts A-BQ describe the preparation of the
compounds of the present invention. All of the starting materials
are prepared by procedures described in these charts or by
procedures analogous thereto, which would be well known to one of
ordinary skill in organic chemistry. All of the final compounds of
the present invention are prepared by procedures described in these
charts or by procedures analogous thereto, which would be well
known to one of ordinary skill in organic chemistry. All of the
variables used in the charts are as defined below or as in the
claims.
[0256] W1.1. 6-Oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides The
preparation of specific examples of heterocycle W1.1 is described
in Chart A. 2-Nitroaniline is iodinated with iodine monochloride to
afford A.1 (Wilson, et. al., Aust. J. Chem., 1983, 36, 2317-2326)
which is heated with diethyl ethoxymethylenemalonate in a mixture
of diphenyl ether/biphenyl, initially at 150.degree. C. to generate
diethyl 2-[(2-amino-4-iodoanilino)methylene]malonate and then at
240.degree. C. to cyclize this intermediate to ethyl
4-hydroxy-6-iodo-8-nitro-3-quinolin- ecarboxylate (A.2). Stannous
chloride reduction of A.2 affords ethyl
8-amino-4-hydroxy-6-iodo-3-quinolinecarboxylate A.3 which reacts
with 4-chlorobenzylamine to give
8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-
-quinolinecarboxamide A.4. Intermediate A.4 reacts with ethyl
orthoformate to give
N-(4-chlorobenzyl)-8-iodo-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-c-
arboxamide (A.5). Palladium mediated carbonylation of A.5 in
presence of tributyl tin hydride or trioctylsilane (Kotsuki et.
al., Synthesis 1996, 470) affords A.6 which is reductively aminated
with morpholine and sodium cyanoborohydride to give A.7. Specific
examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are
prepared as described in Chart B. Palladium catalyzed coupling of
A.5 with an electron-rich acetylene (e.g. propargyl alcohol,
Z=CH.sub.2OH) gives B.1 (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467. or Fisher, M. J. et. al. J. Med.
Chem. 1997, 40, 2085.). Saturation of the alkyne by hydrogenation
catalyzed by palladium on carbon in alcoholic solvents affords
alkyl derivatives of formula B.2 (Z=CH.sub.2OH). 28
[0257] W1.3.
6-Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide- s.
The preparation of specific examples of heterocycle W1.3 is
described in Chart C. Condensation of an indoline C.1 (e.g.
2,2-dimethylindoline, R.sup.13=2,2-dimethyl) with diethyl
ethoxymethylenemalonate followed by cyclization of the resulting
enamine C.2 in a mixture of polyphosphoric acid or Eaton's Reagent
affords esters of the formula C.3. Halogenation such as bromination
employing bromine in acetic acid provides compounds of the general
formula C.4. The resulting product is then coupled with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
to provide the corresponding alkynyl derivative C.5. The resulting
ester is reacted with a substituted benzylamine (e.g.
4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) in
the presence of sodium methoxide or other appropriate amidation
catalyst to afford amides of the formula C.6. Saturation of the
alkyne by hydrogenation catalyzed by palladium on carbon in
alcoholic solvents affords alkyl derivatives of formula C.7 (e.g.
Z=CH.sub.2OH). 29
[0258] Alternatively, intermediates of the formula C.4 are
derivatized as shown in Chart D. The resulting ester is reacted
with a substituted benzylamine (e.g. 4-chlorobenzylamine,
4-fluorobenzylamine, or 4-bromobenzylamine) in the presence of
sodium methoxide or other appropriate amidation catalyst to afford
amides of the formula D.1. Coupling of compounds of the formula D.1
with hydroxymethyl(tributyl)-sta- nnane (Danheiser, R. L.; Romines,
K. R.; Koyama, H. Org. Syn. 1992, 71, 133-139) and a palladium
catalyst (e.g. tetrakistriphenylphosphine palladium) affords
compounds of the formula D.2. Treatment of the resulting alcohol
with methane-sulfonyl chloride in the presence of an amine base
(e.g. collidine) followed by a primary or secondary amine
(HNR.sup.1R.sup.2, e.g. morpholine) provides compounds of the
formula D.3. 30
[0259] As shown in Chart E, radical bromination of compound C.5
(R.dbd.H) with N-bromosuccinimide, benzoyl peroxide, and carbon
tetrachloride affords the benzylic bromide E.1. Displacement of the
bromide with excess azide in an appropriate solvent such as DMF or
THF at temperatures from 0-100.degree. C. provides E.2. Elaboration
of the ester to the carboxamide as described in previous examples
gives intermediates of the formula E.3. This azide is reduced to
give the amine E.4 by treating the azide with triphenylphosphine in
THF followed by water hydrolysis of the iminophosphorane
intermediate at temperatures from 10-65.degree. C. Saturation of
the alkyne by hydrogenation catalyzed by palladium on carbon in
alcoholic solvents affords alkyl derivatives of formula E.5 (e.g.
Z=CH.sub.2OH). The amine can then be alkylated or acylated via
conditions well known to those skilled in the art to give analogs
defined by NR.sup.10R.sup.11. 31
[0260] Alternatively as described in Chart F, intermediate C.3
(R.dbd.H) can be subjected to the same benzylic bromination
conditions to give bromide F.1, followed by displacement of the
bromide to give the azide F.2. The azide can then be reduced to the
amine F.3 as described above and elaborated to the Boc-protected
derivative F.4 by treating with di-t-butyldicarbonate and an
appropriate base (triethylamine, NaHCO.sub.3). Conversion of the
ethyl ester to the carboxamide F.6 can be achieved as described in
prior examples. Palladium catalyzed carbonylation of the aryl
iodide in the presence of tributyltin hydride provides the aryl
aldehyde F.7. Reductive amination of F.7 with a primary or
secondary amine (e.g. morpholine) and sodium cyanoborohydride
affords F.8. Removal of the Boc-group with HCl in dioxane or
trifluoroacetic acid results in analog F.9, which can be alkylated
or acylated to give a variety of analogs. 32
[0261] More specifically examples of heterocycle W1.3 are prepared
as described in Chart G. Reduction of indoline-2-carboxylic acid
(G.1) with borane in THF affords alcohol G.2. Protection of the
indoline nitrogen as the benzyl carbamate can be achieved using
benzyl chloroformate, THF, and aqueous sodium bicarbonate to give
G.3. Iodination using NIS in DMF at elevated temperatures
(40-80.degree. C.) provides compound G.4. The carbamate is removed
using HBr in acetic acid to give acetate G.5, which is cyclized via
a two-step protocol using diethyl ethoxymethylenemalonate and
Eaton's Reagent (or polyphosphoric acid) to give G.6. Condensation
of this ester with a benzylamine (e.g. 4-chlorobenzylamine,
4-bromobenzylamine, or 4-fluorobenzylamine) at high temperatures
affords amides of the formula G.7. This material is then coupled
with an electron-rich acetylene (e.g. propargyl alcohol) catalyzed
by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide either in
diethylamine or in a mixture of DMF and triethylamine to provide
the corresponding alkynyl derivative G.8. Saturation of the alkyne
by hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula G.9. 33
[0262] W 1.5.
7-Oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6--
carboxamides. The preparation of specific examples of heterocycle
W1.5 is described in Chart H following an established literature
precedent (J. Med. Chem. 1988, 31, 991-1001.). Reaction of
.beta.-ketoesters of the formula H.1 (prepared as described in
Chart J, where Y=iodo; Chart K, where Y=morpholinylmethyl; and
Chart L, where Y=4-tetrahydropyranylmethyl- ) with acetic anhydride
and triethylorthoformate followed by treatment of the resulting
enol ether with a formyl-substituted hydrazine (e.g.
1-formyl-1-methylhydrazine, R.sup.7=methyl, U.S. Pat. No.
5,985,874) affords derivatives of the general formula H.2.
Treatment of H.2 with potassium hydroxide followed by formic acid
and formaldehyde affords cyclized compounds of the general formula
H.3. The resulting carboxylic acid H.3 is then coupled with a
benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or
4-bromobenzylamine) mediated by 1,1'-carbonyldiimidazole (or other
suitable carboxylic acid activating agent) to provide amides of the
general formula H.4. 34
[0263] As described in Chart I, to prepare derivatives where
G=3-hydroxypropyl or 3-hydroxy-1-propynyl, intermediate H.4
(Y=iodo) is further derivatized by Sonogashira coupling with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
provides the corresponding alkynyl derivatives of formula I.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula I.2 (Z=CH.sub.2OH). 35
[0264] H.1 (Y=iodo) is prepared as described in Chart J. lodination
of 2,3-difluorobenzoic acid J.1 affords 2,3-difluoro-5-iodobenzoic
acid J.2. Conversion of J.2 to its corresponding imidazolide with
1,1'-carbonyldiimidazole followed by treatment with the
trimethylsilyl ester of ethyl hydrogen malonate in the presence of
DBU (Wang, X.; William, T. M.; Napier, J. J.; Ghannam, A.
Tetrahedron Lett. 1994, 35, 9323-9326.) provides .beta.-ketoester
H.1 (Y=iodo) which may be employed as in Chart H. 36
[0265] H.1 (Y=morpholinylmethyl) is prepared as described in Chart
K. Reductive amination of
3,4-difluoro-4-trifluoromethylbenzaldehyde K.1 with morpholine in
the presence of triacetoxyborohydride and acetic acid affords K.2.
Hydrolysis of K.2 in sulfuric acid provides carboxylic acid K.3.
Conversion of K.3 according to methods analogous to those described
in Chart J affords .beta.-ketoester H.1 (Y=morpholinylmethyl) which
may be employed as in Chart H. 37
[0266] H.1 (Y=4-tetrahydropyranylmethyl) is prepared as described
in Chart L. Wittig olefination between K.1 and
4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky,
W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing
sodium hexamethyldisilazide as base provides the olefin L.1.
Saturation of the olefin by hydrogenation of L.1 employing
palladium on carbon as catalyst affords L.2. Hydrolysis of L.2 in
sulfuric acid provides carboxylic acid L.3. Conversion of L.3
according to methods analogous to those described in Chart J
affords .beta.-ketoester H.1 (Y=4-tetrahydropyranylmethyl) which
may be employed as in Chart H. 38
[0267] W1.6.
7-Oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6--
carboxamides. The preparation of specific examples of heterocycle
W1.6 is described in Chart M following an established literature
precedent (Bull. Chem. Soc. Jpn. 1996, 69, 1371-1376.). Alcohol
AM.4 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) is
treated with thionyl chloride followed by sodium thiol and then
sodium hydride to afford the quinoline M.1. The resulting ester is
then treated with a benzylamine (e.g. 4-chlorobenzylamine,
4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to
afford the corresponding amides of the general formula M.2.
Specific examples where G=3-hydroxypropyl or 3-hydroxy-1-propynyl
are prepared as described in Chart N from intermediate M.2 (Y=iodo)
by Sonogashira coupling with an electron-rich acetylene (e.g.
propargyl alcohol, Z=CH.sub.2OH) catalyzed by
PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide either in
diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine
(Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the
corresponding alkynyl derivatives of formula N.1 (Z=CH.sub.2OH).
Saturation of the alkyne by hydrogenation catalyzed by palladium on
carbon in alcoholic solvents affords alkyl derivatives of formula
N.2 (Z=CH.sub.2OH). 39
[0268] W 1.7.
7-Oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide.
Representative examples of heterocycle W1.7 are prepared as
described in Chart O in analogy to reported pyridobenzthiazino ring
synthesis (Okada, T. et. al. J. Heterocyclic Chem. 1991, 28, 1067).
The reaction of intermediate H.1 (Y=iodo, morpholinylmethyl, or
tetrahydropyranylmethyl) with acetic anhydride and
triethylorthoformate followed by condensation of the resulting enol
ether with an allylic amine (e.g. 3-amino-1-butene, Roberts, J. D.;
Mazur, R. H. J. Am. Chem. Soc. 1951, 73, 2509) affords the enamine
of formula O.1. Cyclization of O.1 in the presence of a base (e.g.
sodium hydride) provides quinolones of the formula O.2. Subsequent
ozonolysis affords the carboxaldehyde O.3 which upon treatment with
sodium hydrosulfide in DMF provides the tricycle O.4. Treatment of
O.4 with thionylchloride followed by lithium chloride promoted
elimination at elevated temperatures affords O.5. The resulting
ester is saponified under dilute acid conditions and coupled with a
benzylamine (e.g. 4-chlorobenzylamine) mediated by
1,1'-carbonyldiimidazole (or other suitable carboxylic acid
activating agent) to provide amides of the general formula 0.7. In
the case where Y=iodo, compounds of the general formula O.7 are
further derivatized as described in Chart P. Sonogashira coupling
between 0.7 (Y=iodo) and an electron-rich acetylene (e.g. propargyl
alcohol, Z=CH.sub.2OH) catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and
copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada,
Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture
of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997,
40, 2085.) provides the corresponding alkynyl derivatives of
formula P.1 (Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula P.2 (Z=CH.sub.2OH).
4041
[0269] Additional examples of heterocycle W1.7 are prepared as
described in Chart Q. 4-Iodo-2-fluoroaniline (Q.1) is condensed
with diethyl ethoxymethylenemalonate under thermal conditions to
provide 4-hydroxyquinoline Q.2. The resulting ester is converted to
the corresponding amide of the formula Q.3 by either heating with a
substituted benzylamine (e.g. 4-chlorobenzylamine), or by
saponification of the ester to the acid, activation of the acid
using a suitable agent (e.g. 1,1'-carbonyldiimidazole), and
condensation with the above substituted benzylamine. The
hydroxyquinolines are then reacted with an .alpha.-bromo ketones to
afford compounds of the formula Q.4 (R is a subset of R.sup.15
including optionally substituted alkyl or cycloalkyl, aryl, or
het). The resulting ketones are treated with sodium hydrosulfide in
DMF to afford compounds of the formula Q.5 directly, or in cases
where elimination is not spontaneous, the intermediate alcohol is
transformed as described above in Chart O. Intermediate Q.5 is
transformed to the corresponding derivatives where G is optionally
unsaturated C.sub.1-4alkyl substituted by hydroxy in a manner
analogous to that previously described in Chart P(P.1, P.2).
Alternatively, Q.5 is formylated employing carbon monoxide, a
palladium catalyst, and an appropriate reducing agent to provide
carboxaldehydes of the formula Q.6. Subsequent reductive amination
between Q.6 and a primary or secondary amine (e.g. morpholine)
affords compounds of the formula Q.7. 42
[0270] W1.8.
7-Oxo-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamides. The
preparation of specific examples of heterocycle W1.8 is described
in Chart R. Hydroxyalkylanilines of the formula R.1 (prepared as
described in Chart T when Y=morpholinylmethyl; Chart U when
Y=tetrahydropyranylmeth- yl; Chart U when Y=iodo and R.sup.13 is
not hydrogen; or according to literature methods when Y=iodo and
R.sup.13 is hydrogen as described by Cambell, S. F. J. Med. Chem.
1988, 31, 2048-2056.) are condensed with diethyl
ethoxymethylenemalonate to provide the corresponding enamine R.2.
Acylation of the hydroxyl group employing the conditions of Tani,
J. et. al. Chem. Pharm. Bull. 1982, 30, 3517. affords malonate R.3.
Cyclization of R.3 under thermal conditions or in a mixture of
Eaton's reagent affords quinoline derivatives of the formula R.4.
The resulting ester is then heated with a benzylamine (e.g.
4-chlorobenzylamine) to afford a corresponding carboxamide such as
R.5. Treatment of R.5 with an acetal or ketal and p-toluenesulfonic
acid in N-methylpyrrolidinone as solvent (EP 373,531) affords
tricycles of the formula R.6. Compounds of formula R.5 react with
1,1'-carbonyldiimidazole in DMF to give the
3,7-dioxo-1H,7H-[1,3]oxazino[5,4,3-ij]quinolines of structure R.6
(R.sup.13 and R.sup.14=.dbd.O). 43
[0271] In the case where Y=iodo, the intermediate R.6 is further
elaborated as described in Chart S by Sonogashira coupling with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
to provide the corresponding alkynyl derivatives of formula S.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula S.2 (Z=CH.sub.2OH). 44
[0272] R.1 (Y=morpholinylmethyl) is prepared as described in Chart
T. Methyl 3-bromomethyl-6-nitrobenzoate T.1 (Bioorg. Med. Chem.
Lett. 1997, 7, 1921.) is treated with morpholine to afford the
N-benzylmorpholine T.2. Reduction of the nitro functionality with
tin(II) chloride provides the aniline T.3 which is further reduced
with diisobutyl aluminum hydride to afford R.1
(Y=morpholinylmethyl, R.sup.13=hydrogen). To prepare compounds in
which R.sup.13 is other than hydrogen, this material can be further
elaborated by manganese dioxide oxidation (J. Heterocyclic Chem.
1993, 30, 1533; J. Med. Chem. 1988, 31, 2048) to afford the
corresponding carboxaldehyde T.4. The reaction of T.4 with alkyl-
or aryllithium and Grignard reagents (e.g. phenyl magnesium
bromide) (Aust. J. Chem. 1992, 45, 21.) provides hydroxyanilines
R.1 (Y=morpholinylmethyl, R.sup.13=optionally substituted alkyl,
aryl, or het). 45
[0273] R.1 (Y=tetrahydropyranylmethyl) is prepared as described in
Chart U. Wittig olefination between
3-methylcarboxylate-4-nitrobenzaldehyde U.1 (J. Med. Chem. 1988,
41, 1476.) and 4-tetrahydropyranylphosphonium bromide (Bestmann, H.
J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.)
employing sodium hexamethyldisilazide as base provides the olefin
U.2. Hydrogenation of U.2 catalyzed by palladium on carbon provides
the aniline U.3 which is further reduced with diisobutyl aluminum
hydride to afford R.1 (Y=tetrahydropyranylmethyl,
R.sup.13=hydrogen). To prepare compounds in which R.sup.13 is other
than hydrogen, this material can be further elaborated as above by
manganese dioxide oxidation to afford the corresponding
carboxaldehyde U.4. The reaction of U.4 with alkyl- or aryllithium
and Grignard reagents (e.g. phenyl magnesium bromide) provides
hydroxyanilines R.1 (Y=tetrahydropyranylmethyl, R.sup.13=optionally
substituted alkyl, aryl, or het). 46
[0274] R.1 (Y=iodo, R.sup.13=optionally substituted alkyl, aryl, or
het) is prepared as described in Chart V.
2-Hydroxymethyl-4-iodoaniline (R.1, Y=iodo, R.sup.13=hydrogen)
(Cambell, S. F. J. Med. Chem. 1988, 31, 2048-2056.) is oxidized
with manganese dioxide to afford the corresponding carboxaldehyde
V.1. The reaction of U.4 with alkyl- or aryl-Grignard reagents
(e.g. phenyl magnesium bromide) provides hydroxyanilines R.1
(Y=iodo, R.sup.13=optionally substituted alkyl, aryl, or het).
47
[0275] W1.9.
7-Oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxa-
mides. The preparation of specific examples of heterocycle W1.9 is
described in Chart X following an established literature precedent
(Chem. Pharm. Bull 1994, 42, 2569.). Reaction of .beta.-ketoesters
of the formula H.1 (prepared as described in Chart I, where Y=iodo;
Chart J, where Y=morpholinylmethyl; and Chart K, where
Y=4-tetrahydropyranylmethyl- ) with acetic anhydride and
triethylorthoformate followed by treatment of the resulting enol
ether with an .beta.-aminoalcohol (e.g. 2-aminophenylethanol,
Y=phenyl) affords derivatives of the general formula X.1.
Cyclization of X.1 in the presence of a sodium carbonate employing
N,N-dimethylformamide as solvent provides quinoline X.2.
Bromination of the resulting alcohol employing carbon tetrabromide
and triphenylphosphine provides alkyl bromide X.3. Hydrolysis of
the ester under acidic conditions followed by treatment of the
resulting acid X.4 with a primary amine (e.g. methylamine) affords
the quinoline X.5. The carboxylic acid is then coupled with a
benzylamine (e.g. 4-chlorobenzylamine) mediated by
1,1'-carbonyldiimidazole (or other suitable carboxylic acid
activating agent) to provide amides of the general formula X.6.
48
[0276] To prepare derivatives where G=3-hydroxypropyl or
3-hydroxy-1-propynyl, intermediate X.6 is further derivatized as in
Chart Y by Sonogashira coupling with an electron-rich acetylene
(e.g. propargyl alcohol, Z=CH.sub.2OH) catalyzed by
PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide either in
diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine
(Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide
the corresponding alkynyl derivatives of formula Y.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula Y.2 (Z=CH.sub.2OH). 49
[0277] The preparation of other specific examples of heterocycles
W1.9 are shown in Charts Y-AD. Compounds of the formula Z.1
(prepared as in Chart AA where Y=morpholinylmethyl; Chart AB where
Y=3-hydroxypropyl or 3-hydroxy-1-propynyl) react with oxalyl
chloride to afford
2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides
of the general formula Z.2. 50
[0278] Z.1 (Y=morpholinylmethyl) is prepared as described in Chart
AA. 2-Nitro-4-methylaniline (AA.1) is heated with diethyl
ethoxymethylenemalonate to afford enamine AA.2 which is cyclized by
refluxing in Dowtherm A to give 3-quinolinecarboxylate AA.3 (Peet,
N. P. J. Med. Chem. 1985, 28, 298-302). Ester AA.3 is reacted with
N-bromosuccinimide in 1,2-dichloroethane to give alkyl bromide
AA.4. The crude reaction product is treated with morpholine to give
AA.5 which is reduced by hydrogenation over palladium on carbon
catalyst to provide AA.6. The resulting ester is reacted with a
substituted benzylamine (e.g. 4-chlorobenzylamine,
4-fluorobenzylamine, or 4-bromobenzylamine) to give amides of the
formula Z.1 (Y=morpholinylmethyl) which may be employed as
described in Chart Z.
[0279] Z.1 (Y=3-hydroxypropyl and 3-hydroxy-1-propynyl) is prepared
as described in Chart AB. Sonogashira coupling of A.2 with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
provides the alkynyl-substituted quinoline AB.1. Stannous chloride
reduction of the nitro group provides the aminoquinoline Z.1.
(Y=3-hydroxy-1-propynyl, Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula Z.1
(Y=3-hydroxypropyl, Z=CH.sub.2OH). 51 52
[0280] Alternatively, compounds of the formula Z.1
(Y=morpholinylmethyl, 3-hydroxypropyl, and 3-hydroxy-1-propynyl)
react with bromoacetic anhydride (R.dbd.H) or 2-bromoalkanoyl
bromides (e.g. 2-bromopropionyl bromide, R=methyl) to give
tricyclic compounds of the formula AC.1, Chart AC. Likewise,
compounds of the formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl,
and 3-hydroxy-1-propynyl) react with ethyl bromoacetate to afford
3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carbo-
xamides according to the general formula AD.1, Chart AD. 53
[0281] Additional examples of heterocycle W1.9. are prepared as
described in Chart AE. The previously described .beta.-ketoester
H.1 is reacted with triethyl orthoformate in refluxing acetic
anhydride to provide enol ether AE.1, which is further reacted with
a mono-tert-butyloxycarbonyl protected ethylenediamine derivitive
(where R is defined according to R.sup.13) to afford compounds of
the formula AE.2. Treatment of AE.2 with cesium carbonate in DMF
effects cyclization to afford tricycles of the formula AE.3.
Palladium catalyzed carbonylation using carbon monoxide gas and
tri-n-butylstannane provides carboxaldehyde AE.4, and subsequent
reductive amination with morpholine and sodium
triacetoxyborohydride affords compounds of the formula AE.5.
Aminolysis of the resulting ester using a substituted benzylamine
(e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or
4-bromobenzylamine) in methanol with catalytic sodium methoxide
provides AE.6, which is converted to AE.7 on exposure to
trifluoromethanesulfonic acid. The nitrogen of the quinoxaline ring
in AE.7 may be alkylated, acylated, sulfonylated, etc. giving
compounds of formula AE.8. 54
[0282] Alternatively, esters of the formula AE.3 are reacted with a
substituted benzylamine (e.g. 4-chlorobenzylamine,
4-fluorobenzylamine, or 4-bromobenzylamine) in methanol employing
catalytic sodium methoxide to provide amides of the structure AF.1,
which is converted to AF.2 on exposure to trifluoromethanesulfonic
acid. The nitrogen of the quinoxaline ring in AF.2 may be
alkylated, acylated, sulfonylated, etc. (R.sup.N as defined
according to R.sup.7) giving compounds of formula AF.3. Palladium
catalyzed coupling of AF.3 with an electron-rich acetylene (e.g.
propargyl alcohol, Z=CH.sub.2OH) gives AF.4 (Sonogashira, K.;
Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. or
Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.). Saturation of
the alkyne by hydrogenation catalyzed by palladium on carbon in
alcoholic solvents affords alkyl derivatives of formula AF.5
(Z=CH.sub.2OH). 55
[0283] As described in Chart AG, condensation of AE.1 (Y=iodo,
morpholinylmethyl, or tetrahydropyranylmethyl) with a
2-aminoalkanoic amide (e.g. glycine methylamide) followed by
treatment with a base such as sodium hydride provides compounds
illustrated by formula AG.1. The resulting ester is treated with a
benzylamine (e.g. 4-chlorobenzylamine) at high temperature to
afford the corresponding carboxamides of the general formula AG.2.
In the case where Y=iodo, AG.2 is further derivatived as in Chart
AH employing a Sonogashira coupling with an electron-rich acetylene
(e.g. propargyl alcohol, Z=CH.sub.2OH) gives AH.1. Saturation of
the alkyne by hydrogenation catalyzed by palladium on carbon in
alcoholic solvents affords alkyl derivatives of formula AF.5
(Z=CH.sub.2OH). 56 57
[0284] W1.10.
7-Oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-
-carboxamides. The preparation of specific examples of heterocycle
W1.10 is described in Chart AI following an established literature
precedent (Bull. Chem. Soc. Jpn. 1996, 69, 1371-1376.). Alcohol
AM.4 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) is
treated with thionyl chloride followed by a primary amine to afford
quinoline AI.1. The resulting ester is then treated with a
benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or
4-fluorobenzylamine) at high temperature to afford the
corresponding amides of the general formula AI.2 Specific examples
where G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as
described in Chart AJ from intermediate AI.2 (Y=iodo) by
Sonogashira coupling with an electron-rich acetylene (e.g.
propargyl alcohol, Z=CH.sub.2OH) catalyzed by
PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide either in
diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine
(Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the
corresponding alkynyl derivatives of formula AJ.1 (Z=CH.sub.2OH).
Saturation of the alkyne by hydrogenation catalyzed by palladium on
carbon in alcoholic solvents affords alkyl derivatives of formula
AJ.2 (Z=CH.sub.2OH). 58
[0285] W1.11.
2,7-Dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carb-
oxamides. The preparation of specific examples of heterocycle W1.11
is described in Chart AK following an established literature
precedent (Tetrahedron 1995, 51, 11125-11140). Intermediates of the
formula AM.3 (Y=iodo, morpholinylmethyl, or
tetrahydropyranylmethyl) are saponified under basic conditions and
the resulting carboxylic acid is coupled with a substituted
benzylamine (e.g. 4-chlorobenzylamine) promoted by
1,1'-carbonyldiimidazole (or another appropriate carboxylic acid
activating agent) to provide carboxamides of the general formula
AK.1. The resulting carboxamides are treated with
1,3-bis(trimethylsilyl)urea and ethyl malonyl chloride to afford
AK.2. Subsequent heating of a DMSO solution of AK.2 in the presence
of Cs.sub.2CO.sub.3 affords the pyridocinnoline AK.3. Hydrolysis
and decarboxylation of AK.3 is accomplished by heating AK.2 in a
mixture of hydrochloric and acetic acid to afford compounds of the
formula AK.4. In the case where Y=iodo, the intermediate AK.4 is
further elaborated as described in Chart AL by Sonogashira coupling
with an electron-rich acetylene (e.g. propargyl alcohol,
Z=CH.sub.2OH) catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and
copper(I) iodide in a mixture of DMF and triethylamine (Fisher, M.
J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the
corresponding alkynyl derivatives of formula AL.1 (Z=CH.sub.2OH).
Saturation of the alkyne by hydrogenation catalyzed by palladium on
carbon in alcoholic solvents affords alkyl derivatives of formula
AL.2 (Z=CH.sub.2OH). 59
[0286] Other representative examples of heterocycle W1.11 are
prepared as described in Chart AM. Ketoester H.1 (Y=iodo,
morpholinylmethyl, or tetrahydropyranylmethyl) is condensed with a
Boc-protected hydrazine (e.g. tert-butyl
1-methylhydrazinecarboxylate, R.sup.7=methyl, prepared as described
by Oliva, G. A. et. al. J. Heterocyclic Chem. 2000, 37, 47) to
provide derivatives of the formula AM.1. Cyclization of AM.1 in the
presence of a base (e.g. sodium hydride) affords quinolones of the
general formula AM.2 which are subsequently deprotected using
common synthetic methods (Green, T. W.; Wuts, P. G. M. Protective
Groups in Organic Synthesis, 1999) to provide AM.3. Condensation of
AM.3 with formaldehyde provides AM.4. Conversion of the hydroxyl
group to an appropriate leaving group such as the chloride upon
treatment with thionyl chloride and then subsequent displacement
with a malonate diester anion affords quinolone malonates of the
formula AM.5. Cyclization of AM.5 by heating in the presence of an
inorganic base (e.g. cesium carbonate) provides AM.6. Hydrolysis
and decarboxylation of AM.6 is accomplished by initially heating in
the presence of an acid (e.g. acetic acid or trifluoroacetic acid)
followed by further decarboxylation by heating a DMSO solution to
135-165.degree. C. resulting in compounds of the formula AM.7. The
resulting carboxylic acid is then coupled with a benzylamine (e.g.
4-chlorobenzylamine) mediated by an appropriate acid activating
reagent (e.g. 1,1'-carbonyldiimidazole) to afford carboxamides of
the formula AM.8. In the case where Y=iodo, the intermediate AM.8
is further elaborated as described in Chart AN by Sonogashira
coupling with an electron-rich acetylene (e.g. propargyl alcohol,
Z=CH.sub.2OH) catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and
copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada,
Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture
of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997,
40, 2085.) to provide the corresponding alkynyl derivatives of
formula AN.1 (Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula AN.2 (Z=CH.sub.2OH).
6061
[0287] W1.13.
7-Oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carb-
oxamides. Enol ether AE.1 is reacted with a 2-mercaptoethylamine
derivative (where in R is defined according to R.sup.13) to afford
compounds of the formula AO.1 as a mixture of E/Z isomers.
Treatment of AO.1 with cesium carbonate in DMF effects cyclization
to benzthiazine AO.2. Aminolysis of the ethyl ester with a
substituted benzylamine (e.g. 4-chlorobenzylamine,
4-fluorobenzylamine, or 4-bromobenzylamine) provides amides of the
formula AO.3, which are reacted with carbon monoxide and
tri-n-butylstannane under palladium catalysis to afford aldehydes
of the formula AO.4. Reductive amination of the aldehyde using
morpholine and sodium triacetoxyborohydride provides AO.5.
Oxidation of the sulfur with metachloroperbenzoic acid affords
derivatives of the formula AO.6 where n=1 (sulfoxide) or n=2
(sulfone). 62
[0288] Alternatively, amides of the formula AO.3 are reacted
through palladium catalyzed coupling with of an electron-rich
acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH) to give alkynes of
the formula AP.1. Saturation of the alkyne by hydrogenation
catalyzed by palladium on carbon in alcoholic solvents affords
alkyl derivatives of formula AP.2 (Z=CH.sub.2OH). Oxidation of the
sulfur atom found in compounds AP.1 or AP.2 with
meta-chloroperbenzoic acid affords sulfoxide (n=1) or sulfone (n=2)
derivatives of the formulas AP.3 and AP.4, respectively. 63
[0289] W1.14.
7-Oxo-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamides. The
preparation of specific examples of heterocycle W1.14 is described
in Chart AQ. Malonates of the formula R.2 (Y=morpholinylmethyl,
tetrahydropyranylmethyl, or iodo) are converted to their
corresponding thiolacetate AQ.1 by treatment with
triphenylphosphine and diisopropyl azodicarboxylate in the presence
of thiolacetic acid (Volante, R. P. Tetrahedron Lett. 1981, 22,
3119-3122.). Cyclization of AQ.1 under thermal conditions or in a
mixture of Eaton's reagent affords quinoline derivatives of the
formula AQ.2. The resulting ester is then heated with a benzylamine
(e.g. 4-chlorobenzylamine) to afford a corresponding carboxamide
such as AQ.3. Treatment of AQ.3 with an acetal or ketal and
p-toluenesulfonic acid in N-methylpyrrolidinone as solvent (EP
373,531) affords tricycles of the formula AQ.4. 64
[0290] In the case where Y=iodo, the intermediate AQ.4 is further
elaborated as described in Chart AR by Sonogashira coupling with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
to provide the corresponding alkynyl derivatives of formula AR.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula AR.2 (Z=CH.sub.2OH). 65
[0291] W1.15.
7-Oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carbox-
amides. The preparation of specific examples of heterocycle W1.15
is described in Chart AS. Alkylaminoanilines of the formula AS.1
(prepared as described in Chart AU when Y=morpholinylmethyl,
tetrahydropyranylmethyl, or Y=iodo) are condensed with a variety of
aldehydes and ketones (e.g. formaldehyde, R.sup.x=R.sup.y=H;
benzaldehyde, R.sup.x=phenyl, R.sup.y=H) employing literature
methods (Wagner, E. C.; Eisner, A. J. Am. Chem. Soc. 1937, 59,
879-883.; Kempter, G. et. al. J. Prakt. Chem. 1982, 324, 832-840.)
to afford tetrahydroquinazolines of the formula AS.2. Condensation
of AS.2 with diethyl ethoxymethylenemalonate provides the malonate
derivatives AS.3 which are cyclized by heating in a mixture of
Eaton's reagent to afford the substituted quinoline derivatives of
the formula AS.4. The resulting ester is then heated with a
benzylamine (e.g. 4-chlorobenzylamine) to afford a corresponding
carboxamide such as AS.5. 66
[0292] In the case where Y=iodo, the intermediate AS.5 is further
elaborated as described in Chart AT by Sonogashira coupling with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
to provide the corresponding alkynyl derivatives of formula AT.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula AT.2 (Z=CH.sub.2OH). 67
[0293] AS.1 is prepared as described in Chart AU.
Hydroxyalkylamines R.1 where Y=morpholinylmethyl,
tetrahydropyranylmethyl, or iodo (prepared as described previously
in Charts N-P) are oxidized with manganese dioxide or other
suitable oxidizing agent to afford the corresponding aldehyde or
ketone AU.1. Compounds AU.1 are then converted to the amine
derivatives AS.1 by a one step reductive amination employing a
primary amine and sodium cyanoborohydride or in a two step sequence
involving first formation of the imine by treatment with a primary
amine and titanium tetrachloride and then reduction with lithium
aluminum hydride (Chem. Pharm. Bull. 1981, 29, 2135.).
Alternatively when R.sup.7=aryl, compounds of the formula AS.1
(R.sup.Z=aryl) are prepared by a Mannich condensation with anilines
AU.2 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo)
employing procedures described in the literature (Wagner, E. C.;
Eisner, A. J. Am. Chem. Soc. 1937, 59, 879-883.). 68
[0294] Additional representative examples of heterocycle W1.15 are
prepared as described in Chart AV.
2-(Hydroxymethyl)-4-methylaniline (AV.1) is condensed with diethyl
ethoxymethylenemalonate to afford the enamine AV.2 which is
acylated by heating in acetic anhydride to provide enamine AV.3.
Cyclization of AV.3 by heating at high temperature in diphenyl
ether affords quinoline AV.4. The resulting quinoline was acylated
on nitrogen by reaction with isobutyl chloroformate and a base
(e.g. sodium hydride) to provide AV.5 which upon irradiation by
light in the presence of N-bromosuccinimide and subsequent
treatment with a primary or secondary amine (e.g. morpholine)
affords compounds illustrated by AV.6. Reductive amination between
AV.6 and a primary amine (e.g. benzylamine, R=benzyl) employing a
reducing agent such as sodium triacetoxyborohydride affords AV.7.
The resulting ester is then heated with a benzylamine (e.g.
4-chlorobenzylamine) to afford a corresponding carboxamide of the
formula AV.8. Condensation of AV.8 with formaldehyde affords
compounds of the formula AV.9. Alternatively, compounds of the
formula AV.8 are condensed with 1,1'-carbonyldiimidazole to provide
derivatives of the formula AW.1, Chart AW. 6970
[0295] W1.17.
7-Oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide- . The
preparation of specific examples of heterocycle W1.17 is described
in Chart AX following an established literature precedent (Russ. J.
Org. Chem. 1999, 35, 1698-1705). Reaction of .beta.-ketoesters of
the formula H.1 (prepared as described in Chart J, where Y=iodo;
Chart K, where Y=morpholinylmethyl; and Chart L, where
Y=4-tetrahydropyranylmethyl) with acetic anhydride and
triethylorthoformate followed by treatment of the resulting enol
ether with a substituted thiosemicarbazide (e.g.
morpholinothiosemicarbazide, R.sup.15=morpholinyl) affords
compounds of the formula AX.1. Upon heating AX.1 in benzene,
thiadiazinoquinoline AX.2 is provided. The resulting ester is then
treated with a benzylamine (e.g. 4-chlorobenzylamine,
4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to
afford the corresponding amides of the general formula AX.3. 71
[0296] To prepare derivatives where G=3-hydroxypropyl or
3-hydroxy-1-propynyl, intermediate AX.3 (Y=iodo) is further
elaborated as in Chart AY by Sonogashira coupling with an
electron-rich acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH)
catalyzed by PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide
either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and
triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.)
to provide the corresponding alkynyl derivatives of formula AY.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of formula AY.2 (Z=CH.sub.2OH). 72
[0297] W1.18. 7-Oxo-2,3-dihydro-1H,7H-pyrazino
[3,2,1-ij][1,7]naphthyridin- e-6-carboxamide. Preparation of
specific examples of heterocycles W1.18 follows an established
literature precedent (Collect. Czech. Chem. Commun. 1991, 56, 2420)
as shown in Chart AZ. 6-Bromo-2-chloro-3-pyridiny- lamine (AZ.1, J.
Med. Chem. 1995, 38, 4830.) is thermally cyclized with methyl
2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to
afford AZ.2. The nitrogen is then alkylated in the presence of
potassium carbonate and 2-bromo-1-chloroethane in acetone to afford
AZ.3. Reaction of AZ.3 with sodium iodide in acetone and treatment
of the resulting iodide with sodium azide forms the alkyl azide
AZ.4. Reduction of the azide with triphenylphosphine affords the
amine AZ.5. The amine is then cyclized thermally to the pyrazine
compound AZ.6. The pyrazino compound AZ.6 is then coupled under
modified Negishi coupling with vinylzinc in the presence of
Pd(PPh.sub.3).sub.4 (Palmgren, A.; et. al J. Org. Chem. 1998, 63,
3764), followed by standard functional group manipulation involving
oxidative cleavage with osmium tetroxide and sodium periodiate to
give the aldehyde AZ.7. This aldehyde is then reacted with
morpholine in the presence of acetic acid and sodium
cyanoborohydride to afford AZ.8. Alternatively as described in
Chart BA, AZ.6 is coupled to an electron-rich alkyne (e.g.
propargyl alcohol) through a modified Sonogashira coupling
(Linstrumelle, G.; et. al, Tetrahedron Lett, 1993, 34, 6403) to
afford BA.1 (Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula BA.2 (Z=CH.sub.2OH).
7374
[0298] W1.19
7-Oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridin-
e-6-carboxamides. The preparation of specific examples of
heterocycle W1.19 is described in Chart BB. Naphthyridine AZ.3 is
reacted with potassium thioacetate in refluxing methanol in the
presence of catalytic amount of sodium methoxide to afford BB.1.
The thiazino compound BB.1 is then coupled under modified Negishi
coupling conditions with vinylzinc in the presence of
Pd(PPh.sub.3).sub.4 (Palmgren, A.; et. al J. Org. Chem. 1998, 63,
3764), followed by standard functional group manipulation involving
oxidative cleavage with osmium tetroxide and sodium periodiate to
give the aldehyde BB.2. This aldehyde is then reacted with
morpholine in the presence of acetic acid and sodium
cyanoborohydride to afford BB.3. Alternatively as described in
Chart BC, BB.2 is coupled to an electron-rich alkyne (e.g.
propargyl alcohol) through a modified Sonogashira coupling
(Linstrumelle, G.; et. al, Tetrahedron Lett, 1993, 34 6403) to
afford BC.1 (Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula BC.2 (Z=CH.sub.2OH).
75
[0299] W1.20.
7-Oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridin-
e-6-carboxamides. The preparation of specific examples of
heterocycle W1.20 is described in Chart BD. Treatment of AZ.3 with
sodium iodide in acetone followed by reaction of the resulting
intermediate iodide with sodium hydroxide to form the alkoxide
which is then cyclized thermally to the oxazine compound BD.1. The
oxazino compound BD.1 is then coupled under modified Negishi
coupling with vinylzinc in the presence of Pd(PPh.sub.3).sub.4
(Palmgren, A.; et. al J. Org. Chem. 1998, 63, 3764), followed by
standard functional group manipulation involving oxidative cleavage
with osmium tetroxide and sodium periodiate to give the aldehyde
BD.2. This aldehyde is then reacted with a primary or secondary
amine (e.g. morpholine) in the presence of acetic acid and sodium
cyanoborohydride to afford BD.3. Alternatively as described in
Chart BE, compound BD.1 is coupled to an electron-rich acetylene
(e.g. propargyl alcohol) through a modified Sonogashira coupling
(Linstrumelle, G.; et. al, Tetrahedron Lett, 1993, 34 6403) to
afford BE.1 (Z=CH.sub.2OH). Saturation of the alkyne by
hydrogenation catalyzed by palladium on carbon in alcoholic
solvents affords alkyl derivatives of formula BE.2 (Z=CH.sub.2OH).
76
[0300] W1.23.
3,7-Dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides. The
preparation of specific examples of heterocycle W1.23 is described
in Chart BF and Chart BG. Compounds of the formula Z.1
(Y=morpholinylmethyl, 3-hydroxypropyl, or 3-hydroxy-1-propynyl)
react with butyl glyoxylate to give pyrido[1,2,3-de]quinoxalines
BF.1 (Y=morpholinylmethyl, 3-hydroxy-1-propynyl, or
3-hydroxypropyl). Alternatively, as described in Chart BG compounds
of the formula AC.1 react with a primary amine (e.g.
4-chlorobenzylamine, R.sup.10=4-chlorobenzyl; benzylamine,
R.sup.10=benzyl) at high temperature to afford derivatives of the
formula BG.1. 77
[0301] W1.24.
2,4,8-Trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,
1-ij]quinoline-7-carboxamides. The preparation of specific examples
of heterocycle W1.24 is described in Chart BH. Compounds of the
formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl, or
3-hydroxy-1-propynyl) react with malonyl chloride to give
diazepinoquinolines BH.1 (Y=morpholinylmethyl,
3-hydroxy-1-propynyl, or 3-hydroxypropyl). Alternatively, compounds
of formula Z.1 react with acryloyl chloride to give
diazepinoquinolines of the formula BH.2. 78
[0302] W1.25.
2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carbox-
amides. The preparation of specific examples of heterocycle W1.25
is described in Chart BI. Compounds of the formula Z.1 react with
1,1'-carbonyl diimidazole in DMF to give
2,6-dioxo-1,2-dihydro-6H-imidazo-
[4,5,1-ij]quinoline-5-carboxamides BI.1 (Y=morpholinomethyl,
3-hydroxypropyl or 3-hydroxypropynyl) which are converted to the
anion with sodium hydride and alkylated with
1-(2-chloroethyl)pyrrolidine or
1-(2-chloroethyl)-4-methylpiperazine to give the products BI.2.
79
[0303] W1.26.
8-Oxo-3,4-dihydro-2H,8H-[1,4]oxazepino[2,3,4-ij]quinoline-7--
carboxamides. The preparation of specific examples of heterocycle
W1.26 is shown in Chart BJ. 3-Hydroxy-4-nitrobenzoic acid (BJ.1) is
coupled with morpholine to afford amide BJ.2. Alkylation of the
phenol with 1-chloro-3-iodopropane yields BJ.3. Catalytic reduction
of the nitro group gives aniline BJ.4. Cyclization affords the
benzoxazepine BJ.5. Reduction of the amide with lithium aluminum
hydride yields BJ.6. Condensation of BJ.6 with diethyl
ethoxymethylenemalonate provides BJ.7. Cyclization employing
polyphosphoric acid affords ester BJ.8 which is converted to amide
BJ.9 by treatment with 4-chlorobenzylamine at elevated temperature.
80
[0304] W1.52.
7-Oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide.
Representative examples of heterocycle W1.52 are prepared as
described in Chart BK in analogy to reported pyridobenzoxazino ring
synthesis (Augeri, D. J.; Fray, A. H.; Kleinman, E. F. J.
Heterocyclic Chem. 1990, 27, 1509). Intermediates of the formula
0.3 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) are
treated with a base (e.g. sodium hydride) to afford tricycles of
the formula BK.1. The resulting ester is saponified under dilute
acid conditions and coupled with a substituted benzylamine (e.g.
4-chlorobenzylamine) mediated by 1,1'-carbonyldiimidazole (or other
suitable carboxylic acid activating agent) to provide amides of the
general formula BK.3. In the case where Y=iodo, compounds of the
general formula BK.3 are further derivatized as described in Chart
BL. Sonogashira coupling between BK.3 (Y=iodo) and an electron-rich
acetylene (e.g. propargyl alcohol, Z=CH.sub.2OH) catalyzed by
PdCl.sub.2(PPh.sub.3).sub.2 and copper(I) iodide either in
diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine
(Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the
corresponding alkynyl derivatives of formula BL.1 (Z=CH.sub.2OH).
Saturation of the alkyne by hydrogenation catalyzed by palladium on
carbon in alcoholic solvents affords alkyl derivatives of formula
BL.2 (Z=CH.sub.2OH). 81
[0305] Alternatively, intermediates of the formula Q.4, cyclize in
the presence of a base to afford tricycles of the formula BM.1.
Employing conditions analogous to that previously described in
Chart BL, intermediate BM.1 is transformed to the corresponding
derivatives where G is optionally unsaturated C.sub.1-4alkyl
substituted by hydroxy (BL.1, BL.2). Alternatively, BM.1 is
formylated employing carbon monoxide, a palladium catalyst, and an
appropriate reducing agent to provide carboxaldehydes of the
formula BM.2. Subsequent reductive amination between BM.2 and a
primary or secondary amine (e.g. morpholine) affords compounds of
the formula BM.3. 82
[0306] W1.57.
8-Oxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinolin-
e-7-carboxamide. Representative examples of heterocycle W1.57 are
prepared as described in Chart BN. Intermediate AV.8 (R is as
defined by R.sup.7 above for optionally substituted alkyl,
optionally substituted cycloalkyl, aryl, or het) is reacted with
bromoacetic anhydride and a tertiary amine base (e.g.
triethylamine) in N-methylpyrrolidinone to afford compounds of the
general formula BN.1. 83
[0307] W3.1.
4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamides- .
The preparation of specific examples of heterocycle W3.1 follows
established precedent as shown in Chart BO. 2-Amino-4-bromopyridine
(BO.1) is reacted with Boc-anhydride in dichloromethane to afford
the Boc-protected amine BO.2 which is then oxidized with
peroxybenzoic acid (Justus Liebigs Ann. Chem. 1972, 758, 111) to
provide BO.3. The nitrogen is then alkylated with 2-bromoethyl
trimethylsilyl ether in the presence of potassium carbonate in
acetone to provide BO.4. The Boc group is then removed under
standard deprotection conditions to afford BO.5. The pyrimidone
BO.5 is then cyclized with methyl 2-(((4-chlorobenzyl)amino)ca-
rbonyl)-3-methoxy-2-propenoate to give BO.6. Deprotection of the
TMS ether followed by alkylation under Mitsunobu conditions
(triphenyl phosphine and DEAD) affords BO.7. Naphthyridine BO.7 is
then coupled under modified Negishi coupling with vinylzinc in the
presence of Pd(PPh.sub.3).sub.4 (Palmgren, A.; et. al J. Org. Chem.
1998, 63, 3764), followed by standard functional group manipulation
involving oxidative cleavage with osmium tetroxide and sodium
periodiate to give the aldehyde BO.8. This aldehyde is then reacted
with a primary or secondary amine (e.g. morpholine) in the presence
of acetic acid and sodium cyanoborohydride to afford BO.9. 84
[0308] Specific examples in which G=3-hydroxypropyl or
3-hydroxy-1-propynyl are prepared as described in Chart BP. Bromide
BO.8 is coupled with an electron-rich acetylene (e.g. propargyl
alcohol) through a modified Sonogashira coupling (Linstrumelle, G.;
et. al, Tetrahedron Lett, 1993, 34 6403) to afford BP.1
(Z=CH.sub.2OH). Saturation of the alkyne by hydrogenation catalyzed
by palladium on carbon in alcoholic solvents affords alkyl
derivatives of the formula BP.2 (Z=CH.sub.2OH). 85
[0309] W4.1. 3-Oxo-9,10-dihydro-3H,8H-pyrido[3,2,
1-ij]quinoline-2-carboxa- mides. The preparation of specific
examples of heterocycle W4.1 is described in Chart BQ. Reduction of
5,6,7,8-tetrahydroquinoline-3-carboni- trile (BQ.1) with DIBAL
affords the corresponding carboxaldehyde BQ.2. Reductive amination
between BQ.2 and a secondary amine (e.g. morpholine) affords a
pyridyl derivative such as BQ.3. Treatment of BQ.3 with tert-butyl
lithium followed by condensation of the resulting anion with
diethyl ethoxymethylenemalonate provides the malonate BQ.4.
Subsequent cyclization mediated by triethylamine affords BQ.5, and
the resulting ester is condensed with a substituted benzylamine
(e.g. 4-chlorobenzylamine) mediated by trimethylaluminum to afford
a corresponding carboxamide of the formula BQ.6. 86
[0310] The inventive compounds may be used in their native form or
as salts. In cases where compounds are sufficiently basic or acidic
to form stable nontoxic acid or base salts, administration of the
compounds as salts may be appropriate. Examples of pharmaceutically
acceptable salts are organic acid addition salts formed with acids
which form a physiological acceptable anion, for example, tosylate,
methanesulfonate, acetate, citrate, malonate, tartarate, succinate,
benzoate, ascorbate, glutarate, and glycerophosphate. Suitable
inorganic salts may also be formed, including hydrochloride,
sulfate, nitrate, bicarbonate, and carbonate salts.
[0311] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0312] Compounds of the present invention can conveniently be
administered in a pharmaceutical composition containing the
compound in combination with a suitable excipient, the composition
being useful in combating viral infections. Pharmaceutical
compositions containing a compound appropriate for antiviral use
are prepared by methods and contain excipients which are well known
in the art. A generally recognized compendium of such methods and
ingredients is Remington's Pharmaceutical Sciences by E. W. Martin
(Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of
the present invention can be administered parenterally (for
example, by intravenous, intraperitoneal or intramuscular
injection), topically (including but not limited to surface
treatment, transdermal application, and nasal application),
intravaginally, orally, or rectally, depending on whether the
preparation is used to treat internal or external viral
infections.
[0313] For oral therapeutic administration, the active compound may
be combined with one or more excipients and used in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like. Such compositions and
preparations should contain at least 0.1% of active compound. The
percentage of the compositions and preparations may, of course, be
varied and may conveniently be between about 2 to about 60% of the
weight of a given unit dosage form. The amount of active compound
in such therapeutically useful compositions is such that an
effective dosage level will be obtained.
[0314] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices such as the osmotic release type devices
developed by the Alza Corporation under the OROS trademark.
[0315] The compounds or compositions can also be administered
intravenously or intraperitoneally by infusion or injection.
Solutions of the active compound or its salts can be prepared in
water, optionally mixed with a nontoxic surfactant. Dispersions can
also be prepared in glycerol, liquid polyethylene glycols,
triacetin, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
[0316] Pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form should be
sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol
(for example, glycerol, propylene glycol, liquid polyethylene
glycols, and the like), vegetable oils, nontoxic glyceryl esters,
and suitable mixtures thereof. The proper fluidity can be
maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0317] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in the
appropriate solvent with various of the other ingredients
enumerated above, as required, followed by filter sterilization. In
the case of sterile powders for the preparation of sterile
injectable solutions, the preferred methods of preparation are
vacuum drying and the freeze drying techniques, which yield a
powder of the active ingredient plus any additional desired
ingredient present in the previously sterile-filtered
solutions.
[0318] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid or a
liquid.
[0319] Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers. Thickeners such as synthetic polymers, fatty
acids, fatty acid salts and esters, fatty alcohols, modified
celluloses or modified mineral materials can also be employed with
liquid carriers to form spreadable pastes, gels, ointments, soaps,
and the like, for application directly to the skin of the user.
[0320] Examples of useful dermatological compositions which can be
used to deliver the compounds of formula I to the skin are known to
the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),
Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No.
4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
[0321] Useful dosages of the compounds of formula I can be
determined by comparing their in vitro activity, and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
to the art; for example, see U.S. Pat. No. 4,938,949.
[0322] The compound is conveniently administered in unit dosage
form; for example, containing 5 to 1000 mg, conveniently 10 to 750
mg, most conveniently, 50 to 500 mg of active ingredient per unit
dosage form. The desired dose may conveniently be presented in a
single dose or as divided doses administered at appropriate
intervals, for example, as two, three, four or more sub-doses per
day. The sub-dose itself may be further divided, e.g., into a
number of discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0323] For internal infections, the compositions can be
administered orally or parenterally at dose levels, calculated as
the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30
mg/kg of mammal body weight, and can be used in man in a unit
dosage form, administered one to four times daily in the amount of
1 to 1000 mg per unit dose.
[0324] For parenteral administration or for administration as
drops, as for eye infections, the compounds are presented in
aqueous solution in a concentration of from about 0.1 to about 10%,
more preferably about 0.1 to about 7%. The solution may contain
other ingredients, such as emulsifiers, antioxidants or
buffers.
[0325] Generally, the concentration of the compound(s) of formula I
in a liquid composition, such as a lotion, will be from about
0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration
in a semi-solid or solid composition such as a gel or a powder will
be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
[0326] The exact regimen for administration of the compounds and
compositions disclosed herein will necessarily be dependent upon
the needs of the individual subject being treated, the type of
treatment and, of course, the judgment of the attending
practitioner. The compounds of the present invention can be
administered to an animal in need of treatment. In most instances,
this will be a human being, but the treatment of livestock and
companion animals is also specifically contemplated as falling
within the scope of the instant invention.
[0327] The compounds of formula (I) and pharmaceutically acceptable
salts thereof are useful as antiviral agents. Thus, they are useful
to combat viral infections in animals, including man. The compounds
are generally active against herpes viruses, and are particularly
useful against the varicella zoster virus, the Epstein-Barr Virus,
the herpes simplex virus types 1 and 2 (HSV-1 and 2), the human
herpes virus types 6, 7 and 8 (HHV-6, 7 and 8) and the human
cytomegalovirus (HCMV).
[0328] The invention will be further described by the following
non-limiting examples.
EXAMPLE 1
[0329]
N-(4-Chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-
-[1,4]-oxazepino [2,3,4-ij]quinoline-7-carboxamide [BJ.9] 87
[0330] A suspension of 3-hydroxy-4-nitrobenzoic acid (18.3 g) and
EDC hydrochloride (23.0 g) in 250 mL of dichloromethane at
0.degree. C. is treated with morpholine (15.0 mL). The reaction is
allowed to warm to room temperature. After 2 days, the resulting
solution is washed with phosphate buffer (pH .about.6). The aqueous
layer is extracted with two portions of dichloromethane. The
combined organic layer is washed with phosphate buffer (pH
.about.7), brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The resulting solid is
crystallized from ethyl acetate in hexane to yield 21.1 g of the
intermediate amide (BJ.2). A solution of this amide (2.52 g) in dry
DMF (25 mL) is treated with cesium carbonate (6.51 g) followed by
1-chloro-3-iodopropane (1.89 mL). The resulting suspension is
heated to 65.degree. C. After 2 days, the resulting mixture is
cooled to room temperature and then partitioned between ethyl
acetate (150 mL) and water (100 mL). The organic layer is washed
with saturated aqueous sodium carbonate. The combined aqueous layer
is back-extracted with ethyl acetate (50 mL). The combined organic
layer is washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The resulting residue is
purified by flash column chromatography on silica gel eluting with
ethyl acetate to yield 1.80 g of the intermediate ether (BJ.3). A
solution of this ether (1.8 g) in THF (50 mL) is treated with 5%
platinum on carbon (0.35 g) and placed under 40 psi of hydrogen
gas. The resulting suspension is shaken overnight and then filtered
through Celite with THF washes of the filter cake. The filtrate is
concentrated under reduced pressure to yield 1.68 g of the crude
intermediate aniline (BJ.4). A mixture of this crude aniline (1.7
g) in toluene (25 mL) is treated with cesium iodide (0.08 g) and
diisopropylethylamine (0.55 mL). The mixture is heated to
100.degree. C. for 3 days and then cooled to room temperature. The
mixture is concentrated under reduced pressure then partitioned
between dichloromethane and aqueous sodium bicarbonate. The organic
layer is washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The resulting residue is
purified by flash column chromatography on silica gel eluting with
ethyl acetate to yield 0.17 g of the intermediate benzoxazepine
(BJ.5). A solution of this benzoxazepine (0.17 g) in THF (5 mL) is
cooled to 0.degree. C. and treated with lithium aluminum hydride
(LAH (0.06 g)). After 0.5 hrs, the mixture is allowed to warm to
room temperature. After 1 hr, the reaction is quenched with water
(0.07 mL), 15% aqueous sodium hydroxide (0.07 mL), and finally
water (0.21 mL). The mixture is vigorously stirred for 0.5 hrs,
filtered, and the resulting precipitate is washed with THF and
dichloromethane. The filtrate is concentrated under reduced
pressure and the resulting residue is purified by flash column
chromatography on silica gel eluting with 1% to 3% methanol in
ethyl acetate to yield 0.08 g of the reduced amide (BJ.6). A
portion of this material (0.08 g) is treated with diethyl
ethoxymethylenemalonate (0.45 mL) and heated to 160.degree. C. in a
tightly capped flask. After 2 hrs, the mixture is cooled to room
temperature. The reaction mixture is purified by flash column
chromatography on silica gel eluting with 1% to 4% methanol in
dichloromethane to yield 0.10 g of the intermediate enamine (BJ.7).
A solution of this enamine (0.10 g) in toluene (2 mL) is treated
with polyphosphoric acid (0.6 g) and heated to 130.degree. C. under
a flow of nitrogen gas. After 1.5 hrs, the mixture is cooled to
room temperature. The reaction mixture is quenched with saturated
aqueous sodium bicarbonate and partitioned with dichloromethane.
The basic aqueous layer is extracted with additional portions of
dichloromethane. The combined organic layer is washed with brine,
dried over sodium sulfate, filtered, and concentrated under reduced
pressure to yield 0.09 g of the crude ester (BJ.8). A solution of
this crude ester (0.09 g) in 4-chlorobenzylamine (0.5 mL) is heated
to 180.degree. C. After 2 hrs, the mixture is cooled to room
temperature and concentrated under reduced pressure. The residue is
purified by flash column chromatography on silica gel eluting with
2% to 5% methanol in dichloromethane and then by crystallization
from acetonitrile to yield 0.08 g of the title compound as a white
solid. Physical characteristics: M.p. 195-197.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 10.3, 8.8, 7.9, 7.4-7.3, 4.6, 4.5, 4.3,
3.6, 3.5, 2.3; MS (ESI+) m/z 468 (M+H).sup.+; Anal. Found: C,
64.05; H, 5.61; N, 8.97.
Preparation 1
[0331] Ethyl
4-hydroxy-6-(4-morpholinylmethyl)-8-nitro-3-quinolinecarboxyl- ate
[AA.5].
[0332] N-Bromosuccinimide (3.52 g) is added to a solution of ethyl
4-hydroxy-6-methyl-8-nitro-3-quinolinecarboxylate (2.76 g) in 1,2
dichloroethane (250 mL). The refluxing solution is irradiated with
a sun lamp (625 watt) for 20 min. The crude ethyl
6-bromomethyl-4-hydroxy-8-nit- ro-3-quinolinecarboxylate thus
formed is reacted with morpholine (5 mL). After evaporation, the
product is partitioned between ethyl acetate and water. Evaporation
of the ethyl acetate gives a solid, which is dissolved in
chloroform and is chromatographed on silica gel with 1%
methanol/chloroform as the initial eluant. Elution of the column
with 10% methanol/chloroform gives the title compound, which is
crystallized from methanol. Physical characteristics: M.p.
214-216.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 1.41, 2.50,
3.68, 3.74, 4.42, 8.69, 8.73, 8.78, 11.6. Anal. Found: C, 56.30; H,
5.32; N, 11.56.
Preparation 2
[0333] Ethyl
8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxyl- ate
[AA.6].
[0334] A solution of ethyl
4-hydroxy-6-(4-morpholinylmethyl)-8-nitro-3-qui- nolinecarboxylate
(Preparation 1, 1.36 g) in DMF (50 mL) is hydrogenated at 50 psi
hydrogen pressure in the presence of 10% Pd/C (400 mg) for 15 min.
The catalyst is filtered off and the filtrate is evaporated. The
residual solid is triturated with methanol to afford 1.12 g of the
title compound. Physical characteristics. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.28, 2.35, 3.44, 3.57, 4.21, 5.59, 6.98,
7.33, 8.41.
Preparation 3
[0335]
8-Amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quin-
olinecarboxamide [Z.1].
[0336] A mixture of ethyl
8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quin- olinecarboxylate
(Preparation 2, 1.0 g) and 4-chlorobenzylamine (4 mL) is heated at
180.degree. C. The solution is cooled and stirred with ether (6 mL)
and water (6 mL). The resulting precipitate is removed by
filtration, washed with water followed by ether and dried to afford
1.05 g of the title compound. Physical characteristics: .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.35, 3.45, 3.57, 4.54, 5.65, 7.02, 7.39,
8.62, 10.6, 11.1.
EXAMPLE 2
[0337]
N-(4-Chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-
-imidazo-[4,5,1-ij]quinoline-5-carboxamide [BI.1]. 88
[0338] A mixture of
8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylm-
ethyl)-3-quinolinecarboxamide (Preparation 3, 331 mg) and
1,1'-carbonyl diimidazole (215 mg) in DMF (2.5 mL) is heated at
80.degree. C. for 1 h. A second portion of 1,1'-carbonyl
diimidazole (167 mg) is added and heating is continued for an
additional 1 h. After cooling, water (8 mL) is added and the
resulting precipitate is filtered off, washed with water and dried
to afford 261 mg of the title compound. Physical characteristics:
M.p. 286.degree. C. (dec); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.39, 3.57, 3.62, 4.57, 7.39, 7.61, 8.88, 10.0, 12.0. Anal.
Found: C, 60.37; H, 4.78; N, 12.49.
EXAMPLE 3
[0339]
N-(4-Chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide [AC.1]. 89
[0340] Bromoacetic anhydride (290 mg) is added to a stirred
solution of
8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinec-
arboxamide (Preparation 3, 426 mg) in anhydrous DMF (5.0 mL). After
30 min, triethylamine (100 mg) and additional bromoacetic anhydride
(100 mg) are added. After 1 h, triethylamine (300 mg) is added and
the solution is heated briefly at 80.degree. C. Methanol (8 mL) is
added and the resulting precipitate is filtered off, washed with
water and dried to afford 262 mg of the title compound as a DMF
solvate. Physical characteristics: .sup.1H NMR (DMSO-d.sub.6)
.delta. 2.37, 2.73, 2.89, 3.53, 3.57, 4.56, 5.11, 7.23, 7.35, 7.40,
7.72, 7.95, 8.72, 10.35, 11.2.
Preparation 4
[0341] Ethyl
9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,-
2,3-de]-quinoxaline-6-carboxylate.
[0342] Bromoacetic anhydride (280 mg) is added to ethyl
8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate
(Preparation 2, 330 mg) in DMF (4.0 mL). Triethylamine (400 mg) is
added and the reaction is heated for 10 min at 60.degree. C. After
1 h, the DMF is removed and the product is chromatographed on
silica gel with 10% methanol as the eluant to give 310 mg of the
title compound as a mixture with triethylamine hydrobromide.
Physical characteristics: .sup.1H NMR (DMSO-d.sub.6) .delta. 1.40,
2.45, 3.56, 3.69, 4.39, 4.88, 7.49, 7.97, 8.34.
EXAMPLE 4
[0343]
N-(4-Chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl-
)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide [BG.1,
Y=morpholinylmethyl, R.sup.10=4-chlorobenzyl]. 90
[0344] A mixture of ethyl
9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxylate (Preparation 4, 280
mg) and 4-chlorobenzylamine (1 mL) is heated at 180.degree. C. The
solution is cooled, diluted with methanol (2 mL), and the
precipitate is filtered off. The resulting solid is washed with
methanol followed by ether and dried to give 117 mg of the title
compound. Physical characteristics: .sup.1H NMR (DMSO-d.sub.6)
.delta. 2.35, 3.49, 3.57, 4.56, 4.60, 5.08, 7.20, 7.34-7.40, 7.64,
8.21, 8.62, 10.6. Anal. Found: C, 62.90; H, 4.99; N, 11.81; Cl,
12.03.
Preparation 5
[0345] 2,3-Dihydro-1H-indol-2-ylmethanol [G.2].
[0346] A slurry of racemic indoline-2-carboxylic acid (5.00 g) and
anhydrous THF (60 mL) is cooled to 0.degree. C. under an atmosphere
of nitrogen. To this slurry is added 1.0 M borane-THF complex (100
mL) via syringe over 40 minutes. The resulting solution is allowed
to warm to room temperature while stirring overnight. Water (ca.
400 mL) is slowly added to quench the reaction. The mixture is
extracted with diethyl ether (400 mL). The combined organic layers
are washed with saturated sodium bicarbonate solution followed by
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated to
afford 4.31 g (94%) of the title compound as a colorless foam.
Physical characteristics: MS (ESI+) nm/z 150 (M+H).sup.+.
Preparation 6
[0347] Benzyl 2-(Hydroxymethyl)-t-indolinecarboxylate [G.3].
[0348] A solution containing 2,3-dihydro-1H-indol-2-ylmethanol
(Preparation 5, 4.31 g) and THF (60 mL) is added to a flask
containing sodium bicarbonate (24.27 g) and water (15 mL).
Benzylchloroformate (4.5 mL) is slowly added. Once addition is
complete, the mixture is stirred overnight. The crude mixture is
filtered and washed with a large amount of CH.sub.2Cl.sub.2. The
filtrate is poured into water and the separated organic phase is
washed with 5% HCl and brine. The organic layer is dried
(Na.sub.2SO.sub.4), filtering, and concentrated to give a yellow
oil. The crude product is chromatographed eluting with
EtOAc/heptane (1/1) to give 8.11 g (99%) of the title compound as a
pale colored oil. Physical characteristics: MS (ESI+) m/z 284
(M+H).sup.+.
Preparation 7
[0349] Benzyl 2-(Hydroxymethyl)-5-iodo-1-indolinecarboxylate
[G.4].
[0350] A solution containing benzyl
2-(hydroxymethyl)-1-indolinecarboxylat- e (Preparation 6, 1.78 g),
N-iodosuccinimide (2.83 g), and anhydrous DMF (12 mL) is stirred
overnight at 60.degree. C. in a foil-covered flask. This solution
is cooled and concentrated to half volume with a stream of
nitrogen. The resulting brown solution is partitioned between water
(50 mL) and CH.sub.2Cl.sub.2 (150 mL). The organic phase is washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated to
give a brown oil. The crude product is chromatographed eluting with
0-40% EtOAc in heptane (300 mL each 10%) to give 2.03 g (79%) of
the title compound as a peach solid. Physical characteristics: M.p.
110-111.degree. C.; HRMS (FAB) m/z 410.0270
(C.sub.17H.sub.16INO.sub.3+H). Anal. Found: C, 49.83; H, 3.95; N,
3.37.
Preparation 8
[0351] (5-Iodo-2,3-dihydro-1H-indol-2-yl)methyl acetate [G.5].
[0352] A 30% wt solution containing HBr in acetic acid (25 mL) is
added to a flask containing benzyl
2-(hydroxymethyl)-5-iodo-1-indolinecarboxylate (Preparation 8, 6.03
g). All of the solids are dissolved and the solution is
concentrated to give a brown solid. The crude product is taken into
CH.sub.2Cl.sub.2 with a small amount of methanol and triethylamine
and purified by column chromatography eluting with heptane (250
mL), 20% EtOAc in heptane (500 mL), and 40% EtOAc in heptane to
give 3.92 g (84%) of the title compound as a red solid. Physical
characteristics: M.p. 64-66.degree. C.; HRMS (FAB) nz/z 318.0006
(C.sub.11H.sub.12INO.sub.2+H). Anal. Found: C, 41.91; H, 3.85; N,
4.35.
Preparation 9
[0353] Ethyl
2-((Acetyloxy)methyl)-8-iodo-6-oxo-1,2-dihydro-6H-pyrrolo[3,2-
,1-ij]-quinoline-5-carboxylate [G.6].
[0354] A mixture of diethyl ethoxymethylenemalonate (2.73 mL) and
(5-iodo-2,3-dihydro-1H-indol-2-yl)methyl acetate (Preparation 8,
3.90 g) is heated to 120.degree. C. under a stream of nitrogen.
After starting material is consumed, the mixture is cooled and
diluted with EtOAc. The crude product is chromatographed eluting
with 20, 40, and 60% EtOAc in heptane (500 mL each) to give 5.28 g
(88%) of the corresponding enamine as a brown oil. A portion of
this material (4.61 g) is dissolved in Eaton's Reagent (10 mL) and
heated to 80.degree. C. for 1 h. Upon cooling, the crude mixture is
poured into a cold beaker and a 50% NaOH solution is slowly added
until pH=7. The cloudy solution is then poured into
CH.sub.2Cl.sub.2. The organic layer is separated and washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated to give
a brown solid. The crude product is chromatographed eluting with
0-4% methanol in CH.sub.2Cl.sub.2 to give 880 mg (21%) of the title
compound as a brown solid. Physical characteristics: MS (ESI+) nvz
442 (M+H).sup.+, 464 (M+Na).sup.+.
Preparation 10
[0355]
N-(4-Chlorobenzyl)-2-(hydroxymethyl)-8-iodo-6-oxo-1,2-dihydro-6H-py-
rrolo[3,2,1-ij]quinoline-5-carboxamide [G.7, X=Cl].
[0356] A mixture of 4-chlorobenzylamine (2 mL) and ethyl
2-((acetyloxy)methyl)-8-iodo-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinol-
ine-5-carboxylate (Preparation 9, 0.70 g) is heated to 120.degree.
C. under a stream of nitrogen for 7 h, to 100.degree. C. for 18 h,
and then to 130.degree. C. for 8 hours. Upon cooling, the mixture
is diluted with a mixture of CH.sub.2Cl.sub.2, EtOAc, and methanol
(2/2/1) and absorbed onto silica gel. This material is
chromatographed eluting with 0-4% methanol in CH.sub.2Cl.sub.2 to
give a wet brown solid. The crude product is recrystallized by
dissolving in hot acetic acid and slowly adding water until
cloudiness persisted. Upon standing, crystals form which are
collected to provide 340 mg (43%) of the title compound as a tan
solid. Physical characteristics: M.p. 222-223.degree. C.; MS (ESI+)
m/z 495 (M+H).sup.+.
EXAMPLE 5
[0357]
N-(4-Chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-
-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide [G.8,
X=Cl]. 91
[0358] A solution containing
N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-iodo-6-
-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide
(Preparation 10, 0.15 g), anhydrous DMF (6 mL), and triethylamine
(0.8 mL) is purged with nitrogen three times before adding
propargyl alcohol (19 .mu.L), copper(I)iodide (14 mg), and
PdCl.sub.2(PPh.sub.3).sub.2 (8 mg). The solution is heated to
65.degree. C. and then is cooled, diluted with CH.sub.2Cl.sub.2 (25
mL), and poured into water (30 mL). The organic layer is washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated to
give a brown residue. The crude product is chromatographed eluting
with 0-6% methanol in CH.sub.2Cl.sub.2 (250 mL each) to give 90 mg
(70%) of the title compound as a white solid. Physical
characteristics: M.p. 224-225.degree. C.; MS (ESI+) m/z 423
(M+H).sup.+.
Preparation 11
[0359] Diethyl
2-((2,2-Dimethyl-2,3-dihydro-1H-indol-1-yl)methylene)malona- te
[C.2]
[0360] A mixture of 2,2-dimethylindoline (1.47 g) and diethyl
ethoxymethylenemalonate (2.0 nml) is heated to 105.degree. C. for
17 hours to afford the title compound as a pale yellow oil.
Physical characteristics: .sup.1H NMR (CDCl.sub.3) .delta. 7.76,
7.18, 7.12, 6.97, 6.74, 4.24, 3.16, 1.50, 1.34.
Preparation 12
[0361] Ethyl
2,2-Dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline--
5-carboxylate [C.3]
[0362] Diethyl
2-((2,2-dimethyl-2,3-dihydro-1H-indol-1-yl)methylene)malona- te
(Preparation 11, 3.14 g) is dissolved in Eaton's Reagent (3.5 mL)
and slowly heated to 100.degree. C. The reaction is cooled and
poured into EtOAc (350 mL). The separated organic layer is washed
with water (2.times.200 mL). The aqueous extracts are extracted
further with CH.sub.2Cl.sub.2 (2.times.100 mL). The organic
extracts are washed with brine and dried over MgSO.sub.4, filtered
and concentrated to a brown oil which is purified by chromatography
over silica gel, eluting with 5% methanol in CH.sub.2Cl.sub.2 to
give 2.3 g (85%) of the title compound as a pale yellow oil that
slowly crystallizes. Physical characteristics: M.p. 117-119.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 8.73, 7.83, 7.61, 7.41,
4.22, 3.41, 1.63, 1.29; IR (diffuse reflectance) 1933, 1677, 1640,
1624, 1601, 1544, 1459, 1367, 1310, 1213, 1176, 1144, 1032, 773,
757 cm; MS (EI) m/z 271 (M.sup.+). Anal. Found: C, 70.48; H, 6.36;
N, 5.12.
Preparation 13
[0363] Ethyl
8-Bromo-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]qu-
inoline-5-carboxylate [C.4]
[0364] Ethyl
2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline--
5-carboxylate (Preparation 12, 1.03 g) is dissolved in acetic acid
(10 .mu.L) and bromine (213 .mu.L) is added dropwise. The reaction
is stirred an additional 30 min and then poured into water (50 mL).
The resulting precipitate is filtered and then washed with ether to
give 506 mg (38%) of the title compound as white crystals. Physical
characteristics: M.p. 227-228.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.76, 7.90, 7.79, 4.23, 3.41, 1.63, 1.29; IR
(diffuse reflectance) 1727, 1636, 1612, 1592, 1547, 1505, 1393,
1373, 1327, 1303, 1217, 1171, 1167, 1128, 804 cm.sup.-1; HRMS (FAB)
350.0386 (C.sub.16H.sub.16BrNO.sub.3+H).
Preparation 14
[0365] Ethyl
8-(3-Hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydro-6H-py-
rrolo[3,2,1-ij]quinoline-5-carboxylate [C.5, Z=CH.sub.2OH]
[0366] A solution of palladium acetate (73 mg) and triphenyl
phosphine (191 mg) in dry THF (6.0 mL) under nitrogen is cooled to
0.degree. C. A solution of n-butyllithium (1.6 M in hexanes, 444
.mu.L) is added dropwise and after 15 min, the solution is warmed
to 22.degree. C. for 15 min. The solution is then canulated into a
mixture of ethyl
8-bromo-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-ca-
rboxylate (Preparation 13, 350 mg), copper iodide (84 mg) and
propargyl alcohol (75.mu.) in diethylamine (6.0 mL). The reaction
is warmed to 45.degree. C. for 2 hours. The reaction is filtered,
diluted with CH.sub.2Cl.sub.2 (100 mL), and washed with water. The
organic layer is dried (MgSO.sub.4), filtered, and concentrated.
The crude product is chromatographed over silica gel, eluting with
5% MeOH in CHCl.sub.3 and recrystallized from EtOAc to afford 229
mg of the title compound as white crystals. Physical
characteristics: M.p. 237.degree. C. (dec); .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.74, 7.81, 7.60, 5.37, 4.33, 4.23, 3.39,
1.63 (s, 6H), 1.29 (t, J=7 Hz, 3H); IR (diffuse reflectance) 2391,
2222, 2058, 1921, 1680, 1637, 1595, 1542, 1510, 1317, 1216, 1186,
1040, 1031, 808 cm.sup.-1; MS (EI) m/z 325 (M+). HRMS (FAB) m/z
326.1385 (C.sub.19H.sub.19NO.sub.4+H).
EXAMPLE 6
[0367]
N-(4-Chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2--
dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide [C.6, X=chloro,
Z=CH.sub.2OH] 92
[0368] 4-Chlorobenzylamine (110 .mu.L) and sodium methoxide (25 mg)
are added to a solution of ethyl
8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo--
1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate
(Preparation 14, 153 mg) in methanol (12 mL). The reaction is
warmed to 50.degree. C. for 48 hours. The reaction mixture is
cooled in a freezer and the resulting white precipitate is filtered
and washed with cold methanol, hexane, and ether to give 150 mg of
the title compound as white crystals. Physical characteristics:
M.p. 228.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6) .delta.
10.43, 8.98, 7.90, 7.66, 7.40, 5.39, 4.54, 4.34, 3.44, 1.66; IR
(diffuse reflectance) 2226, 1907, 1646, 1618, 1568, 1538, 1510,
1493, 1434, 1318, 1307, 1223, 1033, 1012, 808 cm.sup.1; MS (EI) m/z
420 (M+); HRMS (FAB) 421.1332
(C.sub.24H.sub.21ClN.sub.2O.sub.3+H).
Preparation 15
[0369] 5,6,7,8-Tetrahydroquinoline-3-carbaldehyde [BQ.2]
[0370] A 350 mL three neck rounded bottom flask equipped with a
nitrogen inlet, bubbler, magnetic stir bar, and rubber septum is
charged with 5,6,7,8-tetrahydroquinoline-3-carbonitrile (5.03 g)
and 100 mL anhydrous toluene. The resulting solution is cooled to
5.degree. C. with a water/ice bath, and a solution of DIBAL (35 mL
of a 1M methylene chloride solution) is delivered over a 30 min
period. After 3.5 hours at 0-5.degree. C., the reaction mixture is
quenched with 60 mL Na.sub.2CO.sub.3 solution, and the resulting
biphasic solution is stirred for two hours before extracting with
CH.sub.2Cl.sub.2 (100 mL). The organic layers are dried with
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product is
purified by flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) to
afford 3.02 g (60%) of the title compound as a light yellow oil.
Physical characteristics: .sup.1H NMR (CDCl.sub.3) .delta. 9.99,
8.75, 7.78, 2.96, 2.81, 1.90, 1.82; .sup.13C NMR (CDCl.sub.3)
.delta. 190.8, 164.2, 149.2, 136.0, 133.0, 129.4, 33.1, 28.6, 22.6,
22.8.
Preparation 16
[0371] 3-(Morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinoline
[BQ.3]
[0372] A 100 mL three-neck round bottom flask equipped with a
nitrogen inlet, bubbler, and glass stopper is charged with
1,2-dichloroethane (45 ML),
5,6,7,8-tetrahydroquinoline-3-carbaldehyde (Preparation 15, 2.39 g)
and morpholine (1.42 mL). To the above solution is added
NaBH(OAc).sub.3 (5.01 g) in one portion. After 1 hour at room
temperature, the reaction is quenched via slow addition of
Na.sub.2CO.sub.3 (50 mtL of a saturated aqueous solution). The
resulting biphasic solution is stirred for two hours at room
temperature then poured into methylene chloride (100 mL). The
resulting layers are separated, and the organic layer is dried with
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
product is purified by flash chromatography (10%
methanol/CH.sub.2Cl.sub.2) to give 2.60 g (76%) of the title
compound as an oil which crystallizes on standing. Physical
characteristics: M.p. 40.9.degree. C.; .sup.1H NMR (CDCl.sub.3):
.delta. 8.24, 7.31, 3.68, 3.41, 2.88, 2.74, 2.41, 1.87, 1.78;
.sup.13C NMR (CDCl.sub.3) .delta. 156.4, 147.5, 137.6, 131.9,
130.1, 66.9, 60.4, 53.5, 32.2, 28.7, 23.1, 22.7.
Preparation 17
[0373] Diethyl
2-(Ethoxy(3-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinol-
in-8-yl)-methyl)malonate [BQ.4]
[0374] A 500 mL round bottom flask equipped with stir bar, nitrogen
inlet and bubbler is evacuated with nitrogen three times prior to
being charged with
3-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinoline (Preparation
16, 1.53 g) and anhydrous THF (35 mL). Upon dissolution, the
reaction is cooled to -78.degree. C. (external temp).
Tertbutyllithium (4.50 mL of a 1.7 M THF solution) is added
dropwise to the solution over a ten minute period. The solution is
stirred at -78.degree. C. for one hour, diethyl
ethoxymethylenemalonate (1.53 g) is added drop-wise, and the
contents of the flask are allowed to slowly warm to room
temperature overnight (dry ice/acetone bath is not removed). The
reaction mixture is quenched with 1N HCl and stirred. After the
reaction mixture is stirred at room temperature for 30 min, the pH
is adjusted to ca. 12 with 1 N NaOH (litmus), and the aqueous layer
is extracted with MTBE (2.times.100 mL) and CH.sub.2Cl.sub.2
(1.times.100 mL). The combined organic layers are dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product is
flashed through a short plug of silica gel (2.5%
methanol/CH.sub.2Cl.sub.2) to provide 1.8 g (80%) of the title
compound as a yellow oil which is carried on into the next reaction
without further characterization.
Preparation 18
[0375] Ethyl
6-(Morpholin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido[3,2,-
1-ij]-quinoline-2-carboxylate [BQ.5]
[0376] A 250 mL round bottom flask equipped with a condenser is
charged with ethanol (150 mL), triethylamine (0.93 mL) and diethyl
2-(ethoxy(3-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-yl)methyl-
)malonate (Preparation 17, 750 mg). The solution is heated to
reflux. After 12 h, the mixture is concentrated to give a yellow
solid, which is purified by flash chromatography (silica gel, 6%
MeOH: methylene chloride) to give 603 mg of the title compound.
Physical characteristics: .sup.1H NMR (DMSO-d.sub.6): .delta. 9.02,
8.04, 7.58, 4.24, 3.59, 3.57, 3.01, 2.88, 2.42, 1.89, 1.30;
.sup.13C NMR (DMSO-d.sub.6): .delta. 165.3, 154.1, 141.6, 138.3,
134.4, 132.8, 126.9, 125.3, 110.0, 104.3, 66.1, 59.7, 59.1, 52.9,
29.2, 27.8, 20.7, 14.3; IR (KBr) 3079, 3037, 2958, 2931, 2913,
2850, 2828, 1731, 1679, 1647, 1628, 1600, 1509, 1462, 1450, 1297,
1270, 1251, 1227, 1206, 1114, 1097, 1079; HRMS m/z 357.1818.
EXAMPLE 7
[0377]
N-(4-Chlorobenzyl)-6-(morpholin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8-
H-pyrido-[3,2,1-ij]quinoline-2-carboxamide [BQ.6] 93
[0378] To a solution of 4-chlorobenzylamine (142 mg, delivered as a
1M methylene chloride solution) in anhydrous CH.sub.2Cl.sub.2 (3
mL), is added trimethylaluminum (482 .mu.L, 2 M solution in
heptane). After two hours at room temperature, ethyl
6-(morpholin-4-ylmethyl)-3-oxo-9,10-dihy-
dro-3H,8H-pyrido[3,2,1-ij]quinoline-2-carboxylate (Preparation 18,
327 mg) is added as a solid in one portion. Stirring is continued
for 2.5 hours before quenching with 10 mL of a 35% aqueous solution
of Rochelle's salt. This biphasic, gelatinous mixture is stirred
for two hours before separating the layers and extracting the
aqueous layer five times with CH.sub.2Cl.sub.2. The resulting
solution is concentrated in vacuo to give a bright yellow solid
which is recrystallized from acetone (reflux, 62 mL/g) to afford
251 mg (73%) of the title compound as a canary yellow solid.
Physical characteristics: M.p. 200-201.degree. C.; .sup.1H NMR
(CDCl.sub.3); .delta. 10.2, 9.07, 8.54, 7.41, 7.33, 7.28, 4.67,
3.71, 3.53, 3.02, 2.48, 2.02; .sup.13C NMR (CDCl.sub.3): .delta.
165.5, 157.5, 140.6, 138.6, 137.7, 134.7, 132.7, 130.9, 129.0,
128.6, 127.1, 125.2, 113.1, 109.2, 66.8, 60.4, 53.6, 42.9, 30.4,
28.7, 21.3; HRMS m/z 452.1747
(C.sub.25H.sub.26ClN.sub.3O.sub.3+H).
EXAMPLE 8
[0379]
N-(4-Chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-d-
ihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide
[AC. 1, R=methyl] 94
[0380] 2-Bromopropionyl bromide (320 mg) is slowly added to a
solution of
8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinomethyl)-3-quinolineca-
rboxamide (Preparation 3, 130 mg) and pyridine (50 mg) in NMP (1
mL). After 30 min, methanol (1 mL) and triethylamine (500 mg) are
added. Water (2 mL) is added and the precipitate (103 mg) of the
title compound is filtered off and washed with water and ether and
dried under vacuum. Physical characteristics: .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.59, 3.18, 3.36, 3.65, 3.95, 4.52, 4.57,
5.39, 7.3-7.45, 8.03, 8.94, 10.0, 10.2,11.5. Anal. Found
(C.sub.31H.sub.29ClN.sub.4O.sub.6.HBr.H.sub.2O): C, 52.03; H, 4.95;
N, 9.64; Cl, 6.09.
EXAMPLE 9
[0381]
N-(4-Chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetra-
hydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide [BH.2]
95
[0382] Acryloyl chloride (600 mg) is slowly added to a solution of
8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinomethyl)-3-quinolineca-
rboxamide (Preparation 3, 142 mg). After 30 min, the product is
partitioned between ethyl acetate and water. The aqueous phase is
extracted repeatedly with chloroform, and the organic extracts are
evaporated to give 123 mg of
8-(acryloylamino)-N-(4-chlorobenzyl)-4-hydro-
xy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide. A portion of
this product (90 mg) is heated in Dowtherm A (0.8 mL) at
220.degree. C. for 90 min. The reaction mixture is applied to a
silica gel column, which is eluted with 1 to 6% methanol/chloroform
to give 45 mg of the title compound, which is crystallized from
ethyl acetate. Physical characteristics: M.p. 235-240.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 2.51, 3.16, 3.63, 3.72, 4.61,
4.66, 7.34, 7.51, 8.27, 8.48, 8.79, 10.3.
EXAMPLE 10
[0383]
2-(Benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide [BG.1,
Y=morpholinylmethyl, R.sup.10=benzyl] 96
[0384]
N-(4-Chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H-
,7H-pyrido-[1,2,3-de]quinoxaline-6-carboxamide (Example 3, 30 mg)
is heated under reflux with benzylamine (0.5 mL) for 18 h. The
benzylamine is evaporated and the product is triturated with ether
to give the title compound (18 mg), which is crystallized from
ethyl acetate. Physical characteristics: M.p. 235-240.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 2.36, 3.51, 3.57, 4.55, 4.63,
7.2-7.5, 7.64, 8.20, 8.62, 10.5; HRMS m/z 555.2128
(C.sub.31H.sub.30ClN.sub.5O.sub.3).
Preparation 19
[0385] 2,3-Difluoro-5-iodobenzoic Acid [J.2]
[0386] A 500 mL, 3 neck round bottom flask, equipped with an
overhead stirrer is charged with trifluoromethanesulfonic acid (100
g), cooled to 0-5.degree. C. in an ice bath, and treated with
2,3-difluorobenzoic acid (18.96 g). To this mixture is added
N-iodosuccinimide (32.4 g) portion-wise over a 10 min period. After
an additional 3 min, the cooling bath is removed and the reaction
mixture is allowed to warm to room temperature. After a total of 5
h, the reaction mixture is poured into 600 mL of vigorously stirred
crushed ice/water containing 100 mL of 10% sodium sulfite solution.
The beige colored precipitate is collected, washed with ice water
and dried at 50.degree. C. in a vacuum oven overnight to produce
28.2 g (83%) of the title compound. Physical characteristics:
.sup.1H NMR (CDCl.sub.3) .delta. 10.35, 8.12, 7.76; MS (ESI--) m/z
283 (M-H).sup.-.
Preparation 20
[0387] Ethyl 3-(2,3-Difluoro-5-iodophenyl)-3-oxopropanoate [H. 1,
Y=Iodo]
[0388] 2,3-Difluoro-5-iodobenzoic acid (Preparation 19, 18.2 g) in
tetrahydrofuran (100 mL) at room temperature is treated with
1,1'-carbonyldiimidazole (12.46 g) portion-wise over a one minute
period under a nitrogen atmosphere and the mixture is stirred for 6
h. In a separate flask, ethyltrimethylsilyl malonate (14.38 g) in
tetrahydrofuran (40 mL) is cooled to 0-5.degree. C. and DBU (11.20
g) is added dropwise over a period of 15 minutes. After 5.5 h, this
solution is cannulated into the ice cooled imidazolide solution
over a 7 minute period with vigorous stirring. The mixture is
allowed to slowly warm to room temperature overnight. The reaction
mixture is poured into 600 mL of ice/water containing 41 mL of 6N
HCl. The mixture is extracted 3 times with ethyl acetate. The
combined organic extracts are dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The crude product is purified by
chromatography, using 600 g of silica gel, packed and eluted with
methylene chloride/heptane/ethyl acetate/acetic acid
(3/7/0.5%/0.5%), to afford the title compound in 65% yield as an
orange oily solid. Physical characteristics: .sup.1H NMR
(CDCl.sub.3) .delta. 12.65, 8.00, 7.94, 7.73, 7.58, 5.81,
4.35-4.19, 3.96, 1.35, 1.28; IR (diffuse reflectance) 2986, 1647,
1622, 1573, 1489, 1420, 1383, 1293, 1275, 1240, 1215, 1037, 958,
882, 801 cm.sup.-1; MS (EI) m/z 354 (M.sup.+); HRMS (FAB) m/z
354.9648 (C.sub.11H.sub.9F.sub.2IO.sub.3+H). Anal. Found: C, 37.34;
H, 2.50; N, 0.15.
Preparation 21
[0389] Ethyl 2-(2,3-Difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate
[AE.1]
[0390] A flask equipped with a Dean-Stark trap and cold water
condenser, is charged with ethyl
3-(2,3-difluoro-5-iodophenyl)-3-oxopropanoate (Preparation 20, 14.8
g), triethylorthoformate (12.4 g), and acetic anhydride (14.92 g).
The contents are placed in an oil bath initially at 115.degree. C.
and the temperature quickly raised to 150.degree. C. where it is
maintained until the volume of ethyl acetate and ethanol distillate
collected remained constant (ca. 1.25 h). The reaction mixture is
cooled and concentrated at reduced pressure to obtain 16.86 g
(98.5%) of the title compound as a dark golden oil. Physical
characteristics: .sup.1H NMR (CDCl.sub.3) .delta. 8.98, 7.87-7.75,
7.71, 7.69-7.51, 4.36, 4.29-4.08, 3.75, 1.48, 1.35, 1.26,
1.21-1.02; MS (ESI+) m/z 411 (M+H).sup.+.
Preparation 22
[0391] Ethyl
9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]q-
uinoxaline-6-carboxylate. [AG.1]
[0392] Glycine methylamide (1.0 g) is added at room temperature to
a solution of ethyl
2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation
21, 2.0 g) in NMP (20 mL). Sodium hydride (400 mg, 60% dispersion
in mineral oil) is added in two portions to the solution, and the
solution is heated at 100.degree. C. for 30 min. The product is
partitioned between chloroform and water, the chloroform phase is
concentrated and applied to a silica gel column with 1-2% methanol
chloroform as the eluant. The purified fractions are triturated
with ether to give 1.22 g of the title compound. Physical
characteristics: M.p. 278-283.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.29, 3.63, 4.23, 5.10, 7.65, 8.09, 8.55.
Anal. Found: C, 43.49; H, 3.18; N, 6.75.
Preparation 23
[0393]
N-(4-Chlorobenzyl)-9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyri-
do[1,2,3-de]-quinoxaline-6-carboxamide. [AG.2]
[0394] A mixture of ethyl
9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyri-
do[1,2,3-de]quinoxaline-6-carboxylate (Preparation 22, 400 mg) is
stirred at 180.degree. C. in 4-chlorobenzylamine (2.0 mL) for 1 h.
The mixture is cooled and diluted with acetonitrile to give 412 mg
of the title compound. Physical characteristics: M.p.
278-283.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 3.38, 4.55,
5.21, 7.35, 7.39, 7.69, 8.18, 8.76, 10.12. Anal. Found: C, 47.43;
H, 3.01; N, 8.32; Cl, 7.14.
EXAMPLE 11
[0395]
N-(4-Chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3--
dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide. [AH.1]
97
[0396] Propargyl alcohol (50 mg), cuprous iodide (50 mg) and a
solution of PdCl.sub.2(PPh.sub.3).sub.2 (1 mL, 0.15 M in THF) are
added to a suspension of
N-(4-chlorobenzyl)-9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H-
,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide (Preparation 23, 250
mg) in diethylamine (2.0 mL). The reaction is stirred for 90 min
and the product is then extracted into chloroform and is
chromatographed on silica gel. The desired product is eluted with
20% methanol/chloroform. Physical characteristics: .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.40, 4.36, 4.56, 5.22, 5.42, 7.36, 7.40,
7.44, 7.88, 8.76, 10.2. HRMS m/z 436.1064
(C.sub.23H.sub.18ClN.sub.3O.sub.4).
Preparation 24
[0397] Diethyl
2-((2-(Hydroxymethyl)-4-methylanilino)methylene)malonate.
[AV.2]
[0398] A mixture of 2-(hydroxymethyl)-4-methylaniline (10.0 g) and
diethyl ethoxymethylenemalonate (18.5 g) is heated at 110.degree.
C. for 1 h. Crystallization from ether/hexane afforded 19.5 g of
the title compound. Physical characteristics: M.p. 92-95.degree.
C.; Anal. Found: C, 62.49; H, 6.88; N, 4.60.
Preparation 25
[0399] Ethyl
8-((Acetyloxy)methyl)-4-hydroxy-6-methyl-3-quinolinecarboxyla- te
[AV.4]
[0400] A mixture of diethyl
2-((2-(hydroxymethyl)-4-methylanilino)methylen- e)malonate
(Preparation 24, 5.0 g) and acetic anhydride (5.0 mL) is heated at
130.degree. C. for 1 h. The acetic anhydride is evaporated, and the
residual solid is heated at reflux in diphenyl ether (20 ml) for 1
h. The solution is cooled and diluted with acetonitrile (5 mL) and
ether (15 mL). The resulting precipitate is filtered to afford 1.8
g of the title compound.
Preparation 26
[0401] 3-Ethyl 1-Isobutyl
8-((acetyloxy)methyl)-6-methyl-4-oxo-1,3(4H)-qui-
nolinedicarboxylate [AV.5]
[0402] Sodium hydride (3.1 g, 60% dispersion) is added at 0.degree.
C. to a stirred solution of ethyl
8-((acetyloxy)methyl)-4-hydroxy-6-methyl-3-qu- inolinecarboxylate
(Preparation 25, 29.6 g) in N-methylpyrrolidinone (250 ml). The
solution is allowed to warm to room temperature over 10 min and
isobutyl chloroformate (25.5 g) is then added. After 30 min, acetic
acid (3.6 g) is added. The solvent is evaporated under reduced
pressure, and the residual oil is partitioned between ethyl acetate
and water. The ethyl acetate layer is concentrated to give an oil.
The crude product is dissolved in ethyl acetate (50 ml) and is
chromatographed on silica gel with 10% ethyl acetate/hexane as the
initial eluant to give 19.5 g of the title compound. A sample is
recrystallized from ethyl acetate/hexane for analysis. Physical
characteristics: M.p. 101-103.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 1.05, 1.44, 2.12, 2.18, 2.59, 4.15, 4.45, 5.82, 7.74, 7.88,
9.40. Anal. Found: C, 62.42; H, 6.34; N, 3.45.
Preparation 27
[0403] Ethyl
8-Formyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxy- late
[AV.6]
[0404] A stirred solution of 3-ethyl 1-isobutyl
8-((acetyloxy)methyl)-6-me-
thyl-4-oxo-1,3-(4H)-quinolinedicarboxylate (Preparation 26, 3.0 g)
and N-bromosuccinimide (3.0 g) in dichloromethane (300 mL) is
irradiated with a 650 watt sun lamp for 20 min. Morpholine (15 mL)
is added to the solution. After 10 min, ethanol (20 mL) is added,
and the solvents are removed at 50.degree. C./20 mm. The reaction
is repeated on the same scale. The reaction mixtures are combined
and partitioned between chloroform (250 mL) and water (150 mL). The
chloroform layer is washed twice with water, and the chloroform is
evaporated. The residual oil is chromatographed on silica gel (1%
methanol/chloroform) to give 2.15 g of the title compound. Physical
characteristics: M.p. 202-204.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 1.43, 2.50, 3.69, 3.74, 4.42, 8.19, 8.59, 8.67, 10.18,
11.8. Anal. Found: C, 62.42; H, 5.92; N, 8.03.
Preparation 28
[0405] Ethyl
8-((Benzylamino)methyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-q-
uinolinecarboxylate [AV.7]
[0406] Sodium triacetoxyborohydride (1.0 g) is added to a stirred
solution of ethyl
8-formyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylat- e
(Preparation 27, 515 mg), benzylamine (340 mg) and acetic acid (360
mg) in a mixture of ethanol/THF (10 mL, 1/1). The solution is
stirred for 90 min. The solvents are evaporated. The residue is
taken up in chloroform and is applied to a silica gel column which
is eluted with 1-3% methanol/chloroform followed by 4%
methanol/chloroform to afford 697 mg of the title compound which is
crystallized from methanol/ether. Physical characteristics: .sup.1H
NMR (CDCl.sub.3) .delta. 1.43, 2.47, 3.59, 3.72, 3.90, 4.26, 4.42,
7.34, 7.51, 8.23, 8.59. Anal. Found: C, 68.59; H, 6.65; N,
9.64.
Preparation 29
[0407]
8-((Benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholin-
ylmethyl)-3-quinolinecarboxamide [AV.8]
[0408] A mixture of ethyl
8-((benzylamino)methyl)-4-hydroxy-6-(4-morpholin-
ylmethyl)-3-quinolinecarboxylate (Preparation 28, 513 mg) and
4-chlorobenzylamine (2.5 mL) is heated at 200.degree. C. for 20
min. The mixture is concentrated, and the remaining oil is taken up
in chloroform and applied to a silica gel column. The column is
eluted with 1% methanol/chloroform followed by 2-4%
methanol/chloroform to afford 483 mg of the title compound after
crystallization from ethyl acetate/ether. Physical characteristics:
M.p. 214-216.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 2.46,
3.59, 3.71, 3.86, 4.28, 4.67, 7.28-7.43, 7.53, 8.25, 8.84, 10.5.
Anal. Found: C, 67.68; H, 5.89; N, 10.52; Cl, 6.64.
EXAMPLE 12
[0409]
2-Benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihyd-
ro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide [AV.9] 98
[0410] Aqueous formaldehyde (0.25 ml, 37% solution) is added to a
solution of
8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylm-
ethyl)-3-quinolinecarboxamide (Preparation 29, 60 mg) in methanol
(2.5 mL) at 50.degree. C. The solution is allowed to cool and the
resulting precipitate is filtered and washed with methanol to give
38 mg of the title compound. Physical characteristics: M.p.
203-205.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.38, 3.57,
3.73, 4.20, 4.57, 5.29, 7.2-7.4, 7.51, 8.08, 8.74, 10.4. Anal.
Found: C, 68.50; H, 5.72; N, 10.29.
EXAMPLE 13
[0411]
2-Benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-d-
ihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide [AW.1]
99
[0412] A solution of 1,1'-carbonyldiimidazole (82 mg) in NMP (2.0
mL) is added over 15 min to a solution of
8-((benzylamino)methyl)-N-(4-chloroben-
zyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
(Preparation 29, 106 mg) in NMP (6 mL). After an additional 15 min,
the solvent is removed under reduced pressure and the residual
solid is triturated with methanol to afford 93 mg of the title
compound. Physical characteristics: M.p. 201-204.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 2.44, 3.58, 3.70, 4.67, 4.73,
4.87, 7.3-7.45, 7.51, 8.19, 9.90, 10.1; Anal. Found: C, 66.67; H,
5.31; N, 9.99; Cl, 6.35.
EXAMPLE 14
[0413]
2-Benzyl-N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,-
3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide
[BN.1] 100
[0414] Bromoacetic anhydride (40 mg) is added to a stirred solution
of
8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmeth-
yl)-3-quinolinecarboxamide (Preparation 29, 53 mg) in NMP (0.3 mL).
After 30 min, triethylamine (50 mg) is added. The solution is
diluted with water and the resulting precipitate is filtered and
dried under vacuum to give 44 mg of the title compound. Physical
characteristics: HRMS m/z 571.2104
(C.sub.32H.sub.31ClN.sub.4O.sub.4).
Preparation 30
[0415] Ethyl
2-(2,3-Difluoro-5-iodobenzoyl)-3-(2-formyl-2-methylhydrazino)-
prop-2-enoate [H.2]
[0416] A solution of 1-formyl-1-methylhydrazine (0.217 g) in
toluene (0.5 mL) is added to a solution of ethyl
2-(2,3-difluoro-5-iodobenzoyl)-3-etho- xy-2-propenoate (Preparation
21, 1.00 g) in toluene (2.5 mL) at 33.degree. C. After stirring at
ambient temperature for 20 minutes, a precipitate formed and an
additional 1.5 mL of toluene is added. After an additional 1.75 h,
solid anhydrous Na.sub.2CO.sub.3 (0.285 g) is added and the
reaction mixture is heated to reflux. After 1 h, the reaction
mixture is concentrated at reduced pressure and the residue
suspended in 8 mL of water which is used as is in the following
step. Physical characteristics: MS (ESI+) m/z 419 (M+H).sup.+.
Preparation 31
[0417]
9-Iodo-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]qui-
noline-6-carboxylic acid [H.3]
[0418] Ethyl
2-(2,3-difluoro-5-iodobenzoyl)-3-(2-formyl-2-methylhydrazino)-
prop-2-enoate (Preparation 30, 1.02 g) in 8 mL of water is treated
with KOH pellets (0.410 g) and the reaction mixture is heated in an
oil bath, under a nitrogen atmosphere, at 105.degree. C. for 1.75 h
while volatiles were condensed into a Dean-Stark trap. At this
time, the Dean-Stark trap was removed, 1 mL of an aqueous solution
of KOH (0.956 g) is added to the mixture, and heating is continued
at 105.degree. C. for 4 days. The mixture is cooled to room
temperature, treated with formic acid (1.68 g), and is warmed to
45-50.degree. C. A 37% aqueous formaldehyde (0.396 g) is added and
the mixture is heated at 70.degree. C. for 30 minutes. The
resulting slurry is cooled in an ice bath at 0-5.degree. C.,
reacted with 29% aqueous ammonium hydroxide (1.46 mL), and allowed
to warm to room temperature where it is stirred for 35-40 minutes.
Charcoal (44 mg) is added to the mixture which is stirred for 30
minutes and filtered through a pad of solka-floc rinsing with
water. The filtrate is diluted with saturated brine and a mixture
of chloroform/methanol (95/5) and filtered through a pad of
solka-floc. The organic layer is separated, dried with anhydrous
sodium sulfate, and concentrated at reduced pressure to obtain 252
mg (28%) of the title compound. Physical characteristics: MS (ESI+)
m/z 373 (M+H).sup.+.
Preparation 32
[0419]
N-(4-Chlorobenzyl)-9-iodo-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxad-
iazino[6,5,4-ij]quinoline-6-carboxamide [H.4]
[0420] A solution of
9-iodo-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazin-
o[6,5,4-ij]quinoline-6-carboxylic acid (Preparation 31, 0.900 g) in
tetrahydrofuran (25 mL) is refluxed with 1,1'-carbonyldiimidazole
(0.631 g) for 5 h. The reaction mixture is cooled to room
temperature and treated with 4-chlorobenzylamine (0.828 g). The
reaction mixture is diluted with ether (75 mL), filtered, and the
filtrate is concentrated at reduced pressure. The crude product is
purified by chromatography, using 75 g of silica gel packed and
eluted with EtOAc/CH.sub.2Cl.sub.2/heptane (1/4/5), to afford a 57%
yield of the title compound. Physical characteristics: .sup.1H NMR
(DMSO-d.sub.6) .delta. 10.15, 8.67, 8.12, 7.75, 7.37, 5.29, 4.54,
2.98; MS (EI) m/z 495 (M+); HRMS (FAB) m/z 495.9935
(C.sub.19H.sub.15ClIN.sub.3O.sub.3+H). Anal. Found: C, 45.97; H,
3.14; N, 8.39.
EXAMPLE 15
[0421]
N-(4-Chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihy-
dro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide [I.1,
R.sup.7=methyl] 101
[0422] A dry flask is charged with
N-(4-chlorobenzyl)-9-iodo-3-methyl-7-ox-
o-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide
(Preparation 32, 0.100 g), cuprous iodide (0.012 g),
dichlorobistriphenylphosphine palladium (0.0072 g), propargyl
alcohol (0.022 g), and diethylamine (4 mL). The reaction mixture is
stirred at room temperature for 5 h and concentrated at reduced
pressure. The residue is chromatographed, using 20 g of silica gel
packed and eluted with EtOAc/CH.sub.2Cl.sub.2 (1/1), to obtain the
title compound in 80% yield. Physical characteristics: M.p.
231-233.degree. C.; MS (ESI+) m/z 424.0 (M+H.sup.+); HRMS (FAB) m/z
424.1078 (C.sub.22H.sub.18ClN.sub.3O.su- b.4+H).
Preparation 33
[0423] tert-Butyl
2-(2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-3-oxoprop-1-e-
nyl)-1-methylhydrazinecarboxylate [AM. 1, Y=iodo]
[0424] A solution of ethyl
2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-prope- noate (Preparation
21, 7.80 g) in tert-butanol (40 mL) is cooled with a cold water
bath and a solution of tert-butyl 1-methylhydrazinecarboxylate
(2.92 g) in tert-butanol (4 mL) is added. The cooling bath is
removed, the mixture is stirred for 5 min at ambient temperature,
and then is heated in an oil bath at 45.degree. C. for 40 min. The
reaction mixture is poured into 100 mL of crushed ice/water and
extracted two times with ethyl acetate. The combined organic layers
are dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude
product is purified by chromatography, using 300 g of silica gel,
packed and eluted with EtOAc/heptane (1/3), to afford 8.95 g (92%)
of the title compound as a yellow oily foam. Physical
characteristics: .sup.1H NMR (CDCl.sub.3) .delta. 8.14, 8.07,
7.59-7.49, 7.46-7.41, 4.07, 3.30, 3.26, 1.50, 1.09, 0.97; MS (ESI+)
m/z 511 (M+H).sup.+.
Preparation 34
[0425] Ethyl
1-((tert-Butoxycarbonyl)(methyl)amino)-8-fluoro-6-iodo-4-oxo--
1,4-dihydroquinoline-3-carboxylate [AM.2, Y=iodo]
[0426] Sodium hydride (0.256 g, 60% oil dispersion) is added to a
solution of tert-butyl
2-(2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-3-oxoprop-1-enyl-
)-1-methylhydrazinecarboxylate (Preparation 33, 3.20 g) in
N,N-dimethylformamide (18 mL) at room temperature, and the mixture
is stirred for 2 h. The reaction mixture is poured into a mixture
of 100 mL of ice water and 100 mL of saturated brine. The mixture
is extracted 3 times with ethyl acetate. The combined organic
layers are dried (Na.sub.2SO.sub.4) and concentrated under a
nitrogen stream overnight. The crude product is purified by
chromatography, using 200 g of silica gel packed and eluted with
acetone/CH.sub.2Cl.sub.2/heptane (1/3/6), provided 2.76 g (90%) of
the title compound as a white foam. Physical characteristics:
.sup.1H NMR (CDCl.sub.3) .delta. 8.50, 8.31, 7.67, 4.32, 3.37,
1.49, 1.34, 1.25; .sup.13C NMR (CDCl.sub.3) .delta. 168.87, 163.97,
160.01, 155.50, 141.76, 131.84, 131.37, 128.46, 127.24, 110.98,
86.73, 78.64, 61.47, 36.09, 28.00, 14.64; MS (ESI+) m/z 491
(M+H).sup.+; TLC (silica gel GF): R.sub.f=0.44
acetone/CH.sub.2Cl.sub.2/hexane (1/1/3).
Preparation 35
[0427] Ethyl
8-Fluoro-6-iodo-1-(methylamino)-4-oxo-1,4-dihydroquinoline-3--
carboxylate [AM.3, Y=iodo]
[0428] A solution of trifluroacetic acid (6.40 g) in methylene
chloride (5 mL) is added dropwise over a 4 minute period to a
solution of ethyl
1-((tert-butoxycarbonyl)(methyl)amino)-8-fluoro-6-iodo-4-oxo-1,4-dihydroq-
uinoline-3-carboxylate (Preparation 34, 1.10 g) in methylene
chloride (20 mL) at room temperature. After 3.5 h, the mixture is
poured into a mixture of saturated sodium bicarbonate solution (125
mL) and water (50 mL), and extracted two times with ethyl acetate.
The combined organic extracts are dried (Na.sub.2SO.sub.4) and
concentrated at reduced pressure. The resulting gummy solid is
stirred with diethyl ether at room temperature to afford 0.857 g
(98%) of the title compound as a white solid.
Preparation 36
[0429] Ethyl
8-Fluoro-1-((hydroxymethyl)(methyl)amino)-6-iodo-4-oxo-1,4-di-
hydroquinoline-3-carboxylate [AM.4, Y=iodo]
[0430] A mixture of ethyl
1-((tert-butoxycarbonyl)(methyl)amino)-8-fluoro--
6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Preparation 35,
0.200 g), 37% aqueous formaldehyde (4.0 mL), and water (2.0 mL) is
heated in an oil bath for 2.5 h at 85.degree. C. The mixture is
cooled, diluted with ice water (30 mL), and the resulting
precipitate is collected, rinsed with ice water and partially air
dried. The solid is dissolved in a mixture of acetone and
CH.sub.2Cl.sub.2, dried (Na.sub.2SO.sub.4), and concentrated at
reduced pressure to yield 0.194 g (90%) of the title compound as a
white solid. Physical characteristics: MS (ESI+) m/z 421
(M+H).sup.+; TLC (silica gel GF): R.sub.f=0.32
acetone/CH.sub.2Cl.sub.2 (1/4).
Preparation 37
[0431] Di(tert-butyl)
2-(((3-(ethoxycarbonyl)-8-fluoro-6-iodo-4-oxoquinoli- n-1
(4H)-yl]-(methyl)amino)methyl)malonate [AM.5, Y=iodo]
[0432] Thionyl chloride (0.122 g) is added to a solution of ethyl
8-fluoro-1-((hydroxymethyl)
(methyl)amino)-6-iodo-4-oxo-1,4-dihydroquinol- ine-3-carboxylate
(Preparation 36, 0.194 g) suspended in tetrahydrofuran (4 mL) at
room temperature, and the mixture is stirred for 4.5 h. The
reaction mixture is twice suspended in toluene and concentrated on
a rotary evaporator, and the remaining volatiles removed at high
vacuum. The resulting white solid is suspended in tetrahydrofuran
(3 mL), cooled to 0-5.degree. C. in an ice bath, and treated with
sodium hydride (0.040 g, 60% oil dispersion) under a nitrogen
atmosphere. After 30 min, the reaction mixture is treated with a
separately prepared mixture of the anion of di-tert-butylmalonate
by treating di-tert-butylmalonate (0.116 g) with sodium hydride
(0.021 g) at 0-5.degree. C. for a period of 1 h. The combined
intermediates are stirred at 0-5.degree. C. for 1.5 h. The mixture
is diluted with 20 mL of pH 7 buffer, treated with 6N HCl to bring
the pH to 7, and extracted once with ethyl acetate. The organic
layer is washed with saturated brine, dried (Na.sub.2SO.sub.4), and
concentrated at reduced pressure. Chromatography with 30 g of
silica gel, packed and eluted with EtOAc/CH.sub.2Cl.sub.2 (1/5),
gives 0.227 g (80%) of the title compound. Physical
characteristics: .sup.1H NMR (CDCl.sub.3) .delta. 8.60, 7.68, 4.41,
3.60, 3.28, 3.00, 1.42, 1.42; MS (ESI+) m/z 619 (M+H).sup.+; TLC
(silica gel GF): R.sub.f=0.46 EtOAc/CH.sub.2Cl.sub.2 (1/4).
Preparation 38
[0433] 3,3-Di(tert-butyl) 8-Ethyl
5-iodo-1-methyl-7-oxo-1,2-dihydro-3H,7H--
pyrido[3,2,1-ij]-cinnoline-3,3,8-tricarboxylate [AM.6, Y=iodo]
[0434] Cesium carbonate (0.367 g) is added to a solution of
di(tert-butyl)
2-(((3-(ethoxycarbonyl)-8-fluoro-6-iodo-4-oxoquinolin-1
(4H)-yl)(methyl)amino)methyl)malonate (Preparation 37, 0.517 g) in
dimethylsulfoxide (5 mL) and the mixture is heated at 85.degree. C.
in an oil bath under a nitrogen atmosphere for 2 h. The mixture is
cooled in an ice bath, diluted with 65 mL of water containing 2.5
mL of acetic acid, stirred, and the resultant yellow precipitate
collected and dried in a vacuum oven to provide the title compound
in 75% yield as a golden oil. Physical characteristics: .sup.1H NMR
(CDCl.sub.3) .delta. 8.79, 8.54, 8.29, 4.40, 4.16, 2.78, 1.51,
1.41; MS (ESI+) m/z 599 (M+H).sup.+; TLC (silica gel GF):
R.sub.f=0.59 acetone/CH.sub.2Cl.sub.2 (1/4).
Preparation 39
[0435]
5-Iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-
-carboxylic acid [AM.7, Y=iodo]
[0436] A mixture of acetic acid (1 mL), 6N HCl (1 mL), and
3,3-di(tert-butyl) 8-ethyl
5-iodo-1-methyl-7-oxo-1,2-dihydro-3H,7H-pyrido-
[3,2,1-ij]cinnoline-3,3,8-tricarboxylate (Preparation 38, 0.165 g)
is heated in an oil bath at 110.degree. C. for 1.5 h. Additional
acetic acid (1 mL) and 6N HCl (1 mL) is added and heating continued
for 2 h. The reaction vessel is purged with a strong nitrogen
stream while heating in the oil bath at 115.degree. C. until dry
solid remains. Dimethylsulfoxide (2 mL) is then added and the
temperature raised to 150.degree. C. for 1 h. The mixture is
allowed to cool slowly overnight. The mixture is diluted with
chloroform, treated with 2 g of silica gel, and concentrated at
reduced pressure. The residue is chromatographed using 35 g of
silica gel, packed and eluted with
acetone/chloroform/methanol/acetic acid (3/6.6/0.4/0.5%), to obtain
53 mg (52%) of the title compound as a tan colored solid. Physical
characteristics: .sup.1H NMR (DMSO-d.sub.6) .delta. 14.88, 8.80,
8.49, 8.18, 3.50, 3.15, 2.88; MS (ESI+) m/z 371 (M+H).sup.+; TLC
(silica gel GF): R.sub.f=0.46 acetone/chloroform/methano- l/acetic
acid (3/6.5/0.5/0.5%).
Preparation 40
[0437]
N-(4-Chlorobenzyl)-5-iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3-
,2,1-ij]-cinnoline-8-carboxamide [AM.8, Y=iodo, X=chloro]
[0438] A solution of
5-Iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1--
ij]cinnoline-8-carboxylic acid (Preparation 39, 0.900 g) in
tetrahydrofuran (25 mL) is refluxed with 1,1'-carbonyldiimidazole
(0.631 g) for 5 h. The reaction mixture is cooled to room
temperature and treated with 4-chlorobenzylamine (0.828 g). The
reaction mixture is diluted with ether (75 mL), filtered, and the
filtrate is concentrated at reduced pressure. The crude product is
purified by chromatography, using 75 g of silica gel packed and
eluted with EtOAc-CH.sub.2Cl.sub.2-heptane (1:4:5), to afford the
title compound. Physical characteristics: .sup.1H NMR (CDCl.sub.3)
.delta. 8.91, 8.70, 7.87, 7.32, 4.65, 3.51, 3.13, 2.90; MS (ESI+)
m/z 494.0; HRMS (FAB) n/z 494.0142 (C.sub.20H.sub.17ClIN.sub.3O-
.sub.2+H); TLC (silica gel GF): R.sub.f=0.27 EtOAc/CH.sub.2Cl.sub.2
(1/6).
EXAMPLE 16
[0439]
N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihy-
dro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide [AN.1, X=chloro,
Z=CH.sub.2OH] 102
[0440] A dry flask is charged with
N-(4-chlorobenzyl)-5-iodo-1-methyl-7-ox-
o-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide
(Preparation 40, 0.100 g), cuprous iodide (0.012 g),
dichlorobistriphenylphosphine palladium (0.0072 g), propargyl
alcohol (0.022 g), and diethylamine (4 mL). The reaction mixture is
stirred at room temperature for 5 h and concentrated at reduced
pressure. The residue is chromatographed, using 20 g of silica gel
packed and eluted with EtOAc/CH.sub.2Cl.sub.2 (1/1), to obtain the
title compound in 74% yield as a tan colored solid. Physical
characteristics: M.p. 165-167.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 10.21, 8.67, 8.13, 7.74, 7.38, 5.41, 4.55,
4.35, 3.49, 3.12, 2.85; .sup.13C NMR (DMSO-d.sub.6) .delta. 173.69,
162.80, 144.92, 137.79, 133.56, 132.88, 130.54, 128.44, 127.97,
127.49, 126.10, 124.99, 117.98, 109.97, 90.12, 81.73, 48.60, 47.63,
43.24, 40.64, 17.64; MS (ESI+) m/z 422 (M+H).sup.+; HRMS (FAB) m/z
422.1282 (C.sub.23H.sub.20ClN.sub.3O.sub.3+H); TLC (silica gel GF):
R.sub.f=0.22 acetone/chloroform (1/4).
Testing of Inventive Compounds
[0441] The antiviral activity of a compound of the invention can be
determined using pharmacological models which are well known to the
art, or using the test described below.
[0442] While many of the compounds of the present invention can
demonstrate activity against the CMV polymerase, these compounds
may be active against the cytomegalovirus by this or other
mechanisms of action. Thus, the description below of these
compounds' activity against the CMV polymerase is not meant to
limit the present invention to a specific mechanism of action.
[0443] The HCMV polymerase assay is performed using a scintillation
proximity assay (SPA) as described in several references, such as
N.D. Cook, et al., Pharmaceutical Manufacturing International,
pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September
issue (1992); U.S. Pat. No. 4,568,649 (1986); which are
incorporated by reference herein. Reactions are performed in
96-well plates. The assay is conducted in 100 .mu.l volume with 5.4
mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl.sub.2, 0.36 mg/ml BSA,
and 90 nM .sup.3H-dTTP. Assays are run with and without CHAPS,
(3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a
final concentration of 2 mM. HCMV polymerase is diluted in enzyme
dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES
(pH 7.5), 100 .mu.g/ml BSA, and 0.01% sodium azide. The HCMV
polymerase, which is expressed in recombinant baculovirus-infected
SF-9 cells and purified according to literature procedures, is
added at 10% (or 10 .mu.l) of the final reaction volume, i.e., 100
.mu.l. Compounds are diluted in 50% DMSO and 10 .mu.l are added to
each well. Control wells contain an equivalent concentration of
DMSO. Unless noted otherwise, reactions are initiated via the
addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to
reaction mixtures containing the enzyme, substrate, and compounds
of interest. Plates are incubated in a 25.degree. C. or 37.degree.
C. H.sub.2O bath and terminated via the addition of 40
.mu.l/reaction of 0.5 M EDTA (pH 8) per well. Reactions are
terminated within the time-frame during which substrate
incorporation is linear and varied depending upon the enzyme and
conditions used, i.e., 30 min. for HCMV polymerase. Ten .mu.l of
streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added
following termination of the reaction. Plates are incubated 10 min.
at 37.degree. C., then equilibrated to room temperature, and
counted on a Packard Topcount. Linear regressions are performed and
IC.sub.50's are calculated using computer software.
[0444] A modified version of the above HCMV polymerase assay is
performed as described above, but with the following changes:
Compounds are diluted in 100% DMSO until final dilution into assay
buffer. In the previous assay, compounds are diluted in 50% DMSO.
4.5 mM dithiothreitol (DTT) is added to the polymerase buffer.
Also, a different lot of CMV polymerase is used, which appears to
be more active resulting in a more rapid polymerase reaction.
Results of the testing of representative compounds of formula I in
this assay are shown in Table 1 below.
1 TABLE 1 Polymerase IC.sub.50 (.mu.M) Example HCMV HSV VZV 1 0.65
nd nd 2 0.77 0.74 0.52 3 0.14 <0.51 0.06 4 0.16 nd 0.18 5 3.2 nd
nd 6 4.0 nd nd 7 4.0 nd nd 8 0.43 0.2 0.09 9 0.67 0.28 0.17 10 0.31
0.31 0.12 11 1.16 nd nd 12 1.67 nd nd 13 39% @20 .mu.M.sup..dagger.
nd nd 14 6.0 nd nd 15 4.19 nd nd 16 7.95 nd nd nd not determined.
.sup..dagger.Percent inhibition at the given concentration.
[0445] Having described the invention in detail and by reference to
the preferred embodiments thereof, it will be apparent that
modifications and variations are possible without departing from
the scope of the appended claims.
* * * * *