U.S. patent application number 11/098019 was filed with the patent office on 2005-12-22 for tetracyclic azepinoindole compounds.
This patent application is currently assigned to Pfizer. Invention is credited to Acker, Brad A., Ennis, Michael D., Frank, Kristine E., Hester, Jackson B., Jacobsen, Eric Jon, Rogers, Bruce N., Steele, Susan L..
Application Number | 20050282796 11/098019 |
Document ID | / |
Family ID | 26828913 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050282796 |
Kind Code |
A1 |
Acker, Brad A. ; et
al. |
December 22, 2005 |
Tetracyclic azepinoindole compounds
Abstract
The present invention provides compounds of formula I: 1 wherein
R.sub.1, R.sub.2, X and Y have any of the values defined in the
specification, as well as pharmaceutical compositions comprising
the compounds. The invention also provides therapeutic methods as
well as processes and intermediates useful for preparing compounds
of formula (I).
Inventors: |
Acker, Brad A.; (Saint
Charles, MO) ; Ennis, Michael D.; (Chesterfield,
MO) ; Frank, Kristine E.; (Worcester, MA) ;
Hester, Jackson B.; (Galesburg, MI) ; Jacobsen, Eric
Jon; (Chesterfield, MO) ; Rogers, Bruce N.;
(Mystic, CT) ; Steele, Susan L.; (Chicago,
IL) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Assignee: |
Pfizer
|
Family ID: |
26828913 |
Appl. No.: |
11/098019 |
Filed: |
April 1, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11098019 |
Apr 1, 2005 |
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10744999 |
Dec 23, 2003 |
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6875762 |
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10744999 |
Dec 23, 2003 |
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10174203 |
Jun 17, 2002 |
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10174203 |
Jun 17, 2002 |
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09553246 |
Apr 20, 2000 |
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6407092 |
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60130881 |
Apr 23, 1999 |
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Current U.S.
Class: |
514/215 ;
540/579 |
Current CPC
Class: |
A61P 37/04 20180101;
A61P 25/22 20180101; C07D 487/16 20130101; C07D 471/16 20130101;
A61P 25/18 20180101; A61P 25/24 20180101; C07D 513/16 20130101;
C07D 498/16 20130101 |
Class at
Publication: |
514/215 ;
540/579 |
International
Class: |
A61K 031/55; C07D
487/14 |
Claims
1. A compound of formula I: 53wherein, each R.sub.1 is
independently hydroxy, nitro, halo, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, or C.sub.1-7alkanoyloxy of R.sub.1 is
optionally partially unsaturated and is optionally substituted with
aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo,
cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aNR.sub.cR.- sub.d, or
--C(.dbd.O)NR.sub.aR.sub.b; R.sub.2 is hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, arylcarbonyl, aryl, (aryl)C.sub.1-7alkyl,
C.sub.1-7alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or
(aryl)C.sub.1-7alkoxycarbonyl; X and Y together are a 2, 3, or 4
membered saturated or partially unsaturated chain comprising one or
more carbon atoms and optionally comprising one oxy (-O--), thio
(-S--), sulfinyl (-SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in
the chain; wherein the chain is optionally substituted on each
carbon with oxo (.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.f,
--S(O).sub.pR.sub.s, or --OR.sub.t, or with one or two substituents
independently selected from the group consisting of C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl; or wherein the chain is optionally
substituted on a carbon with a 4, 5, or 6 membered spirocyclic
carbon ring; or wherein the chain is optionally substituted on two
adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g.
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) forming a ring that is fused
to the ring comprising X and Y; each m is independently 0, 1, or 2;
n is 0, 1, 2, or 3; p is 0, 1, or 2; each R.sub.a and R.sub.b is
independently hydrogen, C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, or (heteroaryl)C.sub.1-7alkyl; or R.sub.a and R.sub.b
together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, morpholino, or thiomorpholino ring; each
R.sub.a and R.sub.d is independently hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl,
arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or
heteroaryloxycarbonyl; or R.sub.c and R.sub.d together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
morpholino, or thiomorpholino ring; each R.sub.e is independently
hydrogen, C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl,
or (heteroaryl)C.sub.17alkyl; R.sub.f is hydrogen, C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl,
or is a bond to a 2, 3, or 4 membered alkylene chain that forms a
ring that is fused to the ring comprising X and Y; each R.sub.q and
R.sub.a is independently hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl; or
R.sub.q and R.sub.r together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, morpholino, or
thiomorpholino ring; R.sub.s is C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl;
and R.sub.t is hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl;
wherein any aryl or heteroaryl ring of R.sub.1, R.sub.2, X, Y,
R.sub.a-R.sub.f, or R.sub.q-R.sub.t is optionally substituted with
one or more (e.g. 1, 2, 3, or 4) substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, phenyl,
sulfonyl, NR.sub.jR.sub.k, or --C(.dbd.O)NR.sub.jR.sub.k, wherein
each R.sub.j and R.sub.k is independently hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, arylcarbonyl, or aryloxycarbonyl; or R.sub.j
and R.sub.k together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof; provided Y is not
oxy, thio, sulfinyl or NR.sub.f, and provided X and Y together are
not a 2-membered unsaturated chain; and provided no carbon of X and
Y is bonded to more than one oxy, thio, sulfinyl, or NR.sub.f.
2. The compound of claim 1 wherein each R.sub.1 is independently
hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy, aryl, heteroaryl,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, --S(O).sub.mR.sub.e,
or --C(.dbd.O)NR.sub.aR.sub.b, wherein any C.sub.1-7alkyl,
C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, or
C.sub.1-7alkanoyloxy of R.sub.1 is optionally substituted with
aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo,
cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub- .b.
3. The compound of claim 1 wherein each R.sub.1 is independently
hydroxy, nitro, halo, cyano, trifluoromethyl, tifluoromethoxy,
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy, aryl, heteroaryl,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, --S(O).sub.mR.sub.c,
or --C(.dbd.O)NR.sub.aR.sub.b, wherein any C.sub.1-7alkyl or
C.sub.1-7alkoxy of R.sub.1 is optionally substituted with aryl,
aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano,
C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.c,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub- .b.
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. The compound of claim 1 wherein X is --O--, --S--, or
--C(R.sub.g)(R.sub.h)--, wherein R.sub.g and R.sub.h are each
independently hydrogen, C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl or (aryl)oxyC.sub.1-7alkyl,
or R.sub.g and R.sub.h together are oxo.
19. The compound of claim 1 wherein Y is --C(R.sub.g)(R.sub.h)--,
--C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--,
--C(R.sub.g)(R.sub.h)C(R.sub.- g)(R.sub.h)C(R.sub.g)(R.sub.h--,
--C(R.sub.g)(R.sub.h)C(.dbd.O)--,
--(R.sub.g(R.sub.h)C(R.sub.g(R.sub.h)C(.dbd.O)--,
--C(.dbd.O)C(R.sub.g)(R- .sub.h)--, or
--C(.dbd.O)C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--, and each
R.sub.g and R.sub.h is independently hydrogen or
C.sub.1-7alkyl.
20. The compound of claim 1 wherein X is --O--, --S--, or
--C(R.sub.g)(R.sub.h)--; and Y is --C(R.sub.g)(R.sub.h)C(.dbd.O)--,
or --C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--, wherein each R.sub.g
and R.sub.h is independently hydrogen or C.sub.1-7alkyl.
21. The compound of claim 1 wherein X is --O-- or --S--; and Y is
--C(R.sub.g)(R.sub.h)C(.dbd.O)--, --C(.dbd.O)C(R.sub.g)(R.sub.h)--,
or --C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--, wherein each R.sub.g
and R.sub.h is independently hydrogen or C.sub.1-7alkyl.
22. (canceled)
23. (canceled)
24. (canceled)
25. (canceled)
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. (canceled)
31. (canceled)
32. The compound of claim 1 which is:
5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
2-methyl-5,6,9,10,11,12-hexahydro-
-4H,8H-azepino[4',5':4,5)pyrrolo(3,2,1-ij]quinoline;
1-methoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1--
ij]quinoline;
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij]quinoline;
6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-methyl-5,6,9,10,11,12-hexahydro-4H-
,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-methyl-5,6,9,10,11,12--
hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2-
,1-ij]quinoline;
(-)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5'-
:4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-5-methyl-5,6,9,10,11,12-hexahydro-4H,-
8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
(-)-5-methyl-5,6,9,10,11,-
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
(+)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2-
,1-ij]quinoline;
(-)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5'-
:4,5]pyrrolo[3,2,1-ij]quinoline;
4,5,8,9,10,11-hexahydro-7H-azepino(4,5-b]- pyrrolo[3,2,1-hi]indole;
2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b-
]pyrrolo[3,2,1-hi]indole;
2-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-
-b]pyrrolo[3,2,1-hi]indole;
5-methyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,-
5-b]pyrrolo[3,2,1-hi]indole;
4,5-dimethyl-4,5,8,9,10,11-hexahydro-7H-azepi-
no[4,5-b]pyrrolo[3,2,1-hi]indole;
2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-a-
zepino[4',5':4,5]pyrrolo[3,2,1-jk]carbazole;
1-chloro-2-fluoro-4,5,8,9,10,-
11-hexahydro-7-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-
;
2-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indol-
e;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quino-
lin-4-one;
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrro-
lo[3,2,1-ij]quinolin-4-one;
2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5';4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
6-methyl-5,6,9,10,11,12-hexah-
ydro-4H,8H-azepino(4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrol-
o[3,2,1-ij]quinolin-4-one;
2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-i-
j]quinolin-4-one;
6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
5,6,8,9,10,11,12,12a-octahyd-
ro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol;
4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]pyrrolo-
[3,2,1-ij]quinoline;
10-benzoyl-4-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-a-
zepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline; or
4-phenoxy-5,6,9,10,11,12-h-
exahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline; or a
pharmaceutically acceptable salt thereof.
33. The compound
1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3-
,4-hi]indole; or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 which is:
1-fluoro-4,5,8,9,10,11-hexahydro-7H--
azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-fluoro-4,5,8,9,10,11-hexahydro-7H-
-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-bromo-4,5,8,9,10,11-hexahydro-7H-
-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-bromo-4,5,8,9,10,11-hexahydro-7H-
-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-bromo-4,5,8,9,10,11-hexahydro-7H-
-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
3-chloro-1-4,5,8,9,10,11-hexahydro-
-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
2-chloro-1-fluoro-4,5,8,9,10,11-
-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
1-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indol-
e,
3-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]ind-
ole;
4-methyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]in-
dole;
1-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo-
[3,2,1-hi]indole;
2-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4-
,5-b]pyrrolo[3,2,1-hi]indole;
3-(trifluoromethyl)-4,5,8,9,10,11-hexahydro--
7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
4-benzyloxy-5,6,8,9,10,11,12,12a-
-octahydro-4H,7aH-azepino[4',5':4,5]pyrrolo(3,2,1-ij]quinoline;
4-(3-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinoline;
4-(2-chlorophenoxy)5,6,9,10,11,12-hexahydro-4H,8H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-methoxyphenoxy)-5,6,9,1-
0,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyr-
rolo[3,2,1-ij]quinoline;
4-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,-
8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-bromo-2-methoxypheno-
xy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quin-
oline;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinolin-4-amine;
N-phenyl-5,6,9,10,11,12-hexahydro-4H8H-azepino[4',5';4,5]-
pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(4-chlorophenyl)-5,6,9,10,11,12-hexah-
ydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-4amine;
N-(3-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrro-
lo[3,2,1-ij]quinolin-4-amine;
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5}pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinolin-4-amine;
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydr-
o-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinolin-4-amine;
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12--
hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-amine;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoli-
ne-4-thione;
4-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-chlorophenylsulfonyl)-5,6,9,10,11,-
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline;
4-(2-chlorophenylsulfonyl)-5,6,9,10,11,12-h-
exahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinoline; 4-(3-methoxyphenylsulfonyl-5,,6,
10,111,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-bromo-2-methoxyphenylsulfonyl)-5,6,9,-
10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]-
quinolin-5-ol;
5-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-benzyloxy-5,6,8,9,10,11,12,12a-octahy-
dro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1--
ij]quinoline;
5-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-chlorophenoxy)-5,6,9,10,11,12-he-
xahydro-4H,8H-azepino[4',5':4,5)pyrrolo[3,2,1-ij]quinoline;
5-(2-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinoline;
5-(4-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-methoxyphenoxy)-5,6,9-
,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyr-
rolo[3,2,1-ij]quinoline;
5-(4-bromo-2-methoxyphenoxy)-5,6,9,10,11,12-hexah-
ydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoli-
n-5-amine;
N-phenyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrro-
lo[3,2,1-ij]quinolin-5-amine;
N-(4-chlorophenyl)-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(3chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrol-
o[3,2,1-ij]quinolin-5-amine;
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro-4-
H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinolin-5-amine;
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydr-
o-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinolin-5-amine;
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12--
hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-5-amine;
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoli-
ne-5-thione;
5-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-chlorophenylsulfonyl)-5,6,9,10,11,-
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline;
5-(2chlorophenylsulfonyl)-5,6,9,10,11,12-he-
xahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-methoxyphenylsulfonyl)5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline;
5-(3-methoxyphenylsulfonyl)-5,6,9,10,11,12--
hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
5-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinoline;
5-(4-bromo-2-methoxyphenylsufonyl)-5,6,9,1-
0,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
4-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinoline;
1-[2-(4-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexah-
ydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H4,
8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-fluorophenoxy)et-
hoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]qu-
inoline;
1-[2-(4-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azep-
ino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-chlorophenoxy)ethoxy]-5,-
6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1
-[2-(2-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-bromophenoxy)ethoxy]-5,6,9,10,1-
1,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5'-
:4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-bromophenoxy)ethoxy]-5,6,9,10,11,-
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-methoxyphenoxy)ethoxy]-5,6,9,10-
,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-methoxyphenoxy)ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(4-methylphenoxy)ethoxy]-5.6,9,10,-
11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(3-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5-
':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-methylphenoxy)ethoxy]-5,6,9,10,1-
1,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(1-naphthyloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-(2-naphthyloxy)ethoxy]-5,6,9,10,11,12-
-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-([1,1'-biphenyl]-4-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azep-
ino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-[2-([1,1'-biphenyl]-3-yloxy)et-
hoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]qu-
inoline;
1-[2-([1,1'-biphenyl]-2-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H-
,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[4-(trifluoromethox-
y)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5)pyrrolo-
[3,2,1-ij]quinoline;
1-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11-
,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[2-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline;
1-{2-[4(trifluoromethyl)phen-
oxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5)pyrrolo[3,2,1-
-ij]quinoline;
1-{2-[3-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hex-
ahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline, or
1-{2-[2-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4H,8H-a-
zepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline; or a pharmaceutically
acceptable salt thereof.
35. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
36. A method for treating a disease or condition in a mammal
wherein the 5-HT receptor is implicated and modulation of 5-HT
function is desired comprising administering a therapeutically
effective amount of a compound of claim 1 to the mammal.
37. The method of claim 36 wherein the disease or condition is
anxiety, obesity, depression, schizophrenia, a stress related
disease, panic disorder, a phobia, obsessive compulsive disorder,
post-traumatic-stress syndrome, immune system depression, a stress
induced problem with the gastrointestinal or cardiovascular system,
or sexual dysfunction.
38. The method of claim 37 wherein the disease is anxiety, obesity,
depression, or a stress related disease.
39. A method for treating or preventing a disease or disorder of
the central nervous system in a mammal comprising administering a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt thereof to the mammal.
40. The method of claim 39 wherein the disease or disorder of the
central nervous system is obesity, depression, schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional
disorder, a stress related disease, panic disorder, a phobia,
obsessive compulsive disorder, post-traumatic-stress syndrome,
immune system depression, a stress induced problem with the
urinary, gastrointestinal or cardiovascular system,
neurodegenerative disorders, autism, chemotherapy-induced vomiting,
hypertension, migraine, headaches, cluster headaches, sexual
dysfunction, addictive disorder and withdrawal syndrome, an
adjustment disorder, an age-associated learning and mental
disorder, anorexia nervosa, apathy, an attention-deficit disorder
due to general medical conditions, attention-deficit hyperactivity
disorder, behavioral disturbance, bipolar disorder, bulimia
nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic
disorder, dysthymic disorder, fibromyalgia and other somatoform
disorders, generalized anxiety disorder, an inhalation disorder, an
intoxication disorder, movement disorder, oppositional defiant
disorder, peripheral neuropathy, post-traumatic stress disorder,
premenstrual dysphoric disorder, a psychotic disorder, mood
disorder, seasonal affective disorder, a sleep disorder, a specific
development disorder, agitation disorder, selective serotonin
reuptake inhibition syndrome, or a Tic disorder.
41. A compound of formula I: 54wherein, each R.sub.1 is
independently hydroxy, nitro, halo, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, or C.sub.1-7alkanoyloxy of R.sub.1 is
optionally partially unsaturated and is optionally substituted with
aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo,
cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub.b; R.sub.2 is a suitable protecting group;
X and Y together are a 2, 3 or 4 membered saturated or partially
unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (-O--), thio (-S--), sulfinyl
(-SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain; wherein
the chain is optionally substituted on each carbon with oxo
(.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.t, --S(O).sub.pR.sub.s,
or --OR.sub.t or with one or two substituents independently
selected from the group consisting of C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkylaryl, (aryl)C.sub.1-7alkyl,
heteroaryl (heteroaryl)C.sub.1-7alkyl, and (aryl)oxyC.sub.1-7alkyl;
or wherein the chain is optionally substituted on a carbon with a
4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain
is optionally substituted on two adjacent atoms with a 2, 3, or 4
membered alkylene chain (e.g. --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) forming a ring that is fused
to the ring comprising X and Y; each m is independently 0, 1, or 2;
n is 0, 1, 2, or 3; p is 0, 1 or 2; each R.sub.a and R.sub.b is
independently hydrogen, C.sub.1-7allyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, or (heteroaryl)C.sub.1-7alkyl; or R.sub.a and R.sub.b
together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, morpholino, or thiomorpholino ring; each
R.sub.a and R.sub.d is independently hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl,
arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or
heteroaryloxycarbonyl; or R.sub.c and R.sub.d together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
morpholino, or thiomorpholino ring; each R.sub.a is independently
hydrogen, C.sub.1-7alkyl, aryl (aryl)C.sub.1-7alkyl, heteroaryl, or
(heteroaryl)C.sub.1-7alkyl; R.sub.f is hydrogen, C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl
or is a bond to a 2, 3, or 4 membered alkylene chain that forms a
ring that is fused to the ring comprising X and Y; each R.sub.q and
R.sub.r is independently hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl; or
R.sub.q and R.sub.r together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, morpholino, or
thiomorpholino ring; R.sub.s is C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl;
and R.sub.t is hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl;
wherein any aryl or heteroaryl ring of R.sub.1, R.sub.2, X, Y,
R.sub.a-R.sub.f; or R.sub.q-R.sub.t is optionally substituted with
one or more (e.g. 1, 2, 3, or 4) substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, phenyl,
sulfonyl, NR.sub.jR.sub.k, or --C(.dbd.O)NR.sub.jR.sub.k ,; wherein
each R.sub.j and R.sub.k is independently hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, arylcarbonyl, or aryloxycarbonyl; or R.sub.j
and R.sub.k together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
or a pharmaceutically acceptable salt thereof; provided Y is not
oxy, thio, sulfinyl, or NR.sub.f', and provided X and Y together
are not a 2-membered unsaturated chain; and provided no carbon of X
and Y is bonded to more than one oxy, thio, sulfinyl, or
NR.sub.f.
42. The compound of claim 41 wherein R.sub.2 is C.sub.1-4alkyl,
C.sub.1-4alkanoyl, arylcarbonyl, (aryl)C.sub.1-2alkyl,
C.sub.1-4alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or
(aryl)methoxycarbonyl, wherein any aryl is optionaly substituted
with 1, 2, or 3 substituents independently selected from
C.sub.1-4alkyl and trifluoromethyl.
43. The compound of claim 41, wherein R.sub.2 is methyl, ethyl,
propyl, isopropyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl,
benzyl, or p-toluenesulfonyl.
44. The compound of claim 1 which is:
10-benzoyl-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5';4,5]pyrr-
olo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-chloro-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5';4,5]pyrr-
olo[3,2,1-ij]quinolin4-one;
10-benzoyl-2-fluoro-6-methyl-5,6,9,10,11,12-he-
xahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-propyl-5,6,9,10,11,-
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-(trifluoromethyl)5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5-
':4,5]pyrrolo[3,2,1-ij]quinolin4-one;
10-benzoyl-5,6,8,9,10,11,12,12a-octa-
hydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol; or
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinolin,
45. The compound of claim which is: benzyl
5,6,8,9,11,12-hexahydro-4H,10H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate; benzyl
2-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-i-
j]quinoline-10-carboxylate;
10-benzoyl-1-methoxy-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo-[3,2,1-ij]quinoline; benzyl
2-fluoro-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-i-
j]quinoline-10-carboxylate; benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H,10H-
-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
benzyl
5-methyl-5,6,8,9,11,12-hexahydro4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-ij-
]quinoline-10-carboxylate; benzyl
4-methyl-5,6,8,9,11,12-hexahydro-4H,10H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-i-
j]quinoline-10-carboxylate; (-)-benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H-
,10H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl
5-methyl-5,6,8,9,11,12-hexahydro-4H,10-azepino[4',5':4,5]pyrro-
lo[3,2,1-ij]quinoline-10-carboxylate; (-)benzyl
5-methyl-5,6,8,9,11,12-hex-
ahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
(+)-benzyl
4-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinoline-10-carboxylate; (-)-benzyl
4-methyl-5,6,8,9,11,12-h-
exahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylat-
e; benzyl
2-methyl-1,2,7,8,10,11-hexahydro-9H-azepino(4,5-b][1,4]oxazino[2-
,3,4-hi]indole-9-carboxylate; benzyl
2,2-dimethyl-1,2,7,8,10,11-hexahydro--
9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; benzyl
4-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]i-
ndole-9-carboxylate; benzyl
4chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-
-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; benzyl
5-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]i-
ndole-9-carboxylate; benzyl
5-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,-
5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; benzyl
5-methyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]i-
ndole-9-carboxylate; benzyl
6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,-
5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; benzyl
6chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]in-
dole-9-carboxylate; benzyl
6-methyl-1,2,6b,7,8,10,11,11a-octahydro-9H-azep-
ino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; benzyl
6-(trifluoromethyl)-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino-
[2,3,4-hi]indole-9-carboxylate; benzyl
5,6difluoro-1,2,7,8,10,11-hexahydro-
-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylatebenzyl;
benzyl
5-chloro-6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole9-carboxylate; benzyl
5-fluoro-6-chloro-1,2,7,8,10,11-hexahy-
dro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
benzyl
5,6-dichloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4--
hi]indole-9-carboxylate; benzyl
4,6-dichloro-1,2,7,8,10,11-hexahydro-9H-az-
epino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate; 7-benzoyl
4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole;
7-benzoyl
2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-
-hi]indole; 7-benzoyl
2-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]p-
yrrolo[3,2,1-hi]indole;
benzyl-5-methyl-4,5,8,9,10,11-hexahydro-7H-azepino-
[4,5-b]pyrrolo[3,2,1-hi]-7-carboxylate,
benzyl-4,5-dimethyl-4,5,8,9,10,11--
hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
benzyl-2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-azepino[4',5':4,5]pyrrolo[3-
,2,1-jk]carbazole-7-carboxylate;
benzyl-1-chloro-2-fluoro-4,5,8,9,10,11-he-
xahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
benzyl-2-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi-
]indole-7-carboxylate;
benzyl-1-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[-
4,5-b]pyrrolo[3,2,1-hi]indole-7-carboxylate;
10-benzoyl-5,6,9,10,11,12-hex-
ahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-chloro-5,6,9,10,11,12-hexahydro-
-4H,8H-azepino[4',5':4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrr-
olo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-2-fluoro-6-methyl-5,6,9,10,11,12--
hexahydro-4H,8H-azepino[4',5':4,5]-pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
.dbd.,5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-propyl-5,6,9,10-
,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo-[3,2,1-ij]quinolin-4-one;
10-benzoyl-6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
10-benzoyl-5,6,8,9,10,11,12,12a-oc-
tahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol;
and
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinoline.
46. (canceled)
47. (canceled)
Description
PRIORITY OF INVENTION
[0001] This application claims priority from U.S. Provisional
Application No. 60/130,881, filed 23 Apr. 1999.
FIELD OF THE INVENTION
[0002] The present invention provides tetracyclic
1,2,3,4,5,6-hexahydroaze- pino-[4,5-b]indole derivatives having a
ring connecting position 6 (N-6) and position 7 (C-7), and more
specifically, provides compounds of formula (I) described
hereinbelow. These compounds are 5-HT ligands, and are useful for
treating diseases wherein modulation of 5-HT activity is
desired.
BACKGROUND OF THE INVENTION
[0003] Serotonin has been implicated in a number of diseases and
conditions which originate in the central nervous system. These
include diseases and conditions related to sleeping, eating,
perceiving pain, controlling body temperature, controlling blood
pressure, depression, anxiety, schizophrenia, and other bodily
states. R. W. Fuller, Biology of Serotonergic Transmission, 221
(1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316
(1978); J. Barchas, et al., Serotonin and Behavior, (1973).
Serotonin also plays an important role in peripheral systems, such
as the gastrointestinal system, where it has been found to mediate
a variety of contractile, secretory, and electrophysiologic
effects.
[0004] As a result of the broad distribution of serotonin within
the body, there is a tremendous interest in drugs that affect
serotonergic systems. In particular, receptor-specific agonists and
antagonists are of interest for the treatment of a wide range of
disorders, including anxiety, depression, hypertension, migraine,
obesity, compulsive disorders, schizophrenia, autism,
neurodegenerative disorders (e.g. Alzheimer's disease,
Parkinsonism, and Huntington's chorea), and chemotherapy-induced
vomiting. M. D. Gershon, et al., The Peripheral Actions of
5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of
Cardiovascular Pharmacology, 15:Supplement 7 (1990).
[0005] The major classes of serotonin receptors (5-HT.sub.1-7)
contain fourteen to eighteen separate receptors that have been
formally classified. See Glennon, et al., Neuroscience and
Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol.
Rev. 1994, 46, 157-203. Recently discovered information regarding
subtype identity, distribution, structure, and function suggests
that it is possible to identify novel, subtype specific agents,
having improved therapeutic profiles (e.g. fewer side effects).
[0006] For example, the 5-HT.sub.2 family of receptors is comprised
of 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C subtypes, which have
been grouped together on the basis of primary structure, secondary
messenger system, and operational profile. All three subtypes are
G-protein coupled, activate phospholipase C as a principal
transduction mechanism, and contain a seven-transmembrane domain
structure. There are distinct differences in the distribution of
the three 5-HT.sub.2 subtypes. The 5-HT.sub.2B and 5-HT.sub.2A
receptors are widely distributed in the periphery, while the
5-HT.sub.2C receptor has been found only in the central nervous
system, being highly expressed in many regions of the human brain.
See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16,
105-110.
[0007] Subtype 5-HT.sub.2A has been associated with effects
including vasoconstriction, platelet aggregation, and
bronchoconstriction, while subtype 5-HT.sub.2C has been associated
with diseases that include depression, anxiety, obsessive
compulsive disorder, panic disorders, phobias, psychiatric
syndromes, and obesity. Very little is known about the
pharmacologic role of the 5-HT.sub.2B receptor. See F. Jenck, et
al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al.,
J. Med. Chem., 1997, 40,2762-2769; J. R. Martin, et al., The
Journal of Pharmacology and Experimental Therapeutics, 1998, 286,
913-924; S. M. Bromidge, et al., J. Med. Chem., 1998, 41,1598-1612;
G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology, 1999, 38, 415-423.
[0008] U.S. Pat. No. 3,676,558, issued Jul. 11, 1972, discloses
compositions comprising specific
6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5- -b]indole compounds. The
compositions are reported to be useful to suppress hunger in
mammals. This patent also discloses a method for inducing anorexia
in obese subjects to produce weight loss. The azepino[4,5-b]indole
compounds disclosed in this patent lack the ring connecting the
6-position and the 7-position that is present in the compounds of
the instant invention.
[0009] U.S. Pat. No. 3,839,357, issued Oct. 1, 1974, discloses
specific 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole compounds, which
are reported to have sedative or tranquilizing action. The
azepino[4,5-b]indole compounds disclosed in this patent also lack
the ring connecting the 6-position and the 7-position that is
present in the compounds of the instant invention.
[0010] There is currently a need for pharmaceutical agents that are
useful to treat diseases and conditions that are associated with
5-HT receptors.
SUMMARY OF THE INVENTION
[0011] In accordance with the present invention, novel compounds
which demonstrate useful biological activity, and particularly
activity as 5-HT receptor ligands, are provided. Thus, the present
invention provides a compound of formula I: 2
[0012] wherein,
[0013] each R.sub.1 is independently hydroxy, nitro, halo, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.c, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, or C.sub.1-7alkanoyloxy of R.sub.1 is
optionally partially unsaturated and is optionally substituted with
aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo,
cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub.b;
[0014] R.sub.2 is hydrogen, C.sub.1-7alkyl, C.sub.1-7alkanoyl,
arylcarbonyl, aryl, (aryl)C.sub.1-7alkyl, C.sub.1-7alkoxycarbonyl,
aryloxycarbonyl, arylsulfonyl, or
(aryl)C.sub.1-7alkoxycarbonyl;
[0015] X and Y together are a 2, 3, or 4 membered saturated or
partially unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (--O--), thio (--S--), sulfinyl
(--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain;
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.r, --S(O).sub.pR.sub.s,
or --OR.sub.t, or with one or two substituents independently
selected from the group consisting of C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C I .sub.7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl; or wherein the chain is optionally
substituted on a carbon with a 4, 5, or 6 membered spirocyclic
carbon ring; or wherein the chain is optionally substituted on two
adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g.
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) forming a ring that is fused
to the ring comprising X and Y;
[0016] each m is independently 0, 1, or 2;
[0017] n is 0, 1, 2, or 3;
[0018] p is 0, 1, or2;
[0019] each R.sub.a and R.sub.b is independently hydrogen,
C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl, or
(heteroaryl)C.sub.1-7alkyl; or R.sub.a and R.sub.b together with
the nitrogen to which they are attached form a pyrrolidino,
piperidino, morpholino, or thiomorpholino ring;
[0020] each R.sub.c and R.sub.d is independently hydrogen,
C.sub.1-7alkyl, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl,
arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or
heteroaryloxycarbonyl; or R.sub.c and R.sub.d together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
morpholino, or thiomorpholino ring;
[0021] each R.sub.e is independently hydrogen, C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl, heteroaryl, or
(heteroaryl)C.sub.1-7alkyl;
[0022] R.sub.f is hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl, or is
a bond to a 2, 3, or 4 membered alkylene chain that forms a ring
that is fused to the ring comprising X and Y;
[0023] each R.sub.q and R.sub.r is independently hydrogen,
C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl, or
(heteroaryl)C.sub.1-7alkyl; or R.sub.q and R.sub.r together with
the nitrogen to which they are attached form a pyrrolidino,
piperidino, morpholino, or thiomorpholino ring;
[0024] R.sub.s is C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, or (heteroaryl)C.sub.1-7alkyl; and
[0025] R.sub.t is hydrogen, C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, or
(heteroaryl)C.sub.1-7alkyl;
[0026] wherein any aryl or heteroaryl ring of R.sub.1, R.sub.2, X,
Y, R.sub.a-R.sub.f, or R.sub.q-R.sub.t is optionally substituted
with one or more (e.g. 1, 2, 3, or 4) substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, phenyl,
sulfonyl, NR.sub.jR.sub.k, or --C(.dbd.O)NR.sub.jR.sub.k,; wherein
each R.sub.j and R.sub.k is independently hydrogen, C.sub.1-7alkyl,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl,
(aryl)C.sub.1-7alkyl, arylcarbonyl, or aryloxycarbonyl; or R.sub.j
and R.sub.k together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, morpholino, or thiomorpholino
ring;
[0027] or a pharmaceutically acceptable salt thereof;
[0028] provided Y is not oxy, thio, sulfinyl, or NR.sub.f; and
[0029] provided X and Y together are not a 2-membered unsaturated
chain; and
[0030] provided no carbon of X and Y is bonded to more than one
oxy, thio, sulfinyl, or NR.sub.f.
[0031] In another aspect, the present invention also provides:
[0032] a pharmaceutical composition comprising a compound of
formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient (the composition preferably
comprises a therapeutically effective amount of the compound or
salt),
[0033] a method for treating a disease or condition in a mammal
(e.g. a human) wherein a 5-HT receptor is implicated and modulation
of a 5-HT function is desired comprising administering a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof to the mammal,
[0034] a method for treating or preventing a disease or disorder of
the central nervous system in a mammal comprising administering a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof to the mammal, and
[0035] a method for modulating 5-HT receptor function, comprising
administering an effective modulatory amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof.
[0036] The invention also provides novel intermediates and
processes disclosed herein that are useful for preparing compounds
of formula I.
DESCRIPTION OF THE FIGURES
[0037] FIGS. 1-6 illustrate synthetic processes and intermediates
useful for preparing compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The compounds of the invention are useful for treating or
preventing diseases or disorders of the central nervous system.
Specific diseases or disorders of the central nervous system for
which a compound of formula I may have activity include, but are
not limited to: obesity, depression, schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional
disorder, a stress related disease (e.g. general anxiety disorder),
panic disorder, a phobia, obsessive compulsive disorder,
post-traumatic-stress syndrome, immune system depression, a stress
induced problem with the urinary, gastrointestinal or
cardiovascular system (e.g., stress incontinence),
neurodegenerative disorders, autism, chemotherapy-induced vomiting,
hypertension, migraine, headaches, cluster headaches, sexual
dysfunction in a mammal (e.g. a human), addictive disorder and
withdrawal syndrome, an adjustment disorder, an age-associated
learning and mental disorder, anorexia nervosa, apathy, an
attention-deficit disorder due to general medical conditions,
attention-deficit hyperactivity disorder, behavioral disturbance
(including agitation in conditions associated with diminished
cognition (e.g., dementia, mental retardation or delirium)),
bipolar disorder, bulimia nervosa, chronic fatigue syndrome,
conduct disorder, cyclothymic disorder, dysthymic disorder,
fibromyalgia and other somatoform disorders, generalized anxiety
disorder, an inhalation disorder, an intoxication disorder,
movement disorder (e.g., Huntington's disease or Tardive
Dyskinesia), oppositional defiant disorder, peripheral neuropathy,
post-traumatic stress disorder, premenstrual dysphoric disorder, a
psychotic disorder (brief and long duration disorders, psychotic
disorder due to medical condition, psychotic disorder NOS), mood
disorder (major depressive or bipolar disorder with psychotic
features) seasonal affective disorder, a sleep disorder, a specific
development disorder, agitation disorder, selective serotonin
reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder
(e.g., Tourette's syndrome).
[0039] The following definitions are used, unless otherwise
described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy,
etc. denote 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.
[0040] Aryl denotes a phenyl radical or an ortho-fused bicyclic
carbocyclic radical having about nine to ten ring atoms in which at
least one ring is aromatic. Heteroaryl denotes a radical 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,
as well as a radical of an ortho-fused bicyclic heterocycle of
about eight to ten ring atoms derived therefrom, particularly a
benz-derivative or one derived by fusing a propylene, trimethylene,
or tetramethylene diradical thereto.
[0041] 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 5-HT activity using the standard tests which are well
known in the art.
[0042] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum 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.
[0043] 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).
[0044] 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
[0045] Specifically, C.sub.1-7alkyl can be methyl, ethyl, propyl,
isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or
heptyl; C.sub.1-7alkoxy can be methoxy, ethoxy, propoxy,
isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,
hexyloxy, 1-methylhexyloxy, or heptyloxy; C.sub.1-7alkanoyl can be
acetyl, propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl,
hexanoyl, or heptanoyl; C.sub.1-7alkoxycarbonyl can be
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl,
hexyloxycarbonyl, or heptyloxycarbonyl; C.sub.1-7alkanoyloxy can be
acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy,
hexanoyloxy, or heptanoyloxy; aryl can be phenyl, indenyl, or
naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl,
triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, 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).
[0046] A specific value for R.sub.1 is hydroxy, nitro, halo, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, or C.sub.1-7alkanoyloxy of R.sub.1 is
optionally substituted with aryl, aryloxy, heteroaryl,
heteroaryloxy, hydroxy, nitro, halo, cyano, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
S(O).sub.mR.sub.e, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub- .b.
[0047] A specific value for R.sub.1 is hydroxy, nitro, halo, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl or C.sub.1-7alkoxy of R.sub.1 is optionally
substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy,
nitro, halo, cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl,
C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub.b.
[0048] A specific value for R.sub.1 is hydroxy, nitro, halo, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any
C.sub.1-7alkyl is optionally substituted with aryl, aryloxy,
heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano,
C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl,
C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e,
--S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.aR.sub.b.
[0049] A specific value for R.sub.1 is hydroxy, nitro, halo, cyano,
trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy,
C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy,
aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d,
--S(O).sub.mR.sub.e, or --C(.dbd.O)NR.sub.aR.sub.b.
[0050] A specific value for R.sub.1 is independently
C.sub.1-7alkyl, C.sub.1-7alkoxy, trifluoromethyl, or halo.
[0051] A specific value for R.sub.2 is hydrogen.
[0052] A specific value for R.sub.2 is C.sub.1-4alkyl,
C.sub.1-4alkanoyl, arylcarbonyl, (aryl)C.sub.1-2alkyl,
C.sub.1-4alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or
(aryl)methoxycarbonyl, wherein any aryl is optionally substituted
with 1, 2, or 3 substituents independently selected from
C.sub.1-4alkyl and trifluoromethyl.
[0053] A specific value for R.sub.2 is methyl, ethyl, propyl,
isopropyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
or p-toluenesulfonyl.
[0054] A specific value for n is 1, 2, or 3.
[0055] A specific value for n is 0.
[0056] A specific group of compounds are compounds of formula (I)
wherein n is 0. It will be clear to one skilled in the art that
when n is 0, the benz ring of the indole in formula (I) is
substituted with hydrogens.
[0057] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered saturated or
partially unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (--O--), thio (--S--), sulfinyl
(--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain;
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.r, --S(O).sub.pR.sub.s,
or --OR.sub.t, or with one or two substituents independently
selected from the group consisting of C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl.
[0058] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered saturated or
partially unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (--O--), thio (--S--), sulfinyl
(--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain;
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.r, --S(O).sub.pR.sub.s,
or --OR.sub.t.
[0059] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered saturated or
partially unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (--O--), thio (--S--), sulfinyl
(--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain;
wherein the chain is optionally substituted on each carbon with one
or two substituents independently selected from the group
consisting of C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl,
and (aryl)oxyC.sub.1-7alkyl.
[0060] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered chain comprising
one or more carbon atoms and optionally comprising one oxy (--O--),
thio (--S--), sulfinyl (--SO--), sulfonyl (S(O).sub.2--), or
NR.sub.f in the chain; wherein the chain is optionally substituted
on each carbon with oxo (.dbd.O), hydroxy, or C.sub.1-7alkoxy, or
with one or two substituents independently selected from the group
consisting of C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl
and (aryl)oxyC.sub.1-7alkyl; and wherein the chain is optionally
substituted on two adjacent atoms with a 2, 3, or 4 membered
alkylene chain forming a ring that is fused to the ring comprising
X and Y.
[0061] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered chain comprising
one or more carbon atoms and optionally comprising one oxy (--O--),
thio (--S--), sulfinyl (--SO--), sulfonyl (S(O).sub.2--), or
NR.sub.f in the chain; wherein the chain is optionally substituted
on each carbon with oxo (.dbd.O), hydroxy, (aryl)oxy,
heteroaryl(oxy), or C.sub.1-7alkoxy, or with one or two
substituents independently selected from the group consisting of
C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl; and wherein the chain is optionally
substituted on two adjacent atoms with a 2, 3, or 4 membered
alkylene chain forming a ring that is fused to the ring comprising
X and Y.
[0062] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered carbon chain
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), hydroxy, or C.sub.1-7alkoxy, or with one or two
substituents independently selected from the group consisting of
C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1-7al- kyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl and
(aryl)oxyC.sub.1-7alkyl.
[0063] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2, 3, or 4 membered carbon chain
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), hydroxy, (aryl)oxy, heteroaryl(oxy) or C.sub.1-7alkoxy,
or with one or two substituents independently selected from the
group consisting of C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl.
[0064] A specific group of compounds are compounds of formula I
wherein X and Y together are a 2 or 3 membered carbon chain
optionally substituted on each carbon with oxo or hydroxy, or with
one or two C.sub.1-7alkyl.
[0065] A specific group of compounds are compounds of formula I
wherein X is --O--, --S--, or --C(R.sub.g)(R.sub.h)--, wherein
R.sub.g and R.sub.h are each independently hydrogen,
C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1- -7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alky- l or
(aryl)oxyC.sub.1-7alkyl, or R.sub.g and R.sub.h together are
oxo.
[0066] A specific group of compounds are compounds of formula I
wherein Y is --C(R.sub.g)(R.sub.h)--,
--C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--,
--C(R.sub.g(R.sub.h)C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--,
--C(R.sub.g)(R.sub.h)C(.dbd.O)--,
--C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h- )C(.dbd.O)--,
--C(.dbd.O)C(R.sub.g)(R.sub.h)--, or --C(.dbd.O)C(R.sub.g)(R-
.sub.h)C(R.sub.g)(R.sub.h)--, and each R.sub.g and R.sub.h is
independently hydrogen or C.sub.1-7alkyl.
[0067] A specific group of compounds are compounds wherein X is
--O--, --S--, or --C(R.sub.g)(R.sub.h)--; and Y is
--C(R.sub.g)(R.sub.h)C(.dbd.O- )--, or
--C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--, wherein each R.sub.g
and R.sub.h is independently hydrogen or C.sub.1-7alkyl.
[0068] A specific group of compounds are compounds wherein X is
--O-- or --S--; and Y is --C(R.sub.g)(R.sub.h)C(.dbd.O)--,
--C(.dbd.O)C(R.sub.g)(R- .sub.h)--, or
--C(R.sub.g)(R.sub.h)C(R.sub.g)(R.sub.h)--, wherein each R.sub.g
and R.sub.h is independently hydrogen or C.sub.1-7alkyl.
[0069] A specific group of compounds are compounds wherein X and Y
together are --CH(R.sub.g)CH(R.sub.g)--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub- .g)--,
----CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)--,
--C(R.sub.g).dbd.C(R.sub.g)CH(R.sub.g)--,
--C(R.sub.g).dbd.C(R.sub.g)CH(R- .sub.g)CH(R.sub.g)--,
--CH(R.sub.g)C(R.sub.g).dbd.C(R.sub.g)CH(R.sub.g)--,
--O--CH(R.sub.g)CH(R.sub.g)--,
--O--CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)--,
--S--CH(R.sub.g)CH(R.sub.g)--,
--S--CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)--,
--S(O)--CH(R.sub.g)CH(R.sub.g)--,
--S(O)--CH(R.sub.g)CH(R.sub.g)CH(R.sub.- g)--,
--S(O).sub.2--CH(R.sub.g)CH(R.sub.g)--,
--S(O).sub.2--CH(R.sub.g)CH(- R.sub.g)CH(R.sub.g)--,
--NR.sub.f--CH(R.sub.g)CH(R.sub.g)--,
--NR.sub.f--CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)--,
--CH(R.sub.g)C(.dbd.O)--- , --CH(R.sub.g)CH(R.sub.g)C(.dbd.O)--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)- C(.dbd.O)--,
--CH(R.sub.g)OC(.dbd.O)--, --CH(R.sub.g)CH(R.sub.g)OC(.dbd.O)- --,
--OCH(R.sub.g)C(.dbd.O)--, or --OCH(R.sub.g)CH(R.sub.g)C(.dbd.O)--;
wherein each R.sub.g is independently hydrogen, C.sub.1-7alkyl,
aryl, (aryl)C.sub.1-7alkyl or (aryl)oxyC.sub.1-7alkyl.
[0070] A specific group of compounds are compounds wherein X and Y
together are --CH(R.sub.g)CH.sub.2--,
--CH(R.sub.g)CH(R.sub.g)CH.sub.2--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub.g)CH.sub.2--, --CH=CHCH.sub.2--,
--CH.dbd.CHCH(R.sub.g)CH.sub.2--, --CH(R.sub.g)CH.dbd.CHCH.sub.2--,
--O--CH.sub.2CH.sub.2--, --O--CH.sub.2CH(R.sub.g)CH.sub.2--,
--S--CH.sub.2CH.sub.2--, --S--CH.sub.2CH(R.sub.g)CH.sub.2--,
--S(O)--CH.sub.2CH.sub.2--, --S(O)--CH.sub.2CH(R.sub.g)CH.sub.2--,
--S(O).sub.2--CH.sub.2CH.sub.2--,
--S(O).sub.2--CH.sub.2CH(R.sub.g)CH.sub- .2--,
--NR.sub.f--CH.sub.2CH.sub.2--,
--NR.sub.fCH.sub.2CH(R.sub.g)CH.sub.- 2--, --CH.sub.2C(.dbd.O)--,
--CH(R.sub.g)CH.sub.2C(.dbd.O)--,
--CH(R.sub.g)CH(R.sub.g)CH.sub.2C(.dbd.O)--,
--CH.sub.2OC(.dbd.O)--, --CH(R.sub.g)CH.sub.2OC(.dbd.O)--,
--OCH.sub.2C(.dbd.O)--, or --OCH.sub.2CH.sub.2C(.dbd.O)--; wherein
each R.sub.g is independently --NR.sub.qR.sub.r,
--S(O).sub.pR.sub.s, or --OR.sub.t.
[0071] A specific group of compounds are compounds wherein X and Y
together are --CH(R.sub.g)CH(R.sub.g)--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub- .g)--,
--C(R.sub.g).dbd.C(R.sub.g)CH(R.sub.g)--,
--O--CH(R.sub.g)CH(R.sub.- g)--, --S--CH(R.sub.g)CH(R.sub.g)--,
--S(O)--CH(R.sub.g)CH(R.sub.g)--,
--S(O).sub.2--CH(R.sub.g)CH(R.sub.g)--,
--NR.sub.fCH(R.sub.g)CH(R.sub.g)-- -, --CH(R.sub.g)C(.dbd.O)--,
--CH(R.sub.g)CH(R.sub.g)C(.dbd.O)--, --CH(R.sub.g)OC(.dbd.O)--,
--OCH(R.sub.g)C(.dbd.O)--; wherein each R.sub.g is independently
hydrogen or C.sub.1-7alkyl.
[0072] A specific group of compounds are compounds wherein X and Y
together are --CH(R.sub.g)CH(R.sub.g)--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub- .g)--,
--C(R.sub.g).dbd.C(R.sub.g)CH(R.sub.g)--,
--O--CH(R.sub.g)CH(R.sub.- g)--, --S--CH(R.sub.g)CH(R.sub.g)--,
--S(O)--CH(R.sub.g)CH(R.sub.g)--,
--S(O).sub.2--CH(R.sub.g)CH(R.sub.g)--,
--NR.sub.f--CH(R.sub.g)CH(R.sub.g- )--, or
--CH(R.sub.g)CH(R.sub.g)C(.dbd.O)--; wherein each R.sub.g is
independently hydrogen, C.sub.1-7alkyl, or together with an R.sub.g
on an adjacent carbon atom forms a fused 4, 5, or 6, membered
carbocyclic ring.
[0073] A specific group of compounds are compounds wherein X and Y
together are --CH(R.sub.g)CH(R.sub.g)--,
--CH(R.sub.g)CH(R.sub.g)CH(R.sub- .g)--,
--O--CH(R.sub.g)CH(R.sub.g)--, --S--CH(R.sub.g)CH(R.sub.g)--;
wherein each R.sub.g is independently hydrogen, C.sub.1-7alkyl,
aryl, or (aryl)C.sub.1-7alkyl.
[0074] A specific group of compounds are compounds wherein X and Y
together are --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2C(CH.sub.3)H- --,
--CH.sub.2C(CH.sub.3)HCH.sub.2--, --C(CH.sub.3)HCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2C(CH.sub.3)H--,
--C(CH.sub.3)HC(CH.sub.3)- H--, ----CH(R.sub.g)CH(R.sub.g)--,
--O--CH.sub.2CH.sub.2--, --O--C(CH.sub.3)HCH.sub.2--, or
--S--CH.sub.2CH.sub.2--.
[0075] A specific group of compounds are compounds wherein X and Y
together are --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2--, --O--CH.sub.2CH.sub.2--,
--S--CH.sub.2CH.sub.2--, --S(O)--CH.sub.2CH.sub.2--,
--S(O).sub.2--CH.sub.2CH.sub.2--, --NR.sub.f--CH.sub.2CH.sub.2--,
--CH.sub.2C(.dbd.O)--, --CH.sub.2CH.sub.2C(.dbd.O)--,
--CH.sub.2OC(.dbd.O)--, or --OCH.sub.2C(.dbd.O)--.
[0076] A specific group of compounds are compounds of formula (I)
wherein X and Y together are --CH(R.sub.g)CH.sub.2--,
--CH(R.sub.g)CH(R.sub.g)CH.- sub.2--, or --O--CH.sub.2CH.sub.2--,
wherein each R.sub.g is independently --NR.sub.qR.sub.r,
--S(O).sub.pR.sub.s, --OR.sub.t, C.sub.1-7alkyl,
(C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl,
heteroaryl, (heteroaryl)C.sub.1-7alkyl, or
(aryl)oxyC.sub.1-7alkyl.
[0077] A specific group of compounds are compounds of formula (I)
wherein X and Y together are --C(.dbd.O)CH.sub.2--,
--CH.sub.2C(.dbd.O)--, --C(.dbd.S)CH.sub.2--,
--CH.sub.2C(.dbd.S)--, --C(.dbd.O)CH.sub.2CH.sub.2- --,
--CH.sub.2C(.dbd.O)CH.sub.2--, --CH.sub.2CH.sub.2C(.dbd.O)--,
--C(.dbd.S)CH.sub.2CH.sub.2--, --CH.sub.2C(.dbd.S)CH.sub.2--, or
--CH.sub.2CH.sub.2C(.dbd.S)--.
[0078] A specific group of compounds are compounds wherein n is 1
and R.sub.1 is C.sub.1-7alkyl, C.sub.1-7alkoxy, or halo.
[0079] A specific group of compounds are compounds wherein n is 1
and R.sub.1 is methyl, methoxy, chloro, or fluoro.
[0080] A specific group of compounds are compounds wherein X and Y
together are a 2, 3, or 4 membered saturated or partially
unsaturated chain comprising one or more carbon atoms and
optionally comprising one oxy (--O--), thio (--S--), sulfinyl
(--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain;
wherein the chain is optionally substituted on each carbon with oxo
(.dbd.O), hydroxy, or C.sub.1-7alkoxy, or with one or two
substituents independently selected from the group consisting of
C.sub.1-7alkyl, (C.sub.1-7alkoxy)C.sub.1-7alkyl, aryl,
(aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl, and
(aryl)oxyC.sub.1-7alkyl; or wherein the chain is optionally
substituted on a carbon with a 4, 5, or 6 membered spirocyclic
carbon ring; or wherein the chain is optionally substituted on two
adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g.
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) forming a ring that is fused
to the ring comprising X and Y;
[0081] When X and Y together, or R.sub.1, is a "partially
unsaturated" group, such group may comprise one or more (e.g. 1 or
2) carbon-carbon double or triple bonds. For example, when R.sub.1
is a partially unsaturated C.sub.1-7alkyl, 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, 2,4-hexadienyl,
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, 3-hexen-5-ynyl, 4-hexynyl,
or 5-hexynyl.
[0082] Specifically, the invention also provides a method for
treating or preventing anxiety, obesity, depression, schizophrenia,
a stress related disease (e.g. general anxiety disorder), panic
disorder, a phobia, obsessive compulsive disorder,
post-traumatic-stress syndrome, immune system depression, a stress
induced problem with the gastrointestinal or cardiovascular system,
or sexual dysfunction in a mammal (e.g. a human) comprising
administering a therapeutically effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof to the
mammal.
[0083] Specifically, the invention also provides a method of
treating or preventing anxiety, obesity, depression, or a stress
related disease, comprising administering to a mammal (e.g. a
human) in need of such treatment, a therapeutically effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
[0084] Specifically, the invention also provides the use of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof to prepare a medicament for treating or preventing anxiety,
obesity, depression, schizophrenia, a stress related disease (e.g.
general anxiety disorder), panic disorder, a phobia, obsessive
compulsive disorder, post-traumatic-stress syndrome, immune system
depression, a stress induced problem with the gastrointestinal or
cardiovascular system, or sexual dysfunction in a mammal (e.g. a
human).
[0085] Specifically, the invention also provides the use of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof to prepare a medicament for treating or preventing anxiety,
obesity, depression, or a stress related disease in a mammal (e.g.
a human).
[0086] The invention also provides processes and intermediates
useful for preparing compounds of formula (I). For example, an
intermediate useful for preparing a compound of formula (I) wherein
R.sub.2 is hydrogen, is a corresponding compound of formula (I)
wherein R.sub.2 is a suitable protecting group. Thus the invention
provides a compound of formula (I) wherein R.sub.2 is a suitable
protecting group, and wherein R.sub.1, X, Y, and n have any of the
values, specific values or prefered values defined herein. Suitable
amine protecting groups, as well as methods for their preparation
and removal are well known in the art, for example, see Greene, T.
W.; Wutz, P. G. M. "Protecting Groups In Organic Synthesis" third
edition, 1999, New York, John Wiley & sons, Inc. Prefered
protecting groups include benzyloxycarbonyl (CBZ) and benzoyl.
[0087] The invention also provides intermediate compounds of
formula 3, 9, 10, 11, 13, 15, and 17-20 as shown in FIGS. 1-6,
wherein R.sub.2 is a protecting group.
[0088] The invention also provides intermediate salts that are
useful for preparing or purifying compounds of formula (I).
Suitable methods for preparing salts are known in the art and are
disclosed herein. For example, the preparation of an oxylate salt
is shown in Example 41. As will be apparent to one skilled in the
art, such salts can be converted to the corresponding free-base or
to another salt using known methods.
[0089] For example, compounds of formula I wherein R.sub.2 is
C.sub.1-4alkyl, C.sub.1-4alkanoyl, arylcarbonyl,
(aryl)C.sub.1-2alkyl, C.sub.1-4alkoxycarbonyl, aryloxycarbonyl,
arylsulfonyl, or (aryl)methoxycarbonyl, wherein any aryl is
optionaly substituted with 1, 2, or 3 substituents independently
selected from C.sub.1-4alkyl and trifluoromethyl, are particularly
useful as intermediates for preparing corresponding compounds of
formula I wherein R.sub.2 is hydrogen. Preferred compounds of
formula I that are useful for preparing compounds of formula I
wherein R.sub.2 is hydrogen are compounds wherein R.sub.2 is
methyl, ethyl, propyl, isopropyl, acetyl, tert-butoxycarbonyl,
benzyloxycarbonyl, benzyl, or p-toluenesulfonyl.
[0090] The invention also provides a method for preparing a
compound of formula (I) wherein R.sub.2 is hydrogen comprising
deprotecting a corresponding compound of formula (I) wherein
R.sub.2 is a suitable nitrogen protecting group.
[0091] Compounds of the invention can generally be prepared using
the synthetic schemes illustrated in FIGS. 1-6. Starting materials
can be prepared by procedures described in these schemes or by
procedures that would be well known to one of ordinary skill in
organic chemistry. The variables used in the Schemes are as defined
below or as in the claims.
[0092] Compounds of formula I can be prepared by reactions outlined
in FIG. 1. Step 1 involves formation of intermediate N-nitroso
compounds by treatment with isoamylnitrite or other standard acid
catalyzed N-nitrosation conditions. The resulting N-nitroso
compounds are directly reduced to their corresponding hydrazines
(2) by treatment with lithium aluminum hydride in a suitable
solvent such as tetrahydrofuran. In step 2, hydrazines (2) are
condensed by acid catalysis with 1-benzoylhexahydroazepine, which
is available by the process described in J. Org. Chem., Vol. 33, pp
3187-95 (1968), or with benzyl 4-oxo-1-azepanecarboxylate, the
synthesis of which is described in the experimental section.
Fischer/Indole cyclization of the crude hydrazines provides the
desired azepinoindoles (3). The Fischer/Indole cyclization can be
effected with a variety of acids such as formic acid, acetic acid,
trifluoroacetic acid, aqueous hydrochloric acid, aqueous sulfuric
acid, or polyphosphoric acid. Step 3 is effected by either
catalytic hydrogenolysis when R.sub.2 is benzyl or
benzyloxycarbonyl, or by base catalyzed hydrolysis in a suitable
solvent such as ethylene glycol when R.sub.2 is benzoyl.
Azepinoindoles 4 (wherein when R.sub.2 is hydrogen) can
conveniently be isolated as their hydrochloride salts.
[0093] It will be apparent to those skilled in the art that many of
the requisite amines (1) are commercially available or known in the
literature. The necessary 3,4-dihydro-1(2H)-quinolinylamines
required for Examples 1-13 are known compounds. Indolines required
for the synthesis of Examples 14-18 are either commercially
available or readily prepared from known indoles following the
procedure described in Synthesis pp. 859-60 (1977). For the
benzmorpholines and benzthiomorpholines required for Examples
19-25, the synthetic route shown in FIG. 2 was followed.
Nitrophenols 5 were alkylated with ethyl bromoacetate derivatives
to afford 6. The nitro moiety is then reduced with Pd/C in the
presence of hydrogen in a suitable solvent such as ethanol. In situ
cyclization gives amide 7, which is then reduced with borane to
provide the required amines 8.
[0094] Compounds of formula I can also be prepared by the reactions
outlined in FIG. 3. Azapinoindoles 9 are known in the literature (J
Med Chem., 1968, 11, 101-106) and can participate in a Michael
conjugate addition into ethyl acrylate, or a derivative thereof, in
the presence of a suitable base such as cesium carbonate.
Base-catalyzed hydrolysis of esters 10 gives crude acids which then
undergo intramolecular Friedel-Crafts acylation in an acidic media
(e.g. polyphosphoric acid or Eaton's reagent). When R.sub.2 is
benzoyl, azepinoindoles 12 can be obtained from base-catalyzed
hydrolysis in tetrahydrofuran/methanol.
[0095] Aryl ketones 11 can be used as intermediates in the
synthesis of additional compounds of formula I as shown in FIG. 4.
The ketone moiety is reduced with sodium borohydride to give
alcohols 13. When R.sub.2 is benzoyl, base-catalyzed hydrolysis of
alcohols 13 gives azepinoindoles 14. Alternatively, alcohols 13 can
also be used as intermediates in the synthesis of additional
compounds of formula I as shown in FIG. 5. Alcohols 13 can be
alkylated with an alkyl halide in the presence of sodium hydride or
with phenols via Mitsunobu reaction conditions. The use of thiols
or amines in the Mitsunobu reaction can give additional
derivatives. Removal of R.sub.2 gives azepinoindoles 16.
[0096] Azepinoindoles 9 can also be used to make compounds of
formula I as shown in FIG. 6. Alkylation of 9 with
2-bromomethyl-1,3-dioxolane, or a derivative thereof, gives
compounds 17. Acid-catalyzed removal of the acetal group leads to
an aldehyde that can be reacted with trimethylsulfoxonium iodide
and sodium hydride to give epoxides 18. Use of a Lewis acid, such
as boron trifluoride diethyl etherate, would lead to alcohols 19.
These alcohols could be treated as above to give azepinoindoles 20
and 21.
[0097] 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, .alpha.-ketoglutarate, and
.alpha.-glycerophosphate. Suitable inorganic salts may also be
formed, including hydrochloride, sulfate, nitrate, bicarbonate, and
carbonate salts.
[0098] 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.
[0099] Compounds of the present invention can conveniently be
administered in a pharmaceutical composition containing the
compound in combination with a suitable excipient. Such
pharmaceutical compositions can be 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, orally, or
rectally.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] The compound is conveniently administered in unit dosage
form; for example, containing about 0.05 mg to about 500 mg,
conveniently about 0.1 mg to about 250 mg, most conveniently, about
1 mg to about 150 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.
[0109] The compositions can conveniently be administered orally,
sublingually, transdermally, or parenterally at dose levels of
about 0.01 to about 150 mg/kg, preferably about 0.1 to about 50
mg/kg, and more preferably about 0.1 to about 10 mg/kg of mammal
body weight.
[0110] For parenteral administration 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.
[0111] 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.
[0112] The ability of a compound of the invention to act as a 5-HT
receptor agonist or antagonist can also be determined using in
vitro and in vivo assays that are known in the art. The invention
provides compounds of formula I that act as either agonists or as
antagonists of one or more 5-HT receptor subtypes. The compounds
Exemplified herein are 5-HT ligands, which typically displace
>50% of a radiolabeled test ligand from one or more 5-HT
receptor subtype at a concentration of 1 .quadrature.M. The
procedures used for testing such displacement are well known and
would be readily available to one skilled in the art.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0113] Preparation 1.
Preparation of 1-benzyl 4-ethyl 5-oxo-1,4-azepanedicarboxylate
[0114] A dry 500 ml 3-neck flask was charged with benzyl
4-oxo-1-piperidinecarboxylate (35.08 g, 150 mmol). It was dissolved
in 130 ml Et.sub.2O and cooled to -45.degree. C. Ethyldiazoacetate
(20.5 ml, 195 mmol) and boron trifluoride ethyl ether (19.4 ml, 158
mmol) were added simultaneously by syringe pump over 45 minutes.
The temperature was kept below -25.degree. C. The reaction was
stirred for 30 minutes longer, and then quenched with sat.
NaHCO.sub.3. The ice bath was removed. The reaction was diluted
with EtOAc (250 ml) and H.sub.2O (150 ml). The layers were
separated, and the organic phase was dried over MgSO.sub.4. It was
concentrated under reduced pressure to an orange oil. The product
was purified by flash chromatography (silica gel, 40%
EtOAc/hexane), yielding product as pale yellow oil (42.1 g,88%).
.sup.1H NMR (CDCl.sub.3) .delta. 7.39-7.31, 5.15-5.12, 4.42-4.17,
3.96-3.83, 3.75-3.70, 3.65, 3.54-3.37, 2.08-2.03, 1.29-1.24; IR
(liq.) 1743, 1702, 1476, 1455, 1443, 1425, 1371, 1318, 1295, 1238,
1213, 1178, 1098, 1068, 1028 cm.sup.-1.
Preparation of benzyl 4-oxo-1-azepanecarboxylate
[0115] A solution of potassium hydroxide (24.6 g, 375 mmol) in
H.sub.2O (400 ml) was added to a solution of 1-benzyl 4-ethyl
5-oxo-1,4-azepanedicarboxylate (40.0 g, 125 mmol) in ethanol (400
ml). The resulting mixture was heated at reflux for 2.5 hours.
Reaction was then cooled to rt., the ethanol was removed under
reduced pressure, and was diluted with 200 ml brine and 300 ml
ethyl acetate. The layers were separated, and the aqueous phase was
extracted with ethyl acetate (2.times.100 ml). The combined organic
layers were washed with brine, dried over MgSO.sub.4, and
concentrated to an orange oil in vacuo. The product was isolated by
flash chromatography (silica gel, 40% EtOAc/hexane) yielding a
clear, colorless oil (22.6 g, 73%). .sup.1H NMR (CDCl.sub.3)
.delta. 7.31-7.30, 5.12, 3.65-3.63, 2.68-2.60, 1.81-1.78; IR (liq.)
1698, 1475, 1454, 1442, 1423, 1331, 1320, 1295, 1270, 1241, 1191,
1165, 1091, 900, 699 cm.sup.-1.
EXAMPLE 1
Preparation of
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,-
2,1-ij]quinoline hydrochloride
[0116] 3
Step 1. Preparation of 3,4-dihydro-1(2H)-quinolinylamine
hydrochloride
[0117] A neat reaction between 1,2,3,4-tetrahydroquinoline (3.71 g,
27.9 mmol) and isoamylnitrite (8.72 g, 74.4 mmol) was allowed to
stir for 1 hour. The residual isoamylnitrite was removed under
reduced pressure and the N-nitroso intermediate was taken up in
tetrahydrofuran (20 ml). This solution was added dropwise to a
refluxing solution of lithium aluminum hydride in tetrahydrofuran
(55 ml, 1M, 55.0 mmol). One hour after the addition was complete,
the reaction was cooled to 0.degree. C. and quenched. The reaction
was filtered, concentrated under reduced pressure, and extracted
into ether. The ethereal solution was washed with water, brine and
dried over anhydrous potassium carbonate. The resulting brown oil
(4.11 g) was trapped as the hydrochloride salt and recrystallized
from methanol.backslash.ethyl acetate.backslash.hexanes to provide
the title compound (mp 186-189.degree. C.). .sup.1H NMR
(CDCl.sub.3) .delta. 10.55, 7.31, 7.10, 6.98, 6.87, 3.59, 2.74,
2.05;
[0118] IR (drift) 3053, 2956, 2940, 2868, 2841, 2835, 2724, 2667,
1603, 1586, 1580, 1567, 1545, 1499, 747 cm.sup.-1.
Step 2. Preparation of benzyl 5,6,8,9,11,12-hexahydro-4H,10H
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate
[0119] A solution of 3,4-dihydro-1(2H)-quinolinylamine (2.97 g,
20.1 mmol), benzyl 4-oxo-1-azepanecarboxylate (4.96 g, 20.1 mmol),
and glacial acetic acid (0.2 ml) in ethanol (200 ml) was allowed to
reflux for 2.5 hours. The reaction was then cooled and evaporated
in vacuo. The hydrazone product was purified by flash
chromatography (90 g SiO.sub.2, 1% MeOH/CH.sub.2Cl.sub.2) providing
benzyl 4-[3,4-dihydro-1(2H)-quinoliny- limino]-1-azepanecarboxylate
(7.55 g) as an oil. To a solution of benzyl
4-[3,4-dihydro-1(2H)-quinolinylimino]-1-azepanecarboxylate (6.79 g,
17.99 mmol) in ethanol (200 ml) was added trifluoroacetic acid
(6.22 g, 53.96 mmol). The reaction was heated and allowed to stir
at reflux for 2.5 hours, at which time it was cooled to rt.,
evaporated, and extracted into dichloromethane. This extract was
washed with water, brine, dried with anhydrous sodium sulfate, and
evaporated under reduced pressure. Crystallization from ethyl
acetate/hexanes provided 2.93 g of the title compound
[0120] (mp 131-133.degree. C.). .sup.1H NMR (CDCl.sub.3) .delta.
7.38, 7.29, 7.00, 6.86, 5.19, 3.98, 3.78, 2.97, 2.24;
[0121] IR (drift) 2947, 1699, 1473, 1420, 1358, 1260, 1250, 1235,
1216, 1101, 997, 764, 757, 746, 703 cm.sup.-1.
Step 3. Preparation of
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]py- rrolo[3,2,1-ij
]quinoline hydrochloride
[0122] A mixture of benzyl
5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate (2.42 g, 6.71 mmol) and
10 % Pd/C (0.15 g) in ethanol (110 ml) was hydrogenated under 40
psi for 1.5 hours. The mixture was filtered through celite, rinsed
with methanol, dichloromethane and evaporated. Methanolic
hydrochloric acid is added and evaporated. The resulting product is
recrystallized from methanol/ethyl acetate to give 1.40 g (80%) of
the title compound (mp 261-263.degree. C.). .sup.1H NMR
(CD.sub.3OD) .delta. 7.25, 6.95, 6.84, 4.08, 3.48, 3.32, 3.28,
3.20, 2.95, 2.22; IR (drift) 2939, 2894, 2880, 2863, 2832, 2806,
2759, 2743, 2687, 2669, 2645, 2445, 1332, 1253, 743 cm.sup.-1.
EXAMPLE 2
Preparation of
2-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij ]quinoline hydrochloride
[0123] 4
[0124] Following the general procedure of Example 1, making
non-critical variations but starting with
6-methyl-1,2,3,4-tetrahydroquinoline, the title compound was
obtained (mp 268-270.degree. C.). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.6, 6.99, 6.61, 3.98, 3.30, 3.16, 3.03, 2.81, 2.32, 2.08;
IR (drift) 2965, 2949, 2934, 2902, 2880, 2850, 2823, 2791, 2769,
2695, 2659, 2438, 1458, 1251, 839 cm.sup.-1.
EXAMPLE 3
Preparation of
1-methoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]-
pyrrolo[3,2,1-ij]quinoline hydrochloride
[0125] 5
[0126] Following the general procedure of Example 1, making
non-critical variations but starting with
7-methoxy-1,2,3,4-tetrahydroquinoline, the title compound was
obtained&(mp 277-279.degree. C.). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.27, 6.65, 6.32, 3.96, 3.77, 3.29, 3.15, 2.78, 2.05; IR
(drift) 2968, 2953, 2935, 2889, 2832, 2803, 2780, 2765, 2744, 2713,
1594, 1509, 1247, 1152, 781 cm.sup.-1.
EXAMPLE 4
Preparation of
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinoline hydrochloride
[0127] 6
[0128] Following the general procedure of Example 1, making
non-critical variations but starting with
6-fluoro-1,2,3,4-tetrahydroquinoline, the title compound was
obtained (mp 273-276.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta.
6.94, 6.64, 4.07, 3.50, 3.44, 3.32, 3.28, 3.15, 2.94, 2.22; IR
(drift) 2957, 2926, 2894, 2843, 2814, 2799, 2742, 2708, 2665, 2561,
2545, 2440, 1496, 1419, 1129 cm.sup.-1.
EXAMPLE 5
Preparation of
6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2, 1-ij]quinoline hydrochloride
[0129] 7
[0130] Following the general procedure of Example 1, making
non-critical variations but starting with
2-methyl-1,2,3,4-tetrahydroquinoline, the title compound is
obtained (mp 214-217.degree. C.). .sup.1H NMR (CDCl.sub.3) .delta.
9.61, 7.25, 6.93, 6.84, 4.62, 3.32, 3.11, 2.87, 2.12, 2.01, 1.20;
IR (drift) 2968, 2933, 2893, 2814, 2742, 2711, 2669, 2560, 2437,
1463, 1415, 1377, 1335, 1324, 742 cm.sup.-1.
EXAMPLE 6
Preparation of
5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2, 1-ij]quinoline hydrochloride
[0131] 8
[0132] Following the general procedure of Example 1, making
non-critical variations but starting with
3-methyl-1,2,3,4-tetrahydroquinoline, the title compound was
obtained (mp 273-274.degree. C.). .sup.1H NMR (CDCl.sub.3) .delta.
10.10, 7.27, 7.02, 6.88, 4.07, 3.51, 3.37, 3.31, 3.00, 2.65, 2.37,
1.20; IR (drift) 2956, 2923, 2899, 2867, 2831, 2800, 2766, 2686,
2670, 2562, 2448, 1454, 1428, 1257, 740 cm.sup.-1.
EXAMPLE 7
Preparation of
4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2, 1-ij]quinoline hydrochloride
[0133] 9
[0134] Following the general procedure of Example 1, making
non-critical variations but starting with
4-methyl-1,2,3,4-tetrahydroquinoline, the title compound was
obtained (mp 260-263.degree. C.). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.79, 7.22, 6.92, 6.85, 4.10, 4.00, 3.28, 3.20, 3.08, 2.15,
1.80, 1.30; IR (drift) 2959, 2939, 2891, 2873, 2860, 2811, 2800,
2739, 2709, 2662, 2647, 2553, 2542, 2437, 734 cm.sup.-1.
EXAMPLE 8
Preparation of
(+)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline hydrochloride
[0135] 10
[0136] Following the general procedure of Example 5 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
was 5% isopropanol/95% heptane at a flow rate of 75 m/min. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound was obtained (mp 196-199.degree. C.).
EXAMPLE 9
Preparation of
(-)-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline hydrochloride
[0137] 11
[0138] Following the general procedure of Example 5 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
was 5% isopropanol/95% heptane at a flow rate of 75 ml/min. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound was obtained (mp 196-199.degree. C.);
[.alpha.].sup.25.sub.D=-27 (c 0.88, DMSO).
EXAMPLE 10
Preparation of
(+)-5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline hydrochloride
[0139] 12
[0140] Following the general procedure of Example 6 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
was 5% isopropanol/95% heptane at a flow rate of 75 ml/min. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound was obtained (mp 259-262.degree. C.);
[.alpha.].sup.25.sub.D=+20 (c 0.28, DMSO).
EXAMPLE 11
Preparation of
(-)-5-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline hydrochloride
[0141] 13
[0142] Following the general procedure of Example 6 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
is 5% isopropanol/95% heptane at a flow rate of 75 ml/min. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound was obtained (mp 259-262.degree. C.);
[.alpha.].sup.25.sub.D=-21.degree. (.sub.c0.43, DMSO).
EXAMPLE 12
Preparation of
(+)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline hydrochloride
[0143] 14
[0144] Following the general procedure of Example 7 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
was 5% isopropanol/95% heptane at a flow rate of 75 mmin. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound was obtained (mp 261-263.degree. C.);
[.alpha.].sup.25.sub.D=+39 (.sub.c0.41, chloroform).
EXAMPLE 13
Preparation of
(-)-4-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2, 1-ij]quinoline hydrochloride
[0145] 15
[0146] Following the general procedure of Example 7 making
non-critical variations, preparative chiral HPLC was performed
after step two on an EM ST 140R closed loop recycling prep HPLC
system (EM Separations Technology). The column used was a
5.times.50 cm Chiralpak AD column at 30.degree. C. The mobile phase
was 5% isopropanol/95% heptane at a flow rate of 75 ml/min. Peak
collection was monitored by UV detection at 285 nm. Following step
three, the title compound is obtained (mp 261-263.degree. C.);
[.alpha.].sup.25.sub.D=-39 (.sub.c0.51, chloroform).
EXAMPLE 14
Preparation of
4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2, 1-hi]indole
hydrochloride
[0147] 16
[0148] Following the general procedure outlined in EXAMPLE 1,
starting with indoline, and utilizing 1-benzoylhexahydoazepine as
the ketone in step
4,5,7,8,10,11-hexahydro-9H-azepino[4,5-b]pyrrolo[3,2,1-hi]indol-9-yl-
(phenyl)methanone was obtained (mp 130-133.degree. C.). .sup.1H NMR
(CDCl.sub.3) .delta. 7.42, 7.08, 6.94, 6.85, 4.28, 4.00, 3.76,
3.63, 3.15, 2.88; MS (ESI+) for C.sub.21H.sub.20N.sub.2O H m/z
240.1 (M+H).sup.+.
[0149] Step 4 A mixture of 4,5,7,8,
10,11-hexahydro-9H-azepino[4,5-b]pyrro-
lo[3,2,1-hi]indol-9-yl(phenyl)methanone (1.0 g, 3.2 mmol) and
potassium hydroxide (0.89 g, 15.8 mmol) in ethylene glycol (10 ml)
was heated under N.sub.2 at 170.degree. C. for 3 h. The reaction
was cooled to rt, poured into water (50 ml) and extracted with
methylene chloride (4.times.50 ml). The combine organics were
washed with brine, dried over anhydrous potassium carbonate, and
concentrated in vacuo. The residue was trapped as its HCl salt by
treatment of a solution of the product in methanol with ethereal
HCl. The resulting precipitate is recrystallized from methanol and
ethyl acetate to give the desired product (0.4 g) (mp
249-250.degree. C.). .sup.1H NMR (CDCl.sub.3) .delta. 7.16, 6.93,
6.82, 4.38, 3.74, 3.08, 2.94; IR (drift) 2925, 2916, 2885, 2847,
2805, 1510, 1462, 1409, 1350, 1336, 1306, 1279, 767, 758, 746
cm.sup.-1.
EXAMPLE 15
Preparation of
2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3-
,2,1-hi]indole hydrochloride
[0150] 17
[0151] Following the general procedure outlined in EXAMPLE 14, and
making non-critical variations but starting with 5-fluoro indoline,
the title compound was obtained (mp 250-252.degree. C.). .sup.1H
NMR (CD.sub.3OD) .delta. 6.68, 6.43, 4.15, 3.47, 2.88, 2.76; IR
(drift) 2930, 2911, 1661, 1507, 1412, 1354, 1261, 1171, 1112, 938,
857, 848, 839, 708, 688 cm.sup.-1.
EXAMPLE 16
Preparation of
2-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[-
3,2,1-hi]indole hydrochloride
[0152] 18
[0153] Following the general procedure outlined in EXAMPLE 14, and
making non-critical variations but starting with 5-methoxy
indoline, the title compound was obtained (mp 269-271.degree. C.).
.sup.1H NMR (CD.sub.3OD) .delta. 6.70, 6.57, 4.44, 3.80, 3.72,
3.45, 3.23, 3.16; IR (drift) 2974, 2948, 2908, 2891, 2841, 2817,
2805, 2769, 2718, 1509, 1421, 1255, 1244, 1233, 1142 cm.sup.-1.
EXAMPLE 17
Preparation of
5-methyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3-
,2,1-hi]indole hydrochloride
[0154] 19
[0155] Following the general procedure outlined in EXAMPLE 1, and
making non-critical variations but starting with 2-methyl indoline,
the title compound was obtained (mp 243-246.degree. C.). .sup.1H
NMR (CDCl.sub.3) .delta. 7.13, 6.91, 7.80, 4.99-4.87, 3.93,
3.51-3.23, 3.17, 1.47; IR (drift) 2973, 2960, 2941, 2927, 2901,
2883, 2848, 2826, 2794, 2737, 2650, 2549, 2438, 1292, 751
cm.sup.-1.
EXAMPLE 18
Preparation of
4,5-dimethyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrro-
lo[3,2,1-hi]indole hydrochloride
[0156] 20
[0157] Following the general procedure outlined in EXAMPLE 1, and
making non-critical variations but starting with 2,3-dimethyl
indole, the title compound was obtained (mp 195-197.degree. C.).
.sup.1H NMR (CD.sub.3OD) .delta. 7.16, 6.92, 6.81, 4.40, 3.64,
3.53-3.35, 3.16, 1.54, 1.43; IR (drift) 2960, 2938, 2925, 2866,
2847, 2821, 2727, 2657, 2635, 2533, 2427, 1465, 1372, 1287, 746
cm.sup.-1.
EXAMPLE 19
Preparation of
2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-azepino[4',5':4,5]py-
rrolo[3,2,1-jk]carbazole hydrochloride
[0158] 21
[0159] Following the general procedure outlined in EXAMPLE 1, and
making non-critical variations but starting with 1,2,3,4
tetramethyl carbazole, the title compound was obtained (mp
210-212.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 7.16, 6.94,
6.82, 4.75, 4.14, 3.42, 3.25, 3.16, 2.12-1.96, 1.54, 1.41, 1.26,
1.08; IR (drift) 3046, 2936, 2929, 2846, 2810, 2744, 2633, 2541,
2519, 2429, 1460, 1328, 1290, 754, 744 cm.sup.-1;
EXAMPLE 20
Preparation of
6-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0160] 22
Step 5. Preparation of 6-methyl-2H-1,4-benzoxazin-3(4H)-one
[0161] To a solution of 4-methyl-2-nitrophenol (9.95 g, 65.0 mmol)
in acetone (170 ml) was added, in one portion, potassium carbonate
(10.8 g, 78.0 mmol) and ethyl bromoacetate (7.9 ml, 71.5 mmol). The
resulting mixture was heated at reflux for 3.5 hours. The acetone
was removed in vacuo, and the resulting material was partitioned
between ethyl acetate and water. The layers were separated, and the
aqueous phase was extracted twice with ethyl acetate. The ethyl
acetate layer was washed with saturated sodium bicarbonate, brine,
dried over magnesium sulfate, filtered, and evaporated to afford an
orange oil. The intermediate nitro compound was taken up in ethanol
(150 ml ) and hydrogenated with Pd/C (0.33 g) at 51 psi for 90
minutes. The mixture was filtered through celite, and the filtrate
evaporated. The product was recrystallized from methanol to yield
7.29 g of the title compound as an off-white solid (mp
204-205.degree. C.). .sup.1H NMR (DMSO-d.sub.6) .delta. 6.81-6.78,
6.70-6.67, 4.48, 2.18; MS [MH.sup.-]162.1.
Step 6. Preparation of 6-methyl-3,4-dihydro-2H-1,4-benzoxazine
[0162] To a solution of 6-methyl-2H-1,4-benzoxazin-3(4H)-one (7.02
g, 43.0 mmol) in tetrahydrofuran (130 ml) was added borane
dimethylsulfide complex (43 ml, 10M). This solution was stirred at
rt for 2.5 hours, then quenched with 1 M hydrochloric acid. The
solvent was evaporated, and the residue was partitioned between
saturated sodium bicarbonate and dichloromethane. The layers were
separated, and the aqueous phase was extracted twice with
dichloromethane. The dichloromethane layer was washed with brine,
dried over magnesium sulfate, and evaporated to yield 5.1 g of the
title compound as a pale yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta. 6.70-6.68, 6.49-6.46, 6.42, 4.24-4.21, 3.41-3.38, 2.22; MS
[MH.sup.+] 150.2.
[0163] Following the remainder of the general procedure of Example
1 (steps 1-3) and making non-critical variations but starting with
6-methyl-3,4-dihydro-2H-1,4-benzoxazine, the title compound was
obtained (mp 271-273.degree. C.).
[0164] .sup.1H NMR (CD.sub.3OD) .delta. 6.59, 6.40, 4.44, 4.17,
3.52, 3.49, 3.27, 3.24, 2.57; IR (drift) 2979, 2957, 2934, 2872,
2855, 2828, 2792, 2760, 2746, 2683, 2652, 1511, 1265, 1243, 1223
cm.sup.-1.
EXAMPLE 21
Preparation of
1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-
-hi]indole hydrochloride
[0165] 23
[0166] Following the general procedure of Example 20 but starting
with 2 H-1,4-Benzoxazine-3(4 H)-one, utilizing
1-benzoylhexahydoazepine as the ketone in the hydrazone formation
of step two, and thus the deprotection sequence described in step 4
of example 14, the title compound was obtained (mp 217-219.degree.
C.). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.6, 7.01, 6.85, 6.50,
4.46, 4.18, 3.28-3.08, 2.50; IR (drift) 2949, 2925, 2878, 2843,
2812, 2758, 2689, 2673, 1499, 1328, 1247, 1036, 872, 771, 729
cm.sup.-1.
EXAMPLE 22
Preparation of
6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0167] 24
[0168] Following the general procedure of Example 20 and making
non-critical variations but starting with 2-amino4-chlorophenol,
the title compound was obtained (mp decompose >275.degree. C.).
.sup.1H NMR (CD.sub.3OD) .delta. 6.84, 6.50, 4.49-4.48, 4.22-4.20,
3.65-3.63, 3.53-3.48, 3.30-3.27; IR (free amine) (drift) 2932,
2897, 2882, 2823, 1495, 1466, 1379, 1355, 1323, 1277, 1269, 1236,
1217, 1199,1014 cm.sup.-1.
EXAMPLE 23
Preparation of
5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0169] 25
[0170] Following the general procedure of Example 20 and making
non-critical variations but starting with 5-fluoro-2-nitrophenol,
the title compound was obtained (mp decompose >250.degree. C.).
.sup.1H NMR (CD.sub.3OD) .delta. 6.76-6.72, 6.38-6.33, 4.52-4.49,
4.20-4.17, 3.51-3.43, 3.28-3.25, 3.18-3.14; IR (drift) 2950, 2855,
2805, 2767, 2757, 2710, 2675, 2651, 2565, 2449, 1645, 1591, 1500,
1333, 1109 cm.sup.-1.
EXAMPLE 24
Preparation of
5-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0171] 26
[0172] Following the general procedure of Example 20 but starting
from 5-methyl-2-nitrophenol and using glacial acetic acid for the
cyclization in step 3, the title compound was obtained (mp
274-275.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 6.81, 6.37,
4.44, 4.12, 3.48-3.41, 3.22, 3.15, 2.36; IR (drift) 2983, 2965,
2940, 2880, 2856, 2822, 2809, 2758, 2731, 2667, 1590, 1503, 1331,
1031, 847 cm.sup.31 1.
EXAMPLE 25
Preparation of
6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0173] 27
[0174] Following the general procedure of Example 20 but starting
from 4-fluoro-2-nitrophenol and using p-toluene sulfonic acid for
the cyclization in step 3, the title compound was obtained (mp
257-259.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 6.55-6.49,
6.43-6.40, 4.44, 4.17, 3.49-3.44, 3.38-3.33, 3.26-3.23; IR (drift)
2949, 2876, 2845, 2815, 2768, 2685, 2676, 2626, 1511, 1362, 1277,
1224, 1023, 881, 791 cm.sup.-1.
EXAMPLE 26
Preparation of
2-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole hydrochloride
[0175] 28
[0176] Following the general procedure of Example 20 and making
non-critical variations but starting with 2-nitrophenol and
ethyl-2-bromopropionate, the title compound was obtained (mp
255-257.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 7.01, 6.88,
6.54, 4.40-4.35, 4.30, 3.68-3.63, 3.49-3.42, 3.25-3.17, 1.51; IR
(drift) 2967, 2931, 2809, 2790, 2736, 2711, 2655, 2647, 2557, 2439,
1502, 1377, 1322, 1243, 794 cm.sup.-1.
EXAMPLE 27
Preparation of
1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,-
4-hi]indole hydrochloride
[0177] 29
[0178] Following the general procedure of Example 21 but starting
from 2H-1,4-benzothiazin-3(4H)-one and using 10% sulfuric acid for
the cyclization in step 3, the title compound was obtained (mp
263.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 7.24, 6.94, 6.87,
3.36-3.24, 3.12-3.10; IR (drift) 2937, 2929, 2862, 2814, 2718,
2663, 2626, 2594, 2544, 2428, 1463, 1412, 1335, 782, 739
cm.sup.-1.
EXAMPLE 28
Preparation of 2,2-dimethyl-1,2,8,9,10,11-hexahydro-7H-azepino
[4,5-b][1,4]oxazino[2,3,4-hi]indole hydrochloride
[0179] 30
[0180] Following the general procedure of Example 20 but starting
with 2-nitrophenol and ethyl-2-bromoisobutyrate, and using
p-toluene sulfonic acid for the cyclization in step 3, the title
compound was obtained (mp decompose >260.degree. C.). .sup.1H
NMR (CD.sub.3OD) .delta. 7.03, 6.92, 6.52, 3.96, 3.53-3.46,
3.26-3.20, 1.41; IR (drift) 2972, 2948, 2858, 2824, 2766, 2751,
1583, 1498, 1385, 1332, 1245, 1202 cm.sup.31 1.
EXAMPLE 29
Preparation of
4-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole maleic acid
[0181] 31
[0182] Following the general procedure of Example 20 but starting
with 2-fluoro-6-nitrophenol, using p-toluene sulfonic acid for the
cyclization in step 3, and preparing the Maleic acid salt, the
title compound was obtained (mp 176-177.degree. C.). .sup.1H NMR
(CD.sub.3OD) .delta. 6.95, 6.78, 6.24, 4.51, 4.19, 3.42-3.50, 3.23,
3.16; IR (drift) 3009, 2925, 2899, 2879, 2835, 2786, 2714, 1705,
1626, 1550, 1531, 1526, 1486, 1358 cm.sup.-1.
EXAMPLE 30
Preparation of
4-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole maleic acid
[0183] 32
[0184] Following the general procedure of Example 20 but starting
with 6-chloro-2-nitrophenol, using p-toluene sulfonic acid for the
cyclization in step 3, and preparing the Maleic acid salt, the
title compound was obtained (mp 183-184.degree. C.). .sup.1H NMR
(CD.sub.3OD) .delta. 6.99, 6.91, 6.24, 4.56, 4.20, 3.43-3.51, 3.23,
3.16; IR (drift) 1645, 1639, 1627, 1608, 1568, 1536, 1517, 1497,
1476, 1385, 1377, 1372, 1355, 1196cm.sup.31 1.
EXAMPLE 31
Preparation of
5-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxaz-
ino[2,3,4-hi]indole maleic acid
[0185] 33
[0186] Following the general procedure of Example 20 but starting
with 5-chloro-2-nitrophenol, using TFA in EtOH for the cyclization
in step 3, and preparing the Maleic acid salt, the title compound
was obtained (mp 177-179.degree. C. ). .sup.1H NMR (CD.sub.3OD)
.delta. 7.05, 6.55, 6.24, 4.50, 4.18, 3.42-3.50, 3.23-3.25,
3.14-3.16; IR (drift) 2892, 2867, 2779, 2745, 1627, 1569, 1536,
1491, 1466, 1451, 1369, 1329, 1024 cm.sup.31 1.
EXAMPLE 32
Preparation of
6-(trifluoromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5--
b][1,4]oxazino[2,3,4-hi]indole hydrochloride
[0187] 34
[0188] Following the general procedure of Example 20 but starting
with 2-nitro-4-(trifluoro methyl)-phenol, using p-toluene sulfonic
acid for the cyclization in step 3, the title compound was obtained
(mp 248-250.degree. C. ). .sup.1H NMR (CD.sub.3OD) .delta. 7.30,
6.61, 4.55, 4.26, 3.46-3.53; IR (drift) 2815, 2797, 2741, 2670,
2560, 1583, 1333, 1244, 1198, 1158, 1107, 1094, 1060, 1021
cm.sup.31 1.
EXAMPLE 33
Preparation of
5,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]-
oxazino[2,3,4-hi]indole maleic acid
[0189] 35
[0190] Following the general procedure of Example 20 but starting
with 4,5-difluoro-2-nitrophenol, using 10% sulfuric acid in step 3,
and preparing the Maleic acid salt, the title compound was obtained
(mp 184-185.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 6.45,
6.23, 4.46, 4.17, 3.45-3.50, 3.34-3.37, 3.220-3.24; IR (drift)
3070, 2879, 2780, 2728, 1601, 1575, 1518, 1482, 1457, 1373, 1353,
1171, 1042, 1000 cm.sup.31 1.
EXAMPLE 34
Preparation of
5-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b]-
[1,4]oxazino[2,3,4-hi]indole maleic acid
[0191] 36
[0192] Following the general procedure of Example 20 but starting
with 5-chloro-4-fluoro-2-nitrophenol, using 10% sulfuric acid in
step 3, and preparing the Maleic acid salt, the title compound was
obtained (mp 194-195.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta.
6.52, 6.24, 4.46, 4.18, 3.51-3.45, 3.29-3.37, 3.21-3.25; IR (drift)
1615, 1583, 1552, 1501, 1480, 1456, 1368, 1355, 1280, 1222,
1169cm.sup.31 1.
EXAMPLE 35
Preparation of
5-fluoro-6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b]-
[1,4]oxazino[2,3,4-hi]indole maleic acid
[0193] 37
[0194] Following the general procedure of Example 20 but starting
with 4-chloro-5-fluoro-2-nitrophenol, using 10% sulfuric acid in
step 3, and preparing the Maleic acid salt, the title compound was
obtained (mp 173-175.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta.
6.50, 3.25, 4.50, 4.19, 3.56-3.59, 3.44-3.50, 3.22-3.25; IR (drift)
3062, 3028, 2971, 2897, 1626, 1608, 1585, 1498, 1463, 1372, 1365,
1352, 1153, 1036cm.sup.-1.
EXAMPLE 36
Preparation of
5,6-dichloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]-
oxazino[2,3,4-hi]indole maleic acid
[0195] 38
[0196] Following the general procedure of Example 20 but starting
with 4,5-dichloro-2-nitrophenol, using 10% sulfuric acid in step 3,
and preparing the Maleic acid salt, the title compound was obtained
(mp 180-181.degree. C.). .sup.1H NMR (CD.sub.3OD) .delta. 6.68 (s,
1 H), 6.23 (s, 2 H), 4.49 (t, J=4.4 Hz, 2 H), 4.20 (t, J=4.8 Hz, 2
H), 3.59-3.62 (t, J=2 Hz, H), 3.45-3.51 (m, 4 H), 3.22-3.26 (m, 2
H); IR (drift) 2887, 2840, 1625, 1608, 1578, 1551, 1486, 1458,
1372, 1351, 1273, 1023 cm.sup.-1.
EXAMPLE 37
Preparation of
4,6-dichloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]-
oxazino[2,3,4-hi]indole hydrochloride
[0197] 39
[0198] Following the general procedure of Example 20 but starting
with 3,5-dichloro-2-nitrophenol, and using 10% sulfuric acid in
step 3, the title compound was obtained (decompose >255.degree.
C.). .sup.1H NMR (CD.sub.3OD) .delta. 6.89, 4.55, 4.21, 3.56-3.59,
3.44-3.51, 3.23-3.27; IR (drift) 2955, 2895, 2743, 2652, 2635,
2556, 2428, 1494, 1468, 1420, 1345, 1294, 1229 cm.sup.31 1.
EXAMPLE 38
Preparation of
1-chloro-2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]-
pyrrolo[3,2,1-hi]indole maleic acid
[0199] 40
[0200] Following the general procedure outlined in EXAMPLE 14, and
making non-critical variations but starting with 6-chloro-5-fluoro
indoline, the title compound was obtained (amorphous solid).
.sup.1H NMR (CD.sub.3OD) 6.70, 6.23, 4.52, 3.69, 3.34-3.22, 3.08;
IR (drift) 2420 (b), 1628, 1561, 1506 (s), 1449, 1421, 1378 (s),
1350, 1337, 1323, 1300, 1291, 1278, 1254, 1147 cm.sup.-1; MS (ESI+)
for C.sub.14H.sub.14ClFN.sub.2 m/z 265.2 (M+H).sup.+.
EXAMPLE 39
Preparation of
2-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3-
,2,1-hi]indole maleic acid
[0201] 41
[0202] Following the general procedure outlined in EXAMPLE 14, and
making non-critical variations but starting with 5-chloro-indoline,
the title compound was obtained (amorphous solid). .sup.1H NMR
(CD.sub.3OD) 7.16, 6.91, 6.81, 4.45, 3.74, 3.40, 3.24, 3.15;.MS
(ESI+) for C.sub.14H.sub.15ClN.sub.2 m/z 247.2 (M+H).sup.+.
EXAMPLE 40
Preparation of
1-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3-
,2,1-hi]indole maleic acid
[0203] 42
[0204] Following the general procedure outlined in EXAMPLE 14, and
making non-critical variations but starting with 6-chloro-indoline,
the title compound was obtained (amorphous solid). .sup.1H NMR
(CD.sub.3OD) 6.91, 6.81, 6.77, 4.90, 3.69, 3.34, 3.21;.MS (ESI+)
for C.sub.14H.sub.15ClN.sub- .2 m/z 247.2 (M+H).sup.+.
EXAMPLE 41
Preparation of 5,6,9,10,11,
12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3-
,2,1-ij]quinolin-4-one oxalate
[0205] 43
Step 7. Preparation of ethyl
3-(3-benzoyl-2,3,4,5-tetrahydroazepino[4,5-b]-
indol-6(1H)-yl)propanoate
[0206] A mixture of
3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.00 g, 17.2
mmol), cesium carbonate (5.61 g, 17.2 mmol), and ethyl acrylate
(1.90 mL, 17.5 mmol) in acetonitrile (250 mL) was heated under
N.sub.2 at 50.degree. C. for 5 h (reaction can also be run in DMF
at room temperature). Cooled to room temperature, diluted with
H.sub.2O, and extracted with EtOAc. The combined organic extracts
were washed with saturated aqueous NaCl, dried over
Na.sub.2SO.sub.4, decanted, and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography with EtOAc/hexanes (2:1) to give 4.82 g (72%) of the
title compound as a yellow oil. .sup.1H NMR (CDCl.sub.3) .delta.
7.57-7.38, 7.32, 7.23-7.07, 4.49-4.33, 4.20-4.02, 3.77-3.66,
3.28-3.13, 2.94, 2.72, 1.24; IR (liq.) 2981, 1731, 1631, 1467,
1445, 1422, 1381, 1368, 1349, 1319, 1295, 1272, 1242, 1187, 742,
707 cm.sup.-1; MS (ESI) 391.0 (M.sup.++H).
Step 8. Preparation of
10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one
[0207] A solution of potassium hydroxide (0.80 g, 14.3 mmol) in
H.sub.2O (20 mL) was added to a solution of ethyl
3-(3-benzoyl-2,3,4,5-tetrahydroa-
zepino[4,5-b]indol-6(1H)-yl)propanoate (4.25 g, 10.9 mmol) in THF
(30 mL). The reaction mixture was heated at 60.degree. C. for 1 h,
then cooled to room temperature, acidified with 10% aqueous HCl,
and extracted with EtOAc. The combined organic extracts were washed
with saturated aqueous NaCl, dried over Na.sub.2SO.sub.4, decanted,
and concentrated under reduced pressure to give 3.73 g of crude
acid. The crude acid (2.00 g, 5.52 mmol) was then added to neat PPA
(18.6 g) stirring at 100.degree. C. under N.sub.2. After 1.5 h, the
reaction was cooled to room temperature, quenched with ice and 10%
aqueous NaOH, and then extracted with EtOAc. The combined organic
extracts were washed with saturated aqueous NaCl, dried over
Na.sub.2SO.sub.4, decanted, and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography with EtOAc/hexanes (gradient 1:1 to 2:1) to give
0.81 g (43%) of the title compound as a yellow solid (mp
177.5-181.degree. C.). .sup.1H NMR (d-DMSO) .delta. 7.75, 7.46,
7.09, 4.45-4.24, 3.93, 3.61, 3.34, 3.17, 3.11-2.80; IR (drift)
1676, 1628, 1587, 1493, 1483, 1466, 1428, 1357, 1324, 1295, 1276,
1266, 1191, 754, 706 cm.sup.31 1.
Step 9. Preparation of
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]py- rrolo[3,2,1-ij
]quinolin-4-one oxalate
[0208] A solution of
10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one (0.20 g, 0.58 mmol) in
THF/MeOH/50% aqueous NaOH (3:2:1, 9 mL) was heated under N.sub.2 at
reflux for 4 d. Cooled to room temperature, diluted with saturated
aqueous NaCl, and extracted with CH.sub.2Cl.sub.2. The combined
organic extracts were washed with saturated aqueous NaCl, dried
over Na.sub.2SO.sub.4, decanted, and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography with CH.sub.2Cl.sub.2/MeOH/Et.sub.2- NH (gradient
95:5:0 to 95:4:1) to give 0.10 g (74%) of the free base of title
compound as a dark yellow foam. The oxalate salt was prepared by
treating a solution of the free base in methanol with a solution of
oxalic acid in ether to give a precipitate that crystallized from
methanol as small yellow needles of the title compound (mp
199-202.degree. C. [dec.]). .sup.1H NMR (d-DMSO) .delta. 7.78,
7.46, 7.15, 4.39, 4.19, 3.39, 3.34, 3.24, 3.14, 3.02; IR (drift)
2965, 2890, 2841, 2799, 2732, 2516, 2484, 1720, 1673, 1626, 1607,
1591, 1492, 1460, 1206 cm.sup.31 1.
EXAMPLE 42
Preparation of
2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinolin-4-one maleate
[0209] 44
[0210] Following the general procedure of Example 41, making
non-critical variations but starting with
3-benzoyl-9-fluoro-1,2,3,4,5,6-hexahydroazep- ino[4,5-b]indole and
using maleic acid for the salt formation, the title compound was
obtained (mp 242-244.degree. C. [dec.]). .sup.1H NMR (d-DMSO)
.delta. 9.18, 7.67, 7.21, 4.40, 3.33, 3.25, 3.12, 3.04; IR (drift)
3358, 2970, 2959, 2830, 2792, 2785, 2752, 1681, 1593, 1490, 1464,
1383, 1330, 1216, 907 cm.sup.31 1.
EXAMPLE 43
Preparation of
2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinolin-4-one oxalate
[0211] 45
[0212] Following the general procedure of Example 41, making
non-critical variations but starting with
3-benzoyl-9-chloro-1,2,3,4,5,6-hexahydroazep- ino[4,5-b]indole, the
title compound was obtained (mp 236.5-238.degree. C. [dec.]).
.sup.1H NMR (d-DMSO) .delta. 7.89, 7.38, 4.41, 3.69, 3.38, 3.33,
3.23, 3.13, 3.04; IR (mull) 3440, 2644, 2514, 1915, 1686, 1491,
1420, 1327, 1318, 1251, 1138, 1094, 1030, 914, 720 cm.sup.31 1.
EXAMPLE 44
Preparation of
6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinolin-4-one oxalate
[0213] 46
[0214] Following the general procedure of Example 41, making
non-critical variations but using ethyl crotonate in step 7, the
title compound was obtained (mp 215-215.5.degree. C.). .sup.1H NMR
(d-DMSO) .delta. 7.79, 7.47, 4.97, 3.50-3.20, 3.15, 2.73, 1.16; IR
(drift) 3020, 2984, 2969, 1727, 1684, 1609, 1589, 1471, 1327, 1217,
1194, 1178, 1100, 752, 706 cm.sup.31 1.
EXAMPLE 45
Preparation of
2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4'-
,5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one oxalate
[0215] 47
[0216] Following the general procedure of Example 41, making
non-critical variations but starting with
3-benzoyl-9-fluoro-1,2,3,4,5,6-hexahydroazep- ino[4,5-b]indole and
using ethyl crotonate in step 7, the title compound was obtained
(mp 209.5-211.5.degree. C.). .sup.1H NMR (d-DMSO) .delta. 7.69,
7.22, 4.99, 3.44-3.22, 3.12, 2.78, 1.16; IR (drift) 2969, 1743,
1727, 1716, 1688, 1646, 1616, 1480, 1418, 1377, 1214, 1145, 1102,
858, 602 cm.sup.31 1.
EXAMPLE 46
Preparation of
2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one mesylate
[0217] Following the general procedure of Example 41, making
non-critical variations but starting with
3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydro- azepino[4,5-b]indole,
using ethyl crotonate in step 7, and using methanesulfonic acid for
the salt formation, the title compound was obtained (mp
225-230.degree. C. [dec.]). .sup.1H NMR (d-DMSO) .delta. 8.94,
8.12, 4.97, 3.48-3.20, 3.13, 2.77, 2.30, 1.20; IR (drift) 3029,
2979, 2849, 2792, 1683, 1481, 1410, 1312, 1214, 1196, 1184, 1161,
1145, 1040, 775 cm.sup.-1.
EXAMPLE 47
Preparation of
6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinolin-4-one hydrochloride
[0218] 48
[0219] Following the general procedure of Example 41, making
non-critical variations but using ethyl trans-hexenoate in step 7
and using hydrochloric acid for the salt formation, the title
compound was obtained (mp 193-194.5.degree. C.). .sup.1H NMR
(d-DMSO) .delta. 9.38, 7.79, 7.45, 7.14, 4.87, 3.54, 3.45-3.19,
3.16, 2.83, 1.47, 1.13, 0.78; IR (drift) 2957, 2926, 2870, 2853,
2741, 1683, 1588, 1471, 1416, 1354, 1325, 1279, 1191, 795, 751
cm.sup.-1.
EXAMPLE 48
Preparation of
6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one oxalate
[0220] 49
[0221] Following the general procedure of Example 41, making
non-critical variations but using ethyl 4,4,4-trifluorocrotonate in
step 7 and using hydrochloric acid for the salt formation, the
title compound was obtained (mp 201.5-202.5.degree. C.). .sup.1H
NMR (d-DMSO) .delta. 7.86, 7.54, 7.24, 5.94, 3.73, 3.67, 3.43-3.19,
3.16, 3.00; IR (drift) 1726, 1694, 1645, 1639, 1592, 1469, 1416,
1336, 1272, 1253, 1204, 1195, 1177, 1127, 945 cm.sup.31 1.
EXAMPLE 49
Preparation of
5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]pyr-
rolo[3,2,1-ij]quinolin-4-ol
[0222] 50
Step 10 Preparation of
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-az-
epino[4',5':4,5]pyrrolo[3,2,1-ij ]quinolin-4-ol
[0223] A solution of
10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino
[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one (1.46 g, 4.24 mmol) in
ethanol (40 mL) was cooled to 0.degree. C. under N.sub.2. Added
sodium borohydride (0.32 g, 8.46 mmol) and allowed to warm slowly
to room temperature. Concentrated under reduced pressure to
approximately 10 mL, diluted with H.sub.2O, and extracted with
CH.sub.2Cl.sub.2. The combined organic extracts were washed with
saturated aqueous NaCl, dried over Na.sub.2SO.sub.4, decanted, and
concentrated under reduced pressure. The crude product was purified
by silica gel chromatography with EtOAc/heptanes (2:1) to give 1.24
g (84%) of the title compound as a yellow foam. .sup.1H NMR
(CDCl.sub.3) .delta. 7.42, 7.33, 7.12-7.02, 5.10, 4.13, 4.02, 3.68,
3.21, 2.92, 2.38, 2.23, 1.80; IR (drift) 1627, 1614, 1475, 1466,
1457, 1448, 1429, 1372, 1360, 1329, 1292, 1268, 785, 747, 706
cm.sup.-1; MS (ESI) 369.1 (M.sup.++Na).
[0224] The
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':-
4,5]pyrrolo[3,2,1-ij]quinolin-4-ol was then hydrolyzed following
the procedure outlined in step 9 to give
5,6,8,9,10,11,12,12a-octahydro-4H,7a-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol as a tan foam.
.sup.1H NMR (CDCl.sub.3) .delta. 7.43, 7.09,5.11, 4.11, 3.16, 3.02,
2.38, 2.26; IR (drift) 3300, 3047, 2923, 2878, 2828, 2751, 1479,
1454, 1430, 1415, 1371, 1330, 1199, 1074, 746 cm.sup.-1; HRMS (EI)
calcd for C.sub.15H.sub.18N.sub.2O 242.1419, found 242.1422.
EXAMPLE 50
Preparation of
4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',-
5':4,5]pyrrolo[3,2,1-ij]quinoline
[0225] 51
Step 11. Preparation of
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydr-
o-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij ]quinoline
[0226] NaH (60% dispersion in mineral oil, 0.50 g, 1.2 mmol) was
added to a solution of
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4'-
,5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol (0.20 g, 0.58 mmol) in DMF
(5.0 mL) at 0.degree. C. under N.sub.2. After 30 min, iodomethane
(0.040 mL, 0.64 mmol) was added. The reaction was quenched with
saturated aqueous NH.sub.4Cl after 1 h and then allowed to warm to
room temperature prior to extracting with EtOAc. The combined
organic extracts were washed with saturated aqueous NaCl, dried
over Na.sub.2SO.sub.4, decanted, and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography with EtOAc/heptanes (2:1) to give 0.16 g (79%) of
the title compound as a beige foam. .sup.1H NMR (CDCl.sub.3)
.delta. 7.46-7.30, 6.94, 4.51, 4.22-4.03, 4.01-3.79, 3.65-3.41,
3.29, 3.12, 3.04, 2.90, 2.82, 2.34, 2.08; IR (drift) 1631, 1493,
1477, 1459, 1422, 1370, 1359, 1324, 1292, 1267, 1098, 1085, 786,
748, 706 cm.sup.-1; HRMS (FAB) calcd for
C.sub.23H.sub.24N.sub.2O.sub.2+H 361.1916, found 361.1913.
[0227] Following the general procedure of step 4, making
non-critical variations but starting with 1
0-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-o-
ctahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline, the
title compound was obtained as a brown oil. .sup.1H NMR
(CDCl.sub.3) .delta. 7.45, 7.07, 4.56, 4.26, 4.09, 3.42, 3.27-3.13,
3.11-2.94, 2.49, 2.18; IR (liq.) 2926, 2905, 2882, 2820, 1492,
1479, 1453, 1415, 1370, 1332, 1200, 1098, 1083, 1066, 748
cm.sup.-1, HRMS (FAB) calcd for C.sub.16H.sub.20N.sub.2O+H
257.1654, found 257.1665.
EXAMPLE 51
Preparation of
4-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]-
pyrrolo[3,2,1-ij]quinoline
[0228] 52
Step 12. Preparation of
10-benzoyl-4-phenoxy-5,6,9,10,11,12-hexahydro-4H,8-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline
[0229] 1,1'-Azobis(N,N-dimethylformamide) (0.34 g, 2.0 mmol) was
added to a solution of
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4'-
,5':4,5]pyrrolo[3,2,1-ij]quinolin-4-ol (0.45 g, 1.3 mmol), phenol
(0.18 g, 1.9 mmol), and tributylphosphine (0.49 mL, 2.0 mmol) in
dry benzene (4.0 mL) at room temperature under N.sub.2. The
reaction mixture immediately congealed but resumed stirring upon
heating to 60.degree. C. After 5 h, the reaction was cooled to room
temperature and filtered to remove white precipitate. The filtrate
was concentrated under reduced pressure and purified by silica gel
chromatography with heptanes/EtOAc (gradient 3:1 to 3:2) to give
0.26 g (47%) of the title compound as a beige foam. .sup.1H NMR
(CDCl.sub.3) .delta. 7.52-7.38, 7.32, 7.11-6.95, 5.68, 4.21-3.90,
3.69, 3.21, 2.91, 2.63, 2.34; IR (drift) 1630, 1596, 1492, 1458,
1421, 1359, 1327, 1291, 1267, 1226, 1192, 786, 750, 706, 694
cm.sup.-1; MS (ESI) 423.3 (M.sup.++H).
[0230] Following the general procedure of step 4, making
non-critical variations but starting with
10-benzoyl-4-phenoxy-5,6,9,10,11,12-hexahydr-
o-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline, the title
compound was obtained. MS (ESI) 319.2 (M.sup.++H).
EXAMPLE 52
Using Synthetic Procedures Similar to those Described Herein, the
Following Compounds of Formula (I) Wherein R.sub.2 is Hydrogen can
also be Prepared
[0231]
4-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-
-hi]indole (100);
[0232]
5-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-
-hi]indole (101);
[0233]
6-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-
-hi]indole (102);
[0234]
5,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole (103);
[0235]
4,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole (104);
[0236]
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3-
,4-hi]indole (105);
[0237]
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3-
,4-hi]indole (106);
[0238]
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3-
,4-hi]indole (107);
[0239]
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole (108);
[0240]
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole (109);
[0241]
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole (110);
[0242]
5-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole (111);
[0243]
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2-
,3,4-hi]indole (112);
[0244]
4-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (113);
[0245]
5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (114);
[0246]
6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (115);
[0247]
4-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (116);
[0248]
5-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (117);
[0249]
6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (118);
[0250]
4,5-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino-
[2,3,4-hi]indole (119);
[0251]
5,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino-
[2,3,4-hi]indole (120);
[0252]
4,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino-
[2,3,4-hi]indole (121);
[0253]
4-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thi-
azino[2,3,4-hi]indole (122);
[0254]
4-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thi-
azino[2,3,4-hi]indole (123);
[0255]
5-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thi-
azino[2,3,4-hi]indole (124);
[0256]
6-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thi-
azino[2,3,4-hi]indole (125);
[0257]
4-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (126);
[0258]
5-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3-
,4-hi]indole (127);
[0259] 6-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][
1,4]thiazino[2,3,4-hi]indole (128);
[0260]
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,-
3,4-hi]indole (129);
[0261]
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,-
3,4-hi]indole (130);
[0262]
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,-
3,4-hi]indole; (131)
[0263]
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]t-
hiazino[2,3,4-hi]indole (132);
[0264]
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]t-
hiazino[2,3,4-hi]indole (133);
[0265]
6-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]t-
hiazino[2,3,4-hi]indole (134);
[0266]
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[-
2,3,4-hi]indole (135);
[0267] 5-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][ 1
,4]thiazino[2,3,4-hi]indole (136);
[0268]
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[-
2,3,4-hi]indole (137);
[0269]
1-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]-
indole (138);
[0270]
3-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]-
indole (139);
[0271]
1-bromo-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]i-
ndole (140);
[0272]
2-bromo-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]i-
ndole (141);
[0273]
3-bromo-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]i-
ndole (142);
[0274]
3-chloro-1-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-h-
i]indole (143);
[0275]
2-chloro-1-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[-
3,2,1-hi]indole (144);
[0276]
1-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi-
]indole (145);
[0277]
3-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi-
]indole (146);
[0278]
4-methyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi]-
indole (147);
[0279]
1-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrol-
o[3,2,1-hi]indole (148);
[0280]
2-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrol-
o[3,2,1-hi]indole (149);
[0281]
3-(trifluoromethyl)-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrol-
o[3,2,1-hi]indole (150);
[0282]
4-benzyloxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinoline (151);
[0283]
4-(3-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline (152);
[0284]
4-(2-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline (153);
[0285]
4-(4-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (154);
[0286]
4-(3-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (155);
[0287]
4-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (156);
[0288]
4-(4-bromo-2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (157);
[0289]
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinolin-4-amine (158);
[0290]
N-phenyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3-
,2,1-ij]quinolin-4-amine (159);
[0291]
N-(4-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij ]quinolin-4-amine (160);
[0292]
N-(3-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinolin-4-amine (161);
[0293]
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinolin-4-amine (162);
[0294]
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-4-amine (163);
[0295]
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-4-amine (164);
[0296]
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-4-amine (165);
[0297]
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-amine (166);
[0298]
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinoline-4-thione (167);
[0299]
4-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinoline (168);
[0300]
4-(4-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline (169);
[0301]
4-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline (170);
[0302]
4-(2-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline (171);
[0303]
4-(4-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (172);
[0304]
4-(3-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (173);
[0305]
4-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (174);
[0306]
4-(4-bromo-2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (175);
[0307]
5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2-
,1-ij]quinolin-5-ol (176);
[0308]
5-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinoline (177);
[0309]
5-benzyloxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinoline (178);
[0310]
5-phenoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[-
3,2,1-ij]quinoline (179);
[0311]
5-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline (180);
[0312]
5-(3-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (181);
[0313]
5-(2-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline (182);
[0314]
5-(4-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (183);
[0315]
5-(3-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (184);
[0316]
5-(2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo[3,2,1-ij]quinoline (185);
[0317]
5-(4-bromo-2-methoxyphenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (186);
[0318]
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinolin-5-amine (187);
[0319]
N-phenyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3-
,2,1-ij]quinolin-5-amine (188);
[0320]
N-(4-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinolin-5-amine (189);
[0321]
N-(3-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinolin-5-amine (190);
[0322]
N-(2-chlorophenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinolin-5-amine (191);
[0323]
N-(4-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-5-amine (192);
[0324]
N-(3-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-5-amine (193);
[0325]
N-(2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinolin-5-amine (194);
[0326]
N-(4-bromo-2-methoxyphenyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinolin-5-amine (195);
[0327]
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinoline-5-thione (196);
[0328]
5-(phenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5-
]pyrrolo[3,2,1-ij]quinoline (197);
[0329]
5-(4-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline (198);
[0330]
5-(3-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij]quinoline (199);
[0331]
5-(2-chlorophenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4-
',5':4,5]pyrrolo[3,2,1-ij ]quinoline (200);
[0332]
5-(4-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (201);
[0333]
5-(3-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (202);
[0334]
5-(2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (203);
[0335]
5-(4-bromo-2-methoxyphenylsulfonyl)-5,6,9,10,11,12-hexahydro-4H,8H--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (204);
[0336]
4-(4-chlorophenoxy)-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline (205);
[0337]
1-[2-(4-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (206);
[0338]
1-[2-(3-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (207);
[0339]
1-[2-(2-fluorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (208);
[0340]
1-[2-(4-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij ]quinoline (209);
[0341]
1-[2-(3-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (210);
[0342]
1-[2-(2-chlorophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (211);
[0343]
1-[2-(4-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (212);
[0344]
1-[2-(3-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (213);
[0345]
1-[2-(2-bromophenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (214);
[0346]
1-[2-(4-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (215);
[0347]
1-[2-(3-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (216);
[0348]
1-[2-(2-methoxyphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij]quinoline,(217);
[0349]
1-[2-(4-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (218);
[0350]
1-[2-(3-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (219);
[0351]
1-[2-(2-methylphenoxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepin-
o[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (220);
[0352]
1-[2-(1-naphthyloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (221);
[0353]
1-[2-(2-naphthyloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8H-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline (222);
[0354]
1-[2-([1,1'-biphenyl]-4-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (223);
[0355]
1-[2-([1,1'-biphenyl]-3-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (224);
[0356]
1-[2-([1,1'-biphenyl]-2-yloxy)ethoxy]-5,6,9,10,11,12-hexahydro-4H,8-
H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (225);
[0357]
1-{2-[4-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (226);
[0358]
1-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (227);
[0359]
1-{2-[2-(trifluoromethoxy)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro--
4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (228);
[0360]
1-{2-[4-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4-
H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (229);
[0361]
1-{2-[3-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4-
H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (230); and
[0362]
1-{2-[2-(trifluoromethyl)phenoxy]ethoxy}-5,6,9,10,11,12-hexahydro-4-
H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (231).
EXAMPLE 53
Using Synthetic Procedures Similar to those Described Herein, the
Following Compounds of Formula (I) Wherein R.sub.2 is a Protecting
Group can also be Prepared
[0363] benzyl
5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]pyrrolo[3,2-
,1-ij]quinoline-10-carboxylate;
[0364] benzyl
2-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij]quinoline-10-carboxylate;
[0365]
10-benzoyl-1-methoxy-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4-
,5]pyrrolo-[3,2,1-ij]quinoline;
[0366] benzyl
2-fluoro-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij ]quinoline-10-carboxylate;
[0367] benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij]quinoline-10-carboxylate;
[0368] benzyl
5-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij]quinoline-10-carboxylate;
[0369] benzyl
4-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,5]py-
rrolo[3,2,1-ij]quinoline-10-carboxylate;
[0370] (+)-benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0371] (-)-benzyl
6-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0372] (+)-benzyl
5-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0373] (-)-benzyl
5-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0374] (+)-benzyl
4-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0375] (-)-benzyl
4-methyl-5,6,8,9,11,12-hexahydro-4H,10H-azepino[4',5':4,-
5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate;
[0376] benzyl
2-methyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0377] benzyl
2,2-dimethyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole-9-carboxylate;
[0378] benzyl
4-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0379] benzyl
4-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0380] benzyl
5-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0381] benzyl
5-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0382] benzyl
5-methyl-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0383] benzyl
6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0384] benzyl
6-chloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]oxazi-
no[2,3,4-hi]indole-9-carboxylate;
[0385] benzyl
6-methyl-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,-
4]oxazino[2,3,4-hi]indole-9-carboxylate;
[0386] benzyl
6-(trifluoromethyl)-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b-
][1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
[0387] benzyl
5,6-difluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole-9-carboxylatebenzyl;
[0388] benzyl
5-chloro-6-fluoro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][-
1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
[0389] benzyl 5-fluoro-6-chloro-1,2,7,8,10,l
-hexahydro-9H-azepino[4,5-b][-
1,4]oxazino[2,3,4-hi]indole-9-carboxylate;
[0390] benzyl
5,6-dichloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole-9-carboxylate;
[0391] benzyl
4,6-dichloro-1,2,7,8,10,11-hexahydro-9H-azepino[4,5-b][1,4]o-
xazino[2,3,4-hi]indole-9-carboxylate;
[0392] 7-benzoyl
4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,2,1-hi-
]indole;
[0393] 7-benzoyl
2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo-
[3,2,1-hi]indole;
[0394] 7-benzoyl
2-methoxy-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrol-
o[3,2,1-hi]indole;
[0395]
benzyl-5-methyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,-
2,1-hi]-7-carboxylate;
[0396]
benzyl-4,5-dimethyl-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrol-
o[3,2,1-hi]indole-7-carboxylate;
[0397]
benzyl-2,3,4,5,8b,9,10,11,12,12a-decahydro-1H-azepino[4',5':4,5]pyr-
rolo[3,2,1-jk]carbazole-7-carboxylate;
[0398]
benzyl-1-chloro-2-fluoro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]p-
yrrolo[3,2,1-hi]indole-7-carboxylate;
[0399]
benzyl-2-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,-
2,1-hi]indole-7-carboxylate;
[0400]
benzyl-1-chloro-4,5,8,9,10,11-hexahydro-7H-azepino[4,5-b]pyrrolo[3,-
2,1-hi]indole-7-carboxylate;
[0401]
10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo-
[3,2,1-ij]quinolin-4-one;
[0402]
10-benzoyl-2-fluoro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo-[3,2,1-ij]quinolin-4-one;
[0403]
10-benzoyl-2-chloro-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo-[3,2,1-ij]quinolin-4-one;
[0404]
10-benzoyl-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo-[3,2,1-ij]quinolin-4-one;
[0405]
10-benzoyl-2-fluoro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino-
[4',5':4,5]-pyrrolo[3,2,1-ij]quinolin-4-one;
[0406]
10-benzoyl-2,3-dichloro-6-methyl-5,6,9,10,11,12-hexahydro-4H,8H-aze-
pino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-4-one;
[0407]
10-benzoyl-6-propyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,-
5]pyrrolo-[3,2,1-ij]quinolin-4-one;
[0408]
10-benzoyl-6-(trifluoromethyl)-5,6,9,10,11,12-hexahydro-4H,8H-azepi-
no[4',5':4,5]pyrrolo[3,2,1-ij ]quinolin-4-one;
[0409]
10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]-
pyrrolo[3,2,1-ij]quinolin-4-ol; and
[0410]
10-benzoyl-4-methoxy-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[-
4',5':4,5]pyrrolo[3,2,1-ij]quinoline.
[0411] All cited publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *