U.S. patent application number 10/842044 was filed with the patent office on 2004-10-28 for therapeutic compounds.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Badescu, Valentina, McWhorter, William W. JR..
Application Number | 20040214815 10/842044 |
Document ID | / |
Family ID | 26973321 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040214815 |
Kind Code |
A1 |
McWhorter, William W. JR. ;
et al. |
October 28, 2004 |
Therapeutic compounds
Abstract
The present invention provides compounds of formula (I): 1
wherein: R.sub.1, R.sub.2, R.sub.3 R.sub.4, R.sub.5, R.sub.6, X, -
- - , m, and n have any of the values defined in the specification,
as well as pharmaceutical compositions comprising the compounds or
salts thereof. The invention also provides therapeutic methods as
well as processes and intermediates useful for preparing compounds
of formula (I). The compounds are useful as 5-HT ligands.
Inventors: |
McWhorter, William W. JR.;
(Parchment, MI) ; Badescu, Valentina; (Kalamazoo,
MI) |
Correspondence
Address: |
FLYNN, THIEL, BOUTELL & TANIS, P.C.
2026 RAMBLING ROAD
KALAMAZOO
MI
49008-1699
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
26973321 |
Appl. No.: |
10/842044 |
Filed: |
May 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10842044 |
May 7, 2004 |
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10179585 |
Jun 25, 2002 |
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6762191 |
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60303191 |
Jul 5, 2001 |
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60314972 |
Aug 24, 2001 |
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Current U.S.
Class: |
514/217.07 ;
514/227.8; 514/234.2; 514/253.03; 514/291; 540/599; 544/126;
544/361; 544/60; 546/80 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
25/20 20180101; A61P 15/10 20180101; A61P 25/24 20180101; A61P
25/02 20180101; A61P 1/00 20180101; A61P 9/00 20180101; A61P 25/00
20180101; C07D 491/04 20130101; A61P 25/22 20180101; A61P 15/08
20180101; A61P 43/00 20180101; A61P 25/30 20180101; A61P 25/14
20180101; A61P 25/18 20180101; A61P 37/00 20180101; A61P 3/04
20180101; A61P 25/06 20180101 |
Class at
Publication: |
514/217.07 ;
514/291; 514/227.8; 514/234.2; 514/253.03; 540/599; 544/060;
544/126; 544/361; 546/080 |
International
Class: |
A61K 031/55; A61K
031/541; A61K 031/5377; A61K 031/496; A61K 031/4743; C07D
498/02 |
Claims
What is claimed:
1. A compound of formula (I): 269wherein: R.sub.1, R.sub.2,
R.sub.3, and R.sub.4 are independently hydrogen, halo, --CF.sub.3,
--OCF.sub.3, --CN, --NO.sub.2, --C.sub.1-8alkyl,
--C.sub.3-8cycloalkyl, --OR.sub.8, --NR.sub.8R.sub.9, --SR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.5 is hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl, --C(.dbd.O)OR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.6 is hydrogen or
C.sub.1-4alkyl; each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring; m is 0, 1, or 2; n is 1 or 2;
with the proviso that m and n cannot simultaneously be 1; X is oxy
(--O--), thio (--S--) --S(.dbd.O)-- or --SO.sub.2--; and the bond
represented by - - - is absent or present; wherein any
C.sub.1-8alkyl, C.sub.1-8alkylene, C.sub.1-8alkoxy or
C.sub.3-8cycloalkyl of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.8 and R.sub.9 is optionally partially unsaturated;
and wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more substituents independently selected from halo, --CN,
--NO.sub.2, --CF.sub.3, --OCF.sub.3, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heteroaryl, --OR.sub.c, --SR.sub.c,
--C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cC(.dbd.O)R.sub.d, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d or --SO.sub.2R.sub.c; wherein each
R.sub.c and R.sub.d is independently hydrogen, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(hetero- aryl),
--C(.dbd.O)heteroaryl, --C(.dbd.O)Oheteroaryl or R.sub.c and
R.sub.d together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, azepano, piperazino, morpholino, or
thiomorpholino ring; or a pharmaceutically acceptable salt
thereof.
2. The compound of claim 1, wherein the bond represented by - - -
is absent.
3. The compound of claim 1, wherein the bond represented by - - -
is present.
4. The compound of claim 1, wherein X is oxy.
5. The compound of claim 1, wherein X is thio.
6. The compound of claim 1, wherein R.sub.2 is aryl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
7. The compound of claim 6, wherein R.sub.2 is phenyl, optionally
substituted with one or more substituents independently selected
from from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
and --C(.dbd.O)NR.sub.cR.sub.d.
8. The compound of claim 7, wherein R.sub.2 is phenyl, optionally
substituted with one or more substituents independently selected
from halo, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy and thioC.sub.1-6alkyl.
9. The compound of claim 8, wherein R.sub.2 is phenyl, substituted
with one or more substituents independently selected from halo,
cyano, trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
C.sub.1-6alkoxy and thioC.sub.1-6alkyl.
10. The compound of claim 9, wherein R.sub.2 is phenyl, substituted
with one or more substituents independently selected from fluoro,
chloro, bromo, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy,
propoxy, isopropoxy and thiomethyl.
11. The compound of claim 10, wherein R.sub.2 is phenyl substituted
at the 2- or 6-position with fluoro, chloro or bromo.
12. The compound of claim 10, wherein R.sub.2 is phenyl
independently substituted at the 2- and 6-position with fluoro,
chloro or bromo.
13. The compound of claim 10, wherein R.sub.2 is phenyl substituted
at the 2- or 4-position with fluoro, chloro or bromo.
14. The compound of claim 10, wherein R.sub.2 is phenyl
independently substituted at the 2- and 4-position with fluoro,
chloro or bromo.
15. The compound of claim 10, wherein R.sub.2 is phenyl
independently substituted at the 2-, 4- and 6-position with fluoro,
chloro or bromo.
16. The compound of claim 10, wherein R.sub.2 is
2,4-dichlorophenyl, 2,4,6-trichlorophenyl or
2,6-difluoro-4-chlorophenyl.
17. The compound of claim 1, wherein R.sub.2 is heteroaryl,
optionally substituted with one or more substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
18. The compound of claim 17, wherein R.sub.2 is heteroaryl,
optionally substituted with one or more substituents independently
selected from halo, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c and --SR.sub.c.
19. The compound of claim 18, wherein R.sub.2 is heteroaryl,
optionally substituted with one or more substituents independently
selected from fluoro, chloro, bromo, trifluoromethyl,
trifluoromethoxy, methoxy, ethoxy, propoxy, and isopropoxy.
20. The compound of claim 1, wherein R.sub.1 is hydrogen,
C.sub.1-3alkyl, halo, haloC.sub.1-3alkyl, C.sub.1-3alkoxy,
haloC.sub.1-3alkoxy, or --NR.sub.8R.sub.9.
21. The compound of claim 20, wherein R.sub.1 is hydrogen or
C.sub.1-3alkyl.
22. The compound of claim 1, wherein R.sub.3 is hydrogen,
C.sub.1-3alkyl, aryl, halo, haloC.sub.1-3alkyl, C.sub.1-3alkoxy,
haloC.sub.1-3alkoxy or --NR.sub.8R.sub.9.
23. The compound of claim 22, wherein R.sub.3 is hydrogen,
C.sub.1-3alkyl, or aryl.
24. The compound of claim 23, wherein R.sub.3 is hydrogen or
C.sub.1-3alkyl.
25. The compound of claim 1, wherein R.sub.4 is C.sub.1-8alkyl,
--OR.sub.8, --SR.sub.8, --NR.sub.8R.sub.9, aryl or
--C.sub.1-8alkylene(aryl), wherein the aryl groups are optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
26. The compound of claim 25, wherein R.sub.4 is C.sub.1-8alkyl,
--OR.sub.8, --SR.sub.8, --NR.sub.8R.sub.9 or aryl, wherein the aryl
group is substituted with one or more substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
27. The compound of claim 25, wherein R.sub.4 is methyl, ethyl,
propyl, isopropyl, butyl, ethylpropyl, cyclohexyl, phenyl, benzyl,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, (ethylpropyl)oxy,
(cyclohexyl)oxy, phenoxy, (benzyl)oxy, methylthio, ethylthio,
propylthio, isopropylthio, butylthio, (ethylpropyl)thio,
(cyclohexyl)thio, phenylthio, (benzyl)thio, or --NR.sub.8R.sub.9,
wherein R.sub.8 is hydrogen, methyl, ethyl, propyl or cyclohexyl;
and R.sub.9 is methyl, ethyl, propyl, cyclohexyl or phenyl; or
R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring.
28. The compound of claim 27, wherein R.sub.4 is --NR.sub.8R.sub.9,
wherein R.sub.8 is hydrogen, methyl, ethyl, propyl or cyclohexyl
and R.sub.9 is methyl, ethyl, propyl, cyclohexyl or phenyl.
29. The compound of claim 28, wherein R.sub.4 is --NR.sub.8R.sub.9,
wherein R.sub.8 is hydrogen, methyl or ethyl and R.sub.9 is methyl,
ethyl, propyl, cyclohexyl or phenyl.
30. The compound of claim 29, wherein R.sub.4 is --NR.sub.8R.sub.9,
wherein R.sub.8 is hydrogen, methyl or ethyl and R.sub.9 is methyl,
ethyl, cyclohexyl or phenyl.
31. The compound of claim 30, wherein R.sub.4 is --NR.sub.8R.sub.9,
wherein R.sub.8 is methyl or ethyl and R.sub.9 is methyl, ethyl or
cyclohexyl.
32. The compound of claim 27,wherein R.sub.4 is pyrrolidino,
piperidino, azepano, piperazino, morpholino, or thiomorpholino.
33. The compound of claim 1, wherein R.sub.5 is hydrogen,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, aryl,
--C.sub.1-8alkylene(aryl), heteroaryl, or
--C.sub.1-8alkylene(heteroaryl).
34. The compound of claim 33, wherein R.sub.5 is hydrogen or
C.sub.1-8alkyl.
35. The compound of claim 33, wherein R.sub.5 is hydrogen, methyl,
ethyl, benzyl, or phenethyl.
36. The compound of claim 33, wherein R.sub.5 is aryl,
--C.sub.1-8alkylene(aryl), heteroaryl, or
--C.sub.1-8alkylene(heteroaryl)- .
37. The compound of claim 34, wherein R.sub.5 is hydrogen.
38. The compound of claim 1, wherein m is 1.
39. The compound of claim 1, wherein n is 1.
40. The compound of claim 1, wherein m is 0; n is 1; and X is
oxy.
41. The compound of claim 1, wherein m is 2; n is 1; and X is
oxy.
42. The compound of claim 1, wherein m is 0; n is 2; and X is
oxy.
43. The compound of claim 1, wherein m is 1; n is 2; and X is
oxy.
44. The compound of claim 1, wherein m is 2; n is 2; and X is
oxy.
45. The compound of claim 1, wherein m is 0; n is 1; and X is
thio.
46. The compound of claim 1, wherein m is 2; n is 1; and X is
thio.
47. The compound of claim 1, wherein m is 0; n is 2; and X is
thio.
48. The compound of claim 1, wherein m is 1; n is 2; and X is
thio.
49. The compound of claim 1, wherein m is 2; n is 2; and X is
thio.
50. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
51. 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.
52. A compound of formula (I): 270wherein: R.sub.1, R.sub.3, and
R.sub.4 are independently hydrogen, halo, --CF.sub.3, --OCF.sub.3,
--CN, --NO.sub.2, --C.sub.1-8alkyl, --C.sub.3-8cycloalkyl,
--OR.sub.8, --NR.sub.8R.sub.9, --SR.sub.8, --C(.dbd.O)aryl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.2 is aryl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d. R.sub.5 is
hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl, --C(.dbd.O)OR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.6 is hydrogen or
C.sub.1-4alkyl; each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring; m is 0, 1, or 2; n is 1 or 2;
with the proviso that m and n cannot simultaneously be 1; X is oxy
(--O--), thio (--S--) --S(.dbd.O)-- or --SO.sub.2--; and the bond
represented by - - - is absent or present; wherein any
C.sub.1-8alkyl, C.sub.1-8alkylene, C.sub.1-8alkoxy or
C.sub.3-8cycloalkyl of R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.8 and R.sub.9 is optionally partially unsaturated; and
wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more substituents independently selected from halo, --CN,
--NO.sub.2, --CF.sub.3, --OCF.sub.3, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heteroaryl, --OR.sub.c, --SR.sub.c,
--C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cC(.dbd.O)R.sub.d, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d or --SO.sub.2R.sub.c; wherein each
R.sub.c and R.sub.d is independently hydrogen, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(hetero- aryl),
--C(.dbd.O)heteroaryl, --C(.dbd.O)Oheteroaryl or R.sub.c and
R.sub.d together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, azepano, piperazino, morpholino, or
thiomorpholino ring; or a pharmaceutically acceptable salt
thereof.
53. The compound of claim 52, wherein - - - is absent.
54. The compound of claim 53, wherein m is 1.
55. The compound of claim 54, wherein n is 1.
56. The compound of claim 55, wherein R.sub.2 is phenyl optionally
substituted with one or more substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
or --C(.dbd.O)NR.sub.cR.sub.d.
57. The compound of claim 56, wherein R.sub.2 is phenyl optionally
substituted with one or more halo.
58. The compound of claim 57, wherein R.sub.2 is phenyl substituted
at the 2- or 6-position with fluoro, chloro, or bromo.
59. The compound of claim 58, wherein R.sub.2 is phenyl substituted
at the 2- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
60. The compound of claim 57, wherein R.sub.2 is phenyl substituted
at the 2- or 4-position with fluoro, chloro, or bromo.
61. The compound of claim 57, wherein R.sub.2 is phenyl substituted
at the 2- and 4-position with halo independently selected from
fluoro, chloro, and bromo.
62. The compound of claim 57, wherein R.sub.2 is phenyl substituted
at the 2-, 4- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
63. The compound of claim 57, wherein R.sub.2 is
2,4-dichlorophenyl, 2,4,6-trichlorophenyl, or
2,6-difluoro-4-chlorophenyl.
64. The compound of claim 57, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --OR.sub.8, --SR.sub.8, --NR.sub.8R.sub.9, aryl, or
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.- d.
65. The compound of claim 64, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --NR.sub.8R.sub.9, aryl, or
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.d.
66. The compound of claim 65, wherein R.sub.4 is aryl,
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.- d, or --NR.sub.8R.sub.9, wherein R.sub.8
is hydrogen, methyl, ethyl, propyl or cyclohexyl and R.sub.9 is
methyl, ethyl, propyl, cyclohexyl or phenyl.
67. The compound of claim 65, wherein R.sub.4 is halo, --CF.sub.3,
or --CH.sub.3.
68. A compound of formula (I): 271wherein: R.sub.1, R.sub.3,
R.sub.2, and R.sub.4 are independently hydrogen, halo, --CF.sub.3,
--OCF.sub.3, --CN, --NO.sub.2, --C.sub.1-8alkyl,
--C.sub.3-8cycloalkyl, --OR.sub.8, --NR.sub.8R.sub.9, --SR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl), provided that at least one of
R.sub.1, R.sub.3, R.sub.2, and R.sub.4 is aryl optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d; R.sub.5 is
hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl, --C(.dbd.O)OR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.6 is hydrogen or
C.sub.1-4alkyl; each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring; m is 0, 1, or 2; n is 1 or 2;
with the proviso that m and n cannot simultaneously be 1; X is oxy
(--O--), thio (--S--) --S(.dbd.O)-- or --SO.sub.2--; and the bond
represented by - - - is absent or present; wherein any
C.sub.1-8alkyl, C.sub.1-8alkylene, C.sub.1-8alkoxy or
C.sub.3-8cycloalkyl of R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.8 and R.sub.9 is optionally partially unsaturated; and
wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more substituents independently selected from halo, --CN,
--NO.sub.2, --CF.sub.3, --OCF.sub.3, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heteroaryl, --OR.sub.c, --SR.sub.c,
--C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cC(.dbd.O)R.sub.d- , --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub- .cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d or --SO.sub.2R.sub.c; wherein each
R.sub.c and R.sub.d is independently hydrogen, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(ary- l), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(het- eroaryl),
--C(.dbd.O)heteroaryl, --C(.dbd.O)Oheteroaryl or R.sub.c and
R.sub.d together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, azepano, piperazino, morpholino, or
thiomorpholino ring; or a pharmaceutically acceptable salt
thereof.
69. The compound of claim 68, wherein - - - is absent.
70. The compound of claim 69, wherein m is 1.
71. The compound of claim 70, wherein n is 1.
72. The compound of claim 71, wherein R.sub.2 is phenyl optionally
substituted with one or more substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
or --C(.dbd.O)NR.sub.cR.sub.d.
73. The compound of claim 72, wherein R.sub.2 is phenyl optionally
substituted with one or more halo.
74. The compound of claim 73, wherein R.sub.2 is phenyl substituted
at the 2- or 6-position with fluoro, chloro, or bromo.
75. The compound of claim 73, wherein R.sub.2 is phenyl substituted
at the 2- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
76. The compound of claim 73, wherein R.sub.2 is phenyl substituted
at the 2- or 4-position with fluoro, chloro, or bromo.
77. The compound of claim 73, wherein R.sub.2 is phenyl substituted
at the 2- and 4-position with halo independently selected from
fluoro, chloro, and bromo.
78. The compound of claim 73, wherein R.sub.2 is phenyl substituted
at the 2-, 4- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
79. The compound of claim 73, wherein R.sub.2 is
2,4-dichlorophenyl, 2,4,6-trichlorophenyl or
2,6-difluoro-4-chlorophenyl.
80. The compound of claim 73, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --OR.sub.8, --SR.sub.8, --NR.sub.8R.sub.9, aryl, or
--C.sub.1-8alkylene(aryl), wherein the aryl groups are optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
81. The compound of claim 80, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --NR.sub.8R.sub.9, aryl, or
--C.sub.1-8alkylene(aryl), wherein the aryl groups are optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
82. The compound of claim 81, wherein R.sub.4 is aryl,
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.- d, or --NR.sub.8R.sub.9, wherein R.sub.8
is hydrogen, methyl, ethyl, propyl or cyclohexyl and R.sub.9 is
methyl, ethyl, propyl, cyclohexyl or phenyl.
83. The compound of claim 81, wherein R.sub.4 is halo, --CF.sub.3,
or --CH.sub.3.
84. A compound of formula (I): 272wherein: R.sub.1, R.sub.3,
R.sub.2, and R.sub.4 are independently hydrogen, halo, --CF.sub.3,
--OCF.sub.3, --CN, --NO.sub.2, --C.sub.1-8alkyl,
--C.sub.3-8cycloalkyl, --OR.sub.8, --NR.sub.8R.sub.9, --SR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl), provided that at least one of
R.sub.1, R.sub.3, R.sub.2, and R.sub.4 is aryl optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d, and further
provided that at least two of R.sub.1, R.sub.3, R.sub.2, and
R.sub.4 are other than hydrogen; R.sub.5 is hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl, --C(.dbd.O)OR.sub.8,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl); R.sub.6 is hydrogen or
C.sub.1-4alkyl; each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring; m is 1 or 2; n is 1 or 2; with
the proviso that m and n cannot simultaneously be 1; X is oxy
(--O--), thio (--S--) --S(.dbd.O)-- or --SO.sub.2--; and the bond
represented by - - - is absent or present; wherein any
C.sub.1-8alkyl, C.sub.1-8alkylene, C.sub.1-8alkoxy or
C.sub.3-8cycloalkyl of R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.8 and R.sub.9 is optionally partially unsaturated; and
wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more substituents independently selected from halo, --CN,
--NO.sub.2, --CF.sub.3, --OCF.sub.3, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heteroaryl, --OR.sub.c, --SR.sub.c,
--C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cC(.dbd.O)R.sub.d, --C(.dbd.O)NR.sub.cR.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d or --SO.sub.2R.sub.c; wherein each
R.sub.c and R.sub.d is independently hydrogen, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(hetero- aryl),
--C(.dbd.O)heteroaryl, --C(.dbd.O)Oheteroaryl or R.sub.c and
R.sub.d together with the nitrogen to which they are attached form
a pyrrolidino, piperidino, azepano, piperazino, morpholino, or
thiomorpholino ring; or a pharmaceutically acceptable salt
thereof.
85. The compound of claim 84, wherein m is 1.
86. The compound of claim 85, wherein n is 1.
87. The compound of claim 86, wherein R.sub.2 is phenyl optionally
substituted with one or more substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
or --C(.dbd.O)NR.sub.cR.sub.d.
88. The compound of claim 87, wherein R.sub.2 is phenyl optionally
substituted with one or more halo.
89. The compound of claim 88, wherein R.sub.2 is phenyl substituted
at the 2- or 6-position with fluoro, chloro, or bromo.
90. The compound of claim 88, wherein R.sub.2 is phenyl substituted
at the 2- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
91. The compound of claim 88, wherein R.sub.2 is phenyl substituted
at the 2- or 4-position with fluoro, chloro, or bromo.
92. The compound of claim 88, wherein R.sub.2 is phenyl substituted
at the 2- and 4-position with halo independently selected from
fluoro, chloro, and bromo.
93. The compound of claim 88, wherein R.sub.2 is phenyl substituted
at the 2-, 4- and 6-position with halo independently selected from
fluoro, chloro, and bromo.
94. The compound of claim 88, wherein R.sub.2 is
2,4-dichlorophenyl, 2,4,6-trichlorophenyl or
2,6-difluoro-4-chlorophenyl.
95. The compound of claim 88, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --OR.sub.8, --SR.sub.8, --NR.sub.8R.sub.9, aryl or
--C.sub.1-8alkylene(aryl), wherein the aryl groups are optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, and --C(.dbd.O)NR.sub.cR.sub.d.
96. The compound of claim 95, wherein R.sub.4 is halo, --CF.sub.3,
C.sub.1-8alkyl, --NR.sub.8R.sub.9, aryl, or
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.d.
97. The compound of claim 96, wherein R.sub.4 is aryl,
--C.sub.1-8alkylene(aryl), wherein aryl is optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, and
--C(.dbd.O)NR.sub.cR.sub.- d, or --NR.sub.8R.sub.9, wherein R.sub.8
is hydrogen, methyl, ethyl, propyl or cyclohexyl and R.sub.9 is
methyl, ethyl, propyl, cyclohexyl or phenyl.
98. The compound of claim 96, wherein R.sub.4 is halo, --CF.sub.3,
or --CH.sub.3.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. application Ser. No.
10/179,585, filed Jun. 25, 2002, which claims the benefit of U.S.
provisional application Serial No. 60/303,191, filed 5 Jul. 2001,
under 35 USC 119(e)(i), and U.S. provisional application Serial No.
60/314,972, filed 24 Aug. 2001, under 35 USC 119(e)(i), which are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention provides aryl or heteroaryl
substituted benzofuran derivatives, and more specifically, provides
compounds of formula (I) as 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 that 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, ed.
Neville V. Osborne, John Wiley and Sons (1982), p 221; D. J.
Boullin, Serotonin in Mental Abnormalities 1, John Wiley and Sons
(1978), p. 316; J. Barchas, et al., Serotonin and Behavior,
Academic Press, New York, N.Y. (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] Japanese Patent Application S63-149645 discusses a vast
genus of compounds that are reported to be useful to prevent
photochemical browning of organic pigments. The compounds
specifically prepared in the application differ considerably in
structure from the compounds of the invention. For example, they
lack a benzofuran type ring system.
[0009] U.S. Pat. No. 5,616,575 relates to tricyclic ibogaine
analogs of the following formula. 2
[0010] The compounds are reported to be useful to treat cocaine
addiction and the use of other addictive substances. The compounds
differ from the compounds of the invention at the groups R.sub.2
and R.sub.3 in the above formula.
[0011] There is currently a need for pharmaceutical agents that are
useful to treat diseases and conditions associated with 5-HT
receptors.
SUMMARY OF THE INVENTION
[0012] In accordance with the present invention, novel compounds
that demonstrate useful biological activity, and particularly
activity as 5-HT receptor ligands, are provided. Thus, the present
invention provides a compound of formula (I): 3
[0013] wherein:
[0014] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
hydrogen, halo, --CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2,
--C.sub.1-8alkyl, --C.sub.3-8cycloalkyl, --OR.sub.8,
--NR.sub.8R.sub.9, --SR.sub.8, --C(.dbd.O)aryl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl);
[0015] R.sub.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.3-8cycloalkyl, C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl,
--C(.dbd.O)OR.sup.8, --C(.dbd.O)aryl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl);
[0016] R.sub.6 is hydrogen or C.sub.1-4alkyl;
[0017] each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring;
[0018] m is 0, 1, or 2;
[0019] n is 1 or 2;
[0020] X is oxy (--O--), thio (--S--) --S(.dbd.O)-- or
--SO.sub.2--;
[0021] the bond represented by - - - is absent or present; and
[0022] wherein any C.sub.1-8alkyl, C.sub.1-8alkylene,
C.sub.1-8alkoxy or C.sub.3-8cycloalkyl of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.9 is
optionally partially unsaturated; and
[0023] wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more (e.g., 1, 2, 3, or 4) substituents independently
selected from halo, --CN, --NO.sub.2, --CF.sub.3, --OCF.sub.3,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, aryl, heteroaryl,
--OR.sub.c, --SR.sub.c, --C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c,
--C(.dbd.O)NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)R.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub.- cR.sub.d,
--SO.sub.2--NR.sub.cR.sub.d or --SO.sub.2R.sub.c;
[0024] wherein each R.sub.c and R.sub.d is independently hydrogen,
C.sub.1-8alkyl, C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(heteroaryl), --C(.dbd.O)heteroaryl,
--C(.dbd.O)Oheteroaryl or R.sub.c and R.sub.d together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
azepano, piperazino, morpholino, or thiomorpholino ring;
[0025] or a pharmaceutically acceptable salt thereof.
[0026] In another aspect, the present invention also provides:
[0027] 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),
[0028] 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,
[0029] 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,
[0030] a compound of formula (I) or a pharmaceutically acceptable
salt thereof for use in medical diagnosis or therapy (e.g. the
treatment or prevention of 5-HT related disease such as anxiety,
obesity, depression, or a stress-related disease),
[0031] the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof to prepare a medicament useful for treating
or preventing a disease or disorder of the central nervous system
in a mammal, and
[0032] a method for modulating the function of a 5-HT receptor,
comprising contacting the receptor with an effective modulatory
amount of a compound of formula (I), or a pharmaceutically
acceptable salt thereof.
[0033] The invention also provides novel intermediates and
processes disclosed herein that are useful for preparing compounds
of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention provides a compound of formula (I):
4
[0035] wherein:
[0036] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
hydrogen, halo, --CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2,
--C.sub.1-8alkyl, --C.sub.3-8cycloalkyl, --OR.sub.8,
--NR.sub.8R.sub.9, --SR.sub.8, --C(.dbd.O)aryl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl);
[0037] R.sub.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.3-8cycloalkyl, C.sub.1-8alkanoyl, haloC.sub.1-8alkanoyl,
--C(.dbd.O)OR.sup.8, --C(.dbd.O)aryl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)heteroaryl, heteroaryl, or
--C.sub.1-8alkylene(heteroaryl);
[0038] R.sub.6 is hydrogen or C.sub.1-4alkyl;
[0039] each R.sub.8 and R.sub.9 is independently hydrogen,
C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-8cycloalkyl,
--C(.dbd.O)aryl, aryl, --C.sub.1-8alkylene(aryl),
--C(.dbd.O)heteroaryl, heteroaryl, --C.sub.1-8alkylene(heteroaryl)
or R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring;
[0040] m is 0, 1, or 2;
[0041] n is 1 or 2;
[0042] X is oxy (--O--), thio (--S--) --S(.dbd.O)-- or
--SO.sub.2--;
[0043] the bond represented by - - - is absent or present; and
[0044] wherein any C.sub.1-8alkyl, C.sub.1-8alkylene,
C.sub.1-8alkoxy or C.sub.3-8cycloalkyl of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.9 is
optionally partially unsaturated; and
[0045] wherein any aryl or heteroaryl of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.8 or R.sub.9 is optionally substituted with
one or more (e.g., 1, 2, 3, or 4) substituents independently
selected from halo, --CN, --NO.sub.2, --CF.sub.3, --OCF.sub.3,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, aryl, heteroaryl,
--OR.sub.c, --SR.sub.c, --C(.dbd.O)R.sub.c, --CO.sub.2R.sub.c,
--C(.dbd.O)NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)R.sub.d,
--NR.sub.cR.sub.d, --NR.sub.cC(.dbd.O)NR.sub.- cR.sub.d,
--SO.sub.2--NR.sub.cR.sub.d or --SO.sub.2R.sub.c;
[0046] wherein each R.sub.c and R.sub.d is independently hydrogen,
C.sub.1-8alkyl, C.sub.1-8alkanoyl, C.sub.1-8alkoxycarbonyl, aryl,
--C.sub.1-8alkylene(aryl), --C(.dbd.O)aryl, --C(.dbd.O)Oaryl,
heteroaryl, --C.sub.1-8alkylene(heteroaryl), --C(.dbd.O)heteroaryl,
--C(.dbd.O)Oheteroaryl or R.sub.c and R.sub.d together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
azepano, piperazino, morpholino, or thiomorpholino ring;
[0047] or a pharmaceutically acceptable salt thereof.
[0048] In another aspect, the present invention also provides:
[0049] 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),
[0050] 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).
[0051] 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, alkylene or cycloalkyl can be
partially unsaturated, the alkyl chain or cycloalkyl ring may
comprise one or more (e.g., 1, 2, 3, or 4) double or triple bonds
in the chain.
[0052] 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.
[0053] 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.
[0054] 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.1-6alkyl refers
to alkyl of one to six carbon atoms, inclusive.
[0055] 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).
[0056] 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.
[0057] Specifically, C.sub.1-8alkyl can be methyl, ethyl, propyl,
isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl,
heptyl or octyl; C.sub.1-3alkyl can be methyl, ethyl, propyl,
isopropyl; haloC.sub.1-3alkyl can be trifluoromethyl, chloromethyl,
2-chloroethyl, 2,2,2-trifluoroethyl, or perfluoroethyl;
halo-C.sub.1-3alkoxy can be trifluoromethoxy, or
2,2,2-trifluoroethoxy; C.sub.1-8alkoxy can be methoxy, ethoxy,
propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy,
3-pentoxy, hexyloxy, heptyloxy or octyloxy; C.sub.1-8alkanoyl can
be acetyl, propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl,
hexanoyl, heptanoyl or octanoyl; C.sub.1-8alkoxycarbonyl can be
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or
hexyloxycarbonyl, heptyloxycarbonyl or octyloxycarbonyl;
C.sub.1-8alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,
isobutanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy or
octanoyloxy; 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).
[0058] A specific value for R.sub.2 is aryl, optionally substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
or --C(.dbd.O)NR.sub.cR.sub.d.
[0059] Another specific value for R.sub.2 is phenyl, optionally
substituted with one or more substituents independently selected
from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl, --NR.sub.cR.sub.d,
or --C(.dbd.O)NR.sub.cR.sub.d.
[0060] Another specific value for R.sub.2 is phenyl, optionally
substituted with one or more substituents independently selected
from halo, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy or thioC.sub.1-6alkyl.
[0061] Another specific value for R.sub.2 is phenyl, substituted
with one or more substituents independently selected from halo,
cyano, trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
C.sub.1-6alkoxy or thioC.sub.1-6alkyl.
[0062] Another specific value for R.sub.2 is phenyl, substituted
with one or more substituents independently selected from fluoro,
chloro, bromo, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy,
propoxy, isopropoxy or thiomethyl.
[0063] Another specific value for R.sub.2 is phenyl substituted at
the 2- and the 6-position with halo independently selected from
fluoro, chloro and bromo.
[0064] Another specific value for R.sub.2 is phenyl substituted at
the 2- or the 6-position with fluoro, chloro or bromo.
[0065] Another specific value for R.sub.2 is phenyl substituted at
the 2- and the 4-position with halo independently selected from
fluoro, chloro and bromo.
[0066] Another specific value for R.sub.2 is phenyl substituted at
the 2- or the 4-position with fluoro, chloro or bromo.
[0067] Another specific value for R.sub.2 is phenyl substituted at
the 2-, 4- and 6-position with halo independently selected from
fluoro, chloro and bromo.
[0068] Another specific value for R.sub.2 is 2,4-dichlorophenyl,
2,4,6-trichlorophenyl or 2,6-difluoro-4-chlorophenyl.
[0069] Another specific value for R.sub.2 is heteroaryl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d.
[0070] Another specific value for R.sub.2 is heteroaryl, optionally
substituted with one or more substituents independently selected
from halo, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, --OR.sub.c or --SR.sub.c.
[0071] Another specific value for R.sub.2 is heteroaryl, optionally
substituted with one or more substituents independently selected
from fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,
methoxy, ethoxy, propoxy, or isopropoxy.
[0072] Another specific value for R.sub.2 is heteroaryl,
substituted with one or more substituents independently selected
from fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,
methoxy, ethoxy, propoxy, or isopropoxy.
[0073] A specific value for R.sub.1 is hydrogen, C.sub.1-3alkyl,
halo, haloC.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy, or
--NR.sub.8R.sub.9.
[0074] Another specific value for R.sub.1 is hydrogen or
C.sub.1-3alkyl.
[0075] A specific value for R.sub.3 is hydrogen, C.sub.1-3alkyl,
aryl, halo, haloC.sub.1-3alkyl, C.sub.1-3alkoxy,
haloC.sub.1-3alkoxy or --NR.sub.8R.sub.9.
[0076] A specific value for R.sub.3 is hydrogen, C.sub.1-3alkyl or
aryl.
[0077] Another specific value for R.sub.3 is hydrogen or
C.sub.1-3alkyl.
[0078] A specific value for R.sub.4 is C.sub.1-8alkyl, --OR.sub.8,
--SR.sub.8, --NR.sub.8R.sub.9, aryl or --C.sub.1-8alkylene (aryl),
wherein the aryl groups are optionally substituted with one or more
substituents independently selected from halo, hydroxy, cyano,
nitro, trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.cR.sub.d.
[0079] A specific value for R.sub.4 is C.sub.1-8alkyl, --OR.sub.8,
--SR.sub.8, --NR.sub.8R.sub.9, or aryl, wherein aryl is substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.cR.sub.d- .
[0080] A specific value for R.sub.4 is methyl, ethyl, propyl,
isopropyl, butyl, ethylpropyl, cyclohexyl, phenyl, benzyl, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, (ethylpropyl)oxy,
(cyclohexyl)oxy, phenoxy, (benzyl)oxy, methylthio, ethylthio,
propylthio, isopropylthio, butylthio, (ethylpropyl)thio,
(cyclohexyl)thio, phenylthio or (benzyl)thio or --NR.sub.8R.sub.9,
wherein R.sub.8 is hydrogen, methyl, ethyl, propyl or cyclohexyl
and R.sub.9 is methyl, ethyl, propyl, cyclohexyl or phenyl; or
R.sub.8 and R.sub.9 together with the nitrogen to which they are
attached form a pyrrolidino, piperidino, azepano, piperazino,
morpholino, or thiomorpholino ring.
[0081] A specific value for R.sub.4 is --NR.sub.8R.sub.9, wherein
R.sub.8 is hydrogen, methyl, ethyl, propyl or cyclohexyl and
R.sub.9 is methyl, ethyl, propyl, cyclohexyl or phenyl.
[0082] A specific value for R.sub.4 is --NR.sub.8R.sub.9, wherein
R.sub.8 is hydrogen, methyl or ethyl and R.sub.9 is methyl, ethyl,
propyl, cyclohexyl or phenyl.
[0083] A specific value for R.sub.4 is --NR.sub.8R.sub.9, wherein
R.sub.8 is hydrogen, methyl, ethyl or cyclohexyl and R.sub.9 is
methyl, ethyl, cyclohexyl or phenyl.
[0084] A specific value for R.sub.4 is --NR.sub.8R.sub.9, wherein
R.sub.8 is methyl, ethyl or cyclohexyl and R.sub.9 is methyl, ethyl
or cyclohexyl.
[0085] A specific value for R.sub.4 is pyrrolidino, piperidino,
azepano, piperazino, morpholino, or thiomorpholino.
[0086] A specific value for R.sub.5 is hydrogen, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkyl, or
C.sub.3-8cycloalkenyl, aryl, --C.sub.1-8alkylene(aryl), heteroaryl
or --C.sub.1-8alkylene(heteroaryl).
[0087] A group of compounds of Formula I includes compounds where
at least one of R.sub.1, R.sub.3, R.sub.2, and R.sub.4 is aryl
optionally substituted with one or more substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d.
[0088] A group of compounds of Formula I includes compounds where
at least one of R.sub.1, R.sub.3, R.sub.2, and R.sub.4 is aryl
optionally substituted with one or more substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, --OR.sub.c, --SR.sub.c, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d, and at least two
of R.sub.1, R.sub.3, R.sub.2, and R.sub.4 are other than
hydrogen.
[0089] A specific value for R.sub.5 is hydrogen or
C.sub.1-8alkyl
[0090] A specific value for R.sub.5 is aryl, heteroaryl,
--C.sub.1-8alkylene(aryl) or --C.sub.1-8alkylene(heteroaryl).
[0091] A specific value for R.sub.5 is hydrogen, methyl, ethyl,
benzyl, or phenethyl.
[0092] Another specific value for R.sub.5 is hydrogen.
[0093] A specific value for R.sub.6 is hydrogen.
[0094] A specific compound of formula (I) is a compound wherein m
is 1 and n is 1.
[0095] A specific compound of formula (I) is a compound wherein m
is 0; n is 1; and X is oxy.
[0096] A specific compound of formula (I) is a compound wherein m
is 1; n is 1; and X is oxy.
[0097] A specific compound of formula (I) is a compound wherein m
is 2; n is 1; and X is oxy.
[0098] A specific compound of formula (I) is a compound wherein m
is 0; n is 2; and X is oxy.
[0099] A specific compound of formula (I) is a compound wherein m
is 1; n is 2; and X is oxy.
[0100] A specific compound of formula (I) is a compound wherein m
is 2; n is 2; and X is oxy.
[0101] A specific compound of formula (I) is a compound wherein m
is 0; n is 1; and X is thio.
[0102] A specific compound of formula (I) is a compound wherein m
is 1; n is 1; and X is thio.
[0103] A specific compound of formula (I) is a compound wherein m
is 2; n is 1; and X is thio.
[0104] A specific compound of formula (I) is a compound wherein m
is 0; n is 2; and X is thio.
[0105] A specific compound of formula (I) is a compound wherein m
is 1; n is 2; and X is thio.
[0106] A specific compound of formula (I) is a compound wherein m
is 2; n is 2; and X is thio.
[0107] A specific compound of formula (I) is a compound wherein the
bond represented by - - - is absent, and R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, m, and n have any of the values,
specific values, more specific values, or preferred values
described herein.
[0108] A specific compound of formula (I) is a compound having the
formula (II): 5
[0109] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, m, and n have any of the values, specific values, more
specific values, or preferred values described herein.
[0110] A specific compound of formula (I) is a compound wherein the
bond represented by - - - is present, and R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, m, and n have any of the
values, specific values, more specific values, or preferred values
described herein.
[0111] A specific compound of the present invention is a compound
of formula (III): 6
[0112] wherein:
[0113] R.sub.11 is aryl or heteroaryl;
[0114] R.sub.12 is hydrogen, halo, cyano, C.sub.1-3alkyl,
haloC.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy, or
--NR.sub.aR.sub.b;
[0115] R.sub.13 is hydrogen, C.sub.1-6alkyl, arylC.sub.1-6alkyl, or
aryloxyC.sub.1-6alkyl;
[0116] m is 0, 1, or 2;
[0117] n is 1 or 2;
[0118] X is oxy (--O--) or thio (--S--);
[0119] the bond represented by - - - is absent or present; and
[0120] R.sub.a and R.sub.b are each independently hydrogen,
C.sub.1-6alkyl, aryl, (aryl)C.sub.1-6alkyl, heteroaryl, or
(heteroaryl)C.sub.1-6alkyl; 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;
[0121] wherein any aryl or heteroaryl of R.sub.11, R.sub.12,
R.sub.13, R.sub.a, or R.sub.b 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.1-6alkyl, C.sub.1-6alkoxy, phenyl, --NR.sub.cR.sub.d, or
--C(.dbd.O)NR.sub.cR.sub.d- ;
[0122] wherein each R.sub.c and R.sub.d is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkoxycarbonyl, aryl,
(aryl)C.sub.1-6alkyl, arylcarbonyl, or aryloxycarbonyl; 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;
[0123] or a pharmaceutically acceptable salt thereof.
[0124] A specific compound of formula (III) is a compound wherein
the bond represented by - - - is absent, and R.sub.11, R.sub.12,
R.sub.13, m, and n have any of the values, specific values, more
specific values, or preferred values described herein.
[0125] A specific compound of formula (III) is a compound wherein
the bond represented by - - - is present, and R.sub.11, R.sub.12,
R.sub.13, m, and n have any of the values, specific values, more
specific values, or preferred values described herein.
[0126] A specific value for R.sub.11 is aryl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d- .
[0127] Another specific value for R.sub.11 is phenyl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d.
[0128] Another specific value for R.sub.11 is phenyl, optionally
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, or C.sub.1-6alkoxy.
[0129] Another specific value for R.sub.11 is phenyl, substituted
with one or more substituents independently selected from halo,
hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C.sub.1-6alkyl,
or C.sub.1-6alkoxy.
[0130] Another specific value for R.sub.11 is phenyl, substituted
with one or more substituents independently selected from fluoro,
chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy,
ethoxy, propoxy, or isopropoxy.
[0131] Another specific value for R.sub.11 is heteroaryl,
optionally substituted with one or more substituents independently
selected from halo, hydroxy, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, phenyl,
--NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.cR.sub.d.
[0132] Another specific value for R.sub.11 is heteroaryl,
optionally substituted with one or more substituents independently
selected from halo, hydroxy, cyano, trifluoromethyl,
trifluoromethoxy, C.sub.1-6alkyl, or C.sub.1-6alkoxy.
[0133] Another specific value for R.sub.11 is heteroaryl,
optionally substituted with one or more substituents independently
selected from fluoro, chloro, bromo, hydroxy, trifluoromethyl,
trifluoromethoxy, methoxy, ethoxy, propoxy, or isopropoxy.
[0134] Another specific value for R.sub.11 is heteroaryl,
substituted with one or more substituents independently selected
from halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy,
C.sub.1-6alkyl, or C.sub.1-6alkoxy.
[0135] Another specific value for R.sub.11 is heteroaryl,
substituted with one or more substituents independently selected
from fluoro, chloro, bromo, hydroxy, trifluoromethyl,
trifluoromethoxy, methoxy, ethoxy, propoxy, or isopropoxy.
[0136] A more specific value for R.sub.11 is phenyl, optionally
substituted with one or more substituents independently selected
from fluoro, chloro, bromo, hydroxy, trifluoromethyl,
trifluoromethoxy, methoxy, ethoxy, propoxy, or isopropoxy.
[0137] A specific value for R.sub.12 is hydrogen or
C.sub.1-3alkyl.
[0138] Another specific value for R.sub.12 is halo,
haloC.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy, or
--NR.sub.aR.sub.b.
[0139] A specific value for R.sub.13 is C.sub.1-6alkyl,
arylC.sub.1-6alkyl, or aryloxyC.sub.1-6alkyl.
[0140] Another specific value for R.sub.13 is hydrogen.
[0141] Another specific value for R.sub.13 is C.sub.1-6alkyl.
[0142] Another specific value for R.sub.13 is arylC.sub.1-6alkyl or
aryloxyC.sub.1-6alkyl.
[0143] A more specific value for R.sub.13 is hydrogen, methyl,
ethyl, phenyl, or benzyl.
[0144] 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.
[0145] 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.
[0146] 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).
[0147] 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).
[0148] The invention also provides processes useful for preparing
compounds of formula (I). Accordingly, the invention provides:
[0149] a method for preparing a compound of formula (I) wherein the
bond represented by - - - is absent comprising reducing a
corresponding compound of formula (I) wherein the bond represented
by - - - is present (as illustrated in Scheme 1 below);
[0150] a method for preparing a compound of formula (I) wherein
R.sub.1 is hydrogen, comprising deprotecting a corresponding
compound of formula (I) wherein R.sub.1 is a suitable nitrogen
protecting group (as illustrated in Scheme 2 below); and
[0151] a method for preparing a compound of formula (I) wherein
R.sub.1 is other than hydrogen, comprising alkylating or acylating
a corresponding compound of formula (I) wherein R.sub.1 is hydrogen
with the requisite alkylating or acylating agent.
[0152] Suitable nitrogen 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. Preferred protecting groups include benzyloxycarbonyl
(CBZ), tert-butoxycarbonyl (BOC), and benzoyl.
[0153] The invention also provides novel intermediates disclosed
herein that are useful for preparing compounds of formula (I). For
example, the invention provides an intermediate compound of formula
(I) wherein R.sub.1 is a suitable nitrogen protecting group.
[0154] Compounds of the invention can generally be prepared using
synthetic techniques that are known in the art. They can also be
prepared using the synthetic procedures illustrated in Schemes 1
and 2 below. 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. It is
understood that other compounds of formula (I) can be prepared
using procedures similar to those illustrated in the Schemes by
modifying the starting materials or by performing additional steps
to modify the products.
[0155] Compounds of formula (I) can be prepared by reactions
outlined in Scheme 1. 7
[0156] Bromosalicylaldehyde, I-1, is treated with ethyl
bromoacetate in the presence of a base, such as potassium
carbonate, in an appropriate solvent, such as dimethyl formamide,
at elevated temperature to yield bromoindole-2-carboxylic acid
ethyl ester, I-2. See for example A E Jakobs, L E Christiaens, M J
Renson, Tetrahedron 50(31) 9315-24 (1994). The ethyl ester I-2 is
treated with a reducing agent, such as NaBH.sub.4, in an
appropriate solvent, such as tetrahydrofuran, at room temperature
to yield alcohol I-3. See for example International Patent
Application Publication Number WO 9734885 A1. The alcohol I-3 is
treated with an activating agent, such as methane sulfonyl
chloride, in the presence of a base, such as triethylamine, in an
appropriate solvent, such as methylene chloride at low temperature.
The activated intermediate is treated with appropriate reagents,
such as trimethylsilylcyanide and tetrabutylammonium fluoride, in
an appropriate solvent, such as acetonitrile, at elevated
temperature to yield the nitrile I-4. See for example E D Soli, A S
Manoso, M C Patterson, P DeShong, D A Favor, R Hirschmann, A B
Smith, J. Org. Chem. 64 3171-7 (1999). Nitrile I-4 is converted to
aryl substituted benzofuran nitrile I-5 by means of an appropriate
coupling reaction, such as the Suzuki coupling reaction. See for
example N Miyaura, A Suzuki, Chem. Rev. 95 2457-83 (1995). The
nitrile I-4 is reacted with an appropriately substituted
phenylboronic acid in the presence of an appropriate catalyst, such
as dichlorobis(triphenylphosphine)-palladium (II), and an
appropriate base, such as aqueous sodium carbonate (2N), in an
appropriate solvent, such as benzene, at elevated temperature to
yield aryl substituted benzofuran nitrile I-5. Benzofuran nitrile
I-5 is treated with a reducing agent, such as borane
dimethylsulfide complex, in an appropriate solvent, such as
tetrahydrofuran, at elevated temperature to yield amine I-6. See
for example R Perrone, F Berardi, N A Colabufo, M Leopoldo, V
Tortorella, J. Med. Chem. 43(2) 270-7 (2000). Amine I-6 is treated
with formaldehyde or an equivalent under acidic conditions to yield
the tetrahydrobenzofuropyridine I-7, which is a compound of the
invention. See for example N Sotomayor, et. al., Tetrahedron 51
12159-68 (1995). Tetrahydrobenzofuropyridine I-7 is reduced with a
reducing agent, such as potassium borohydride, in an appropriate
solvent, such as trifluoroacetic acid, to yield
hexahydrobenzofuropyridine I-8, which is also a compound of the
invention. See for example L N Borisova, G S Rozenberg, N F
Kucherova, V A Zagorevskii, Chemistry of Heterocyclic Compounds
17(9) 869-71 (1981).
[0157] Compounds of formula (I) can also be prepared by reactions
outlined in Scheme 2. 8
[0158] O-Phenylhydroxylamine is reacted with 4-piperidone in the
presence of an acid catalyst, such as hydrochloric acid, in an
appropriate solvent, such as 2-propanol, at elevated temperature to
yield tetrahydrobenzofuropyridine II-1. See for example
International Patent Application Publication Number WO 0037466 A1.
Tetrahydrobenzofuropyridine II-1 is treated with a reducing agent,
such as H.sub.2 and an appropriate catalyst, such as Pearlman's
catalyst (20% Pd(OH).sub.2 on carbon), in an appropriate solvent,
such as 1:1:1 acetic acid:ethanol:water at room temperature to
yield hexahydrobenzofuropyridine II-2. See for example P. J.
Coleman, et al., Tetrahedron Lett., 2000, 41, 5803-5806. The amino
nitrogen of compound II-2 is protected with a suitable protecting
group, such as t-butyl carbamate (Boc), by reaction with
di-tert-butyl dicarbonate in the presence of a base, such as
potassium carbonate, in an appropriate solvent, such as a mixture
of water and tetrahydrofuran at room temperature to yield
hexahydrobenzofuran II-3 (R=tert-butoxy). Compound II-3 is
halogenated with a halogenating agent, such as bromine, in an
appropriate solvent, such as chloroform, at room temperature to
yield halogenated hexahydrobenzofuran II-4 (Z=halo). Compound II-4
is converted to an aryl or heteroaryl substituted
hexahydrobenzofuropyridine II-5 (R.sub.1=aryl or heteroaryl) by
means of an appropriate coupling reaction such as the Suzuki
coupling reaction. See for example N Miyaura, A Suzuki, Chem. Rev.
95 2457-83 (1995). Compound II-4 is reacted with an appropriately
substituted phenylboronic acid in the presence of an appropriate
catalyst, such as dichlorobis(triphenylphosphine)palladium (II),
and an appropriate base, such as aqueous sodium carbonate (2N), in
an appropriate solvent, such as benzene, at elevated temperature to
yield compound II-5. Compound II-5 is treated with an acid, such as
trifluoroacetic acid, at room temperature to deprotect the nitrogen
and provide amine II-6, which is a compound of the invention.
[0159] 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
that 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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 of
the invention 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 .mu.M. The procedures used for testing such
displacement are well known and would be readily available to one
skilled in the art. For example, see L. W. Fitzgerald et al., Mol.
Pharmacol, 2000, 57, 1, 75-81; and D. B. Wainscott, et al., J.
Pharmacol Exp Ther, 1996, 276, 2, 720-727.
[0175] The invention will now be illustrated by the following
non-limiting Examples.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0176]
8-(2,4-Dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyrid-
ine; 9
[0177] tert-Butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[-
3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved
in CH.sub.2Cl.sub.2 (7 mL). Trifluoracetic acid (0.81 mL, 20
equiv.) was added, and the reaction mixture was stirred at rt under
N.sub.2 for 2 h. The reaction mixture was cooled to -5.degree. C.
and 2N aqueous NaOH (8 mL) was added. The reaction mixture was
partitioned between CH.sub.2Cl.sub.2 and water. The water layer was
extracted with CH.sub.2Cl.sub.2 (2.times.) and with 25:1
CH.sub.2Cl.sub.2:CH.sub.3OH (2.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to provide the title compound (0.16 g, 98%). MS
(ESI+) for C.sub.17H.sub.15Cl.sub.2NO m/z 320.1 (M+H).sup.+.
[0178] The intermediate tert-Butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrah-
ydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was prepared as
follows.
[0179] a. 1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine
hydrochloride. A mixture of O-phenylhydroxylamine hydrochloride
(0.500 g, 3.43 mmol) and 4-piperidone monohydrate hydrochloride
(0.575 g, 3.74 mmol) in 2-propanol (3.9 mL) was stirred at rt.
Concentrated HCl (2 mL) was added dropwise. The reaction mixture
was refluxed for 3 hours. The reaction mixture was cooled to room
temperature. The precipitate was collected by filtration, washed
with diethylether and air dried, to yield 1,2,3,4-tetrahydro[1]ben-
zofuro[3,2-c]pyridine hydrochloride as a white solid (0.72 g, 100%
yield). MS (ESI+) for C.sub.11H.sub.11NO m/z 174.2 (M+H).sup.+. See
for example International Patent Application Publication Number: WO
00/37466.
[0180] b. 1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine
hydrochloride. 1,2,3,4-Tetrahydro[1]benzofuro[3,2-c]pyridine
hydrochlordide (1.0 g, 4.8 mmol) was dissolved in 1:1:1
CH.sub.3COOH:EtOH:H.sub.2O (75 mL). Pearlman's catalyst (20%
Pd(OH).sub.2 on carbon, 1.718 g) was added and the reaction mixture
was stirred under H.sub.2 (1 atm) at room temperature. After 10
hours, the starting material was consumed. The reaction mixture was
filtered through a short pad of celite, the celite pad was rinsed
with methanol and the filtrate was evaporated under reduced
pressure. The acetic acid was removed by azeotropic distillation
with toluene. After drying,
1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine hydrochloride
(1.02 g) was obtained as a white amorphous solid. MS (ESI+) for
C.sub.11H.sub.13NO m/z 176.1 (M+H).sup.+.
[0181] c. tert-Butyl
3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-
-carboxylate. 1,2,3,4,4a,9b-Hexahydro[1]benzofuro[3,2-c]pyridine
hydrochloride (1.02 g) was dissolved in THF (25 mL) and water (17
mL). K.sub.2CO.sub.3 (3.0 g) was added and the biphasic mixture was
stirred at room temperature under N.sub.2. Di-tert-butyl
dicarbonate (1.04 g) was added in 3 equal portions over 1.5 hours.
After 2 hours, the solvent was removed in vacuo at reduced
pressure. The residue was partitioned between EtOAc and water. The
aqueous layer was extracted with EtOAc (2.times.). The combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered and concentrated. tert-Butyl 3,4,4a,9b-tetrahydro[1]-
benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.82 g, 63% yield) was
obtained after purification by flash chromatography using 15%
EtOAc/Hexane as the eluent. MS (ESI+) for C.sub.16H.sub.21NO.sub.3
m/z 276.1 (M+H).sup.+.
[0182] d. tert-butyl
8-bromo-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridi-
ne-2(1H)-carboxylate. tert-Butyl
3,4,4a,9b-tetrahydro[1]benzofuro-[3,2-c]p-
yridine-2(1H)-carboxylate (0.82 g, 2.98 mmol) was dissolved in
CHCl.sub.3 (20 mL) and cooled to -5.degree. C. Bromine (0.145 mL,
2.83 mmol, 1 equiv.) was dissolved in CHCl.sub.3 (0.8 mL) and added
dropwise to the cold reaction mixture over 4 hours. 5% aqueous
NaHCO.sub.3 (30 mL) was added to the reaction mixture (pH about
12). The reaction mixture was partitioned between CHCl.sub.3 and
water. The aqueous layer was extracted with CHCl.sub.3 (2.times.).
The combined organic layers were dried over MgSO.sub.4, filtered
and concentrated under reduced pressure to afford tert-butyl
8-bromo-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)--
carboxylate (0.6g) in 50% yield. MS (ESI+) for
C.sub.16H.sub.20BrNO.sub.3 m/z 354.0 (M+H).sup.+.
[0183] e. tert-butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]-benzof-
uro[3,2-c]pyridine-2(1H)-carboxylate. tert-Butyl
8-bromo-3,4,4a,9b-tetrahy-
dro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.250 g, 0.706
mmol) was dissolved in benzene (15 mL). 2,4-Dichlorobenzen-boronic
acid (0.270 g, 1.41 mmol) was added.
Bis(triphenylphosphine)-palladiumdichloride (0.035 g, 0.05 mmol)
and 2M aqueous Na.sub.2CO.sub.3 (1.2 mL) were added to the reaction
mixture. Ar was bubbled through the reaction mixture for 20
minutes. The reaction mixture was refluxed under N.sub.2 for 22
hours. The solvent was evaporated at reduced pressure to yield a
dark slurry. The crude material was partitioned between EtOAc and
water. The aqueous layer was extracted with EtOAc (2.times.) and
the combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography (15:1
toluene:EtOAc) and tert-butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro-[3,2-c]pyridine-2-
(1H)-carboxylate (0.221 g) was obtained in 74% yield. MS (ESI+) for
C.sub.22H.sub.23Cl.sub.2NO.sub.3 m/z 420.0 (M+H).sup.+.
[0184] Using synthetic procedures similar to those described
herein, the following compounds of formula (I) can also be
prepared: 10
[0185]
8-(2,4-dichlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridin-6-amine, 2; 11
[0186]
8-(2,4,6-trichlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9b,-hexahydro[1]b-
enzofuro[3,2-c]pyridin-6-amine, 3; 12
[0187]
8-(2,6-difluoro-4-chlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 4; 13
[0188]
8-(2,4-dichlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridin-6-amine, 5; 14
[0189]
8-(2,4,6-trichlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridin-6-amine, 6; 15
[0190]
8-(2,6-difluoro-4-chlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridin-6-amine, 7; 16
[0191]
8-(2,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridin-6-amine, 8; 17
[0192]
8-(2,4,6-trichlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9b,-hexahydro[1]b-
enzofuro[3,2-c]pyridin-6-amine, 9; 18
[0193]
8-(2,6-difluoro-4-chlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 10; 19
[0194]
8-(2,4-dichlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridin-6-amine, 11; 20
[0195]
8-(2,4,6-trichlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridin-6-amine, 12; 21
[0196]
8-(2,6-difluoro-4-chlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridin-6-amine, 13; 22
[0197]
8-(2,4-dichlorophenyl)-N-methyl-N-ethyl-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridin-6-amine, 14; 23
[0198]
8-(2,4-dichlorophenyl)-N-methyl-N-propyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridin-6-amine, 15; 24
[0199]
8-(2,4-dichlorophenyl)-N-methyl-N-cyclohexyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 16; 25
[0200]
8-(2,4-dichlorophenyl)-N-ethyl-N-propyl-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridin-6-amine, 17; 26
[0201]
8-(2,4-dichlorophenyl)-N-ethyl-N-cyclohexyl-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridin-6-amine, 18; 27
[0202]
8-(2,4-dichlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridin-6-amine, 19; 28
[0203]
8-(2,4-dichlorophenyl)-N-propyl-N-cyclohexyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 20; 29
[0204]
8-(2,4-dichlorophenyl)-N,N-dicyclohexyl-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridin-6-amine, 21; 30
[0205]
8-(2,4-dichlorophenyl)-6-methyl-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 22; 31
[0206]
8-(2,4-dichlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-hexahydro[1]benzofuro-
[3,2-c]pyridine, 23; 32
[0207]
8-(2,4-dichlorophenyl)-6-propyl-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 24; 33
[0208]
8-(2,4-dichlorophenyl)-6-isopropyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 25; 34
[0209]
8-(2,4-dichlorophenyl)-6-butyl-1,2,3,4,4a,9b,-hexahydro[1]benzofuro-
[3,2-c]pyridine, 26; 35
[0210]
8-(2,4-dichlorophenyl)-6-(1-ethylpropyl)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 27; 36
[0211]
8-(2,4-dichlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridine, 28; 37
[0212]
8-(2,4-dichlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 29; 38
[0213]
8-(2,4-dichlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 30; 39
[0214]
8-(2,4,6-trichlorophenyl)-6-methyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 31; 40
[0215]
8-(2,4,6-trichlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-hexahydro[1]benzof-
uro[3,2-c]pyridine, 32; 41
[0216]
8-(2,4,6-trichlorophenyl)-6-propyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 33; 42
[0217]
8-(2,4,6-trichlorophenyl)-6-isopropyl-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridine, 34; 43
[0218]
8-(2,4,6-trichlorophenyl)-6-butyl-1,2,3,4,4a,9b,-hexahydro[1]benzof-
uro[3,2-c]pyridine, 35; 44
[0219]
8-(2,4,6-trichlorophenyl)-6-(1-ethylpropyl)-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 36; 45
[0220]
8-(2,4,6-trichlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9b,-hexahydro[1]b-
enzofuro[3,2-c]pyridine, 37; 46
[0221]
8-(2,4,6-trichlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 38; 47
[0222]
8-(2,4,6-trichlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 39; 48
[0223]
8-(2,6-difluoro-4-chlorophenyl)-6-methyl-1,2,3,4,4a,9b,-hexahydro[1-
]-benzofuro[3,2-c]pyridine, 40; 49
[0224]
8-(2,6-difluoro-4-chlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridine, 41; 50
[0225]
8-(2,6-difluoro-4-chlorophenyl)-6-propyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 42; 51
[0226]
8-(2,6-difluoro-4-chlorophenyl)-6-isopropyl-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 43; 52
[0227]
8-(2,6-difluoro-4-chlorophenyl)-6-butyl-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridine, 44; 53
[0228]
8-(2,6-difluoro-4-chlorophenyl)-6-(1-ethylpropyl)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 45; 54
[0229]
8-(2,6-difluoro-4-chlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 46; 55
[0230]
8-(2,6-difluoro-4-chlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 47; 56
[0231]
8-(2,6-difluoro-4-chlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 48; 57
[0232]
8-(2,4-dichlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridine, 49; 58
[0233]
8-(2,4-dichlorophenyl)-6-(ethylthio)-1,2,3,4,4a,9b,-hexahydro[1]ben-
zofuro[3,2-c]pyridine, 50; 59
[0234]
8-(2,4-dichlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridine, 51; 60
[0235]
8-(2,4-dichlorophenyl)-6-(isopropylthio)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 52; 61
[0236]
8-(2,4-dichlorophenyl)-6-(butylthio)-1,2,3,4,4a,9b,-hexahydro[1]ben-
zofuro[3,2-c]pyridine, 53; 62
[0237]
8-(2,4-dichlorophenyl)-6-[(1-ethylpropyl)thio]-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 54; 63
[0238]
8-(2,4-dichlorophenyl)-6-(cyclohexylthio)-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 55; 64
[0239]
8-(2,4-dichlorophenyl)-6-(phenylthio)-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridine, 56; 65
[0240]
8-(2,4-dichlorophenyl)-6-(benzylthio)-1,2,3,4,4a,9b,-hexahydro[1]be-
nzofuro[3,2-c]pyridine, 57; 66
[0241]
8-(2,4,6-trichlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 58; 67
[0242]
8-(2,4,6-trichlorophenyl)-6-(ethylthio)-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridine, 59; 68
[0243]
8-(2,4,6-trichlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 60; 69
[0244]
8-(2,4,6-trichlorophenyl)-6-(isopropylthio)-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 61; 70
[0245]
8-(2,4,6-trichlorophenyl)-6-(butylthio)-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridine, 62; 71
[0246]
8-(2,4,6-trichlorophenyl)-6-[(1-ethylpropyl)thio]-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 63; 72
[0247]
8-(2,4,6-trichlorophenyl)-6-(cyclohexylthio)-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 64; 73
[0248]
8-(2,4,6-trichlorophenyl)-6-(phenylthio)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 65; 74
[0249]
8-(2,4,6-trichlorophenyl)-6-(benzylthio)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 66; 75
[0250]
8-(2,6-difluoro-4-chlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 67; 76
[0251]
8-(2,6-difluoro-4-chlorophenyl)-6-(ethylthio)-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 68; 77
[0252]
8-(2,6-difluoro-4-chlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 69; 78
[0253]
8-(2,6-difluoro-4-chlorophenyl)-6-(isopropylthio)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 70; 79
[0254]
8-(2,6-difluoro-4-chlorophenyl)-6-(butylthio)-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 71; 80
[0255]
8-(2,6-difluoro-4-chlorophenyl)-6-[(1-ethylpropyl)thio]-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 72; 81
[0256]
8-(2,6-difluoro-4-chlorophenyl)-6-(cyclohexylthio)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 73; 82
[0257]
8-(2,6-difluoro-4-chlorophenyl)-6-(phenylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 74; 83
[0258]
8-(2,6-difluoro-4-chlorophenyl)-6-(benzylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 75; 84
[0259]
8-(2,4-dichlorophenyl)-6-methoxy-1,2,3,4,4a,9b,-hexahydro[1]benzofu-
ro[3,2-c]pyridine, 76; 85
[0260]
8-(2,4-dichlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 77; 86
[0261]
8-(2,4-dichlorophenyl)-6-propoxy-1,2,3,4,4a,9b,-hexahydro[1]benzofu-
ro[3,2-c]pyridine, 78; 87
[0262]
8-(2,4-dichlorophenyl)-6-isopropoxy-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridine, 79; 88
[0263]
8-(2,4-dichlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-hexahydro[1]benzofur-
o[3,2-c]pyridine, 80; 89
[0264]
8-(2,4-dichlorophenyl)-6-[(1-ethylpropyl)oxy]-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 81; 90
[0265]
8-(2,4-dichlorophenyl)-6-(cyclohexyloxy)-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 82; 91
[0266]
8-(2,4-dichlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,-hexahydro[1]benzofu-
ro[3,2-c]pyridine, 83; 92
[0267]
8-(2,4-dichlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,9b,-hexahydro[1]ben-
zofuro[3,2-c]pyridine, 84; 93
[0268]
8-(2,4,6-trichlorophenyl)-6-methoxy-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridine, 85; 94
[0269]
8-(2,4,6-trichlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 86; 95
[0270]
8-(2,4,6-trichlorophenyl)-6-propoxy-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridine, 87; 96
[0271]
8-(2,4,6-trichlorophenyl)-6-isopropoxy-1,2,3,4,4a,9b,-hexahydro[1]b-
enzofuro[3,2-c]pyridine, 88; 97
[0272]
8-(2,4,6-trichlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-hexahydro[1]benzo-
furo[3,2-c]pyridine, 89; 98
[0273]
8-(2,4,6-trichlorophenyl)-6-[(1-ethylpropyl)oxy]-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 90; 99
[0274]
8-(2,4,6-trichlorophenyl)-6-(cyclohexyloxy)-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 91; 100
[0275]
8-(2,4,6-trichlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,-hexahydro[1]benz-
ofuro[3,2-c]pyridine, 92; 101
[0276]
8-(2,4,6-trichlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,9b,-hexahydro[1]-
benzofuro[3,2-c]pyridine, 93; 102
[0277]
8-(2,6-difluoro-4-chlorophenyl)-6-methoxy-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 94; 103
[0278]
8-(2,6-difluoro-4-chlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 95; 104
[0279]
8-(2,6-difluoro-4-chlorophenyl)-6-propoxy-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 96; 105
[0280]
8-(2,6-difluoro-4-chlorophenyl)-6-(2-propoxy)-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 97; 106
[0281]
8-(2,6-difluoro-4-chlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 98; 107
[0282]
8-(2,6-difluoro-4-chlorophenyl)-6-[(1-ethylpropyl)oxy]-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridine, 99; 108
[0283]
8-(2,6-difluoro-4-chlorophenyl)-6-(cyclohexyloxy)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 100; 109
[0284]
8-(2,6-difluoro-4-chlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 101; 110
[0285]
8-(2,6-difluoro-4-chlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 102; 111
[0286]
8-(2,4-dichlorophenyl)-6-piperidin-1-yl-1,2,3,4,4a,9b-hexahydro[1]b-
enzofuro[3,2-c]pyridine 112
[0287]
8-(2,4,6-trichlorophenyl)-6-piperidin-1-yl-1,2,3,4,4a,9b-hexahydro[
[0288] 1]benzofuro[3,2-c]pyridine 113
[0289]
8-(2,6-difluoro-4-chlorophenyl)-6-piperidin-1-yl-1,2,3,4,4a,9b-hexa-
hydro[1]benzofuro[3,2-c]pyridine 114
[0290]
8-(2,4-dichlorophenyl)-6-azepano-1-yl-1,2,3,4,4a,9b-hexahydro[1]ben-
zofuro[3,2-c]pyridine 115
[0291]
8-(2,4,6-trichlorophenyl)-6-azepano-1-yl-1,2,3,4,4a,9b-hexahydro[1]-
benzofuro[3,2-c]pyridine 116
[0292]
8-(2,6-difluoro-4-chlorophenyl)-6-azepano-1-yl-1,2,3,4,4a,9b-hexahy-
dro[1]benzofuro[3,2-c]pyridine 117
[0293]
8-(2,4-dichlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-hexahydro[1]-
benzofuro[3,2-c]pyridine 118
[0294]
8-(2,4,6-trichlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-hexahydro-
[1]benzofuro[3,2-c]pyridine 119
[0295]
8-(2,6-difluoro-4-chlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-hex-
ahydro[1]benzofuro[3,2-c]pyridine 120
[0296]
8-(2,4-dichlorophenyl)-5-morpholin-4-yl-1,2,3,4,4a,9b-hexahydro[1]b-
enzofuro[3,2-c]pyridine 121
[0297]
8-(2,4,6-trichlorophenyl)-5-morpholin-4-yl-1,2,3,4,4a,9b-hexahydro[-
1]benzofuro[3,2-c]pyridine 122
[0298]
8-(2,6-difluoro-4-chlorophenyl)-5-morpholin-4-yl-1,2,3,4,4a,9b-hexa-
hydro[1]benzofuro[3,2-c]pyridine 123
[0299]
8-(2,4-dichlorophenyl)-6-thiomorpholin-4-yl-1,2,3,4,4a,9b-hexahydro-
[1]benzofuro[3,2-c]pyridine 124
[0300]
8-(2,4,6-trichlorophenyl)-6-thiomorpholin-4-yl-1,2,3,4,4a,9b-hexahy-
dro[1]benzofuro[3,2-c]pyridine 125
[0301]
8-(2,6-difluoro-4-chlorophenyl)-6-thiomorpholin-4-yl-1,2,3,4,4a,9b--
hexahydro[1]benzofuro[3,2-c]pyridine 126
[0302]
8-(2,4-dichlorophenyl)-6-piperazin-1-yl-1,2,3,4,4a,9b-hexahydro[1]b-
enzofuro[3,2-c]pyridine 127
[0303]
8-(2,4,6-trichlorophenyl)-6-piperazin-1-yl-1,2,3,4,4a,9b-hexahydro[-
1]benzofuro[3,2-c]pyridine; 128
[0304]
8-(2,6-difluoro-4-chlorophenyl)-6-piperazin-1-yl-1,2,3,4,4a,9b-hexa-
hydro[1]benzofuro[3,2-c]pyridine; 129
[0305]
8-(2,4,6-trichlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9b,-hexahydro[1]b-
enzofuro[3,2-c]pyridin-6-amine, 241; and 130
[0306]
8-(2,6-difluoro-4-chlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 242.
[0307]
8-(2,4-Dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]py-
ridine, 245; 131
[0308] tert-Butyl
3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]-2-(1H)-carboxyla- te (0.82
g, 2.98 mmol) was dissolved in CHCl.sub.3 (20 mL) and cooled to
-5.degree. C. Bromine (0.145 mL, 2.83 mmol, 1 equiv.) was dissolved
in CHCl.sub.3 (0.8 mL) and added dropwise to the cold reaction
mixture over 4 h. 5% aqueous NaHCO.sub.3 (30 mL) was added to the
reaction mixture (pH.about.12). The reaction mixture was
partitioned between CHCl.sub.3 and water. The aqueous layer was
extracted with CHCl.sub.3 (2.times.). The combined organic layers
were dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The crude product was treated with di-tert-butyl
dicarbonate and K.sub.2CO.sub.3 in 3:2 THF:H.sub.2O and worked up
as described above. The crude product was recrystallized from
hexane to afford tert-butyl
8-bromo-3,4,4a,9b-tetrahydro[1]benzofuro[3,2--
c]pyridine-2(1H)-carboxylate (0.6 g) in 50% yield. MS (ESI+) for
C.sub.16H.sub.20BrNO.sub.3 m/z 354.0 (M+H).sup.+.
[0309] tert-Butyl
8-bromo-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine--
2(1H)-carboxylate (0.250 g, 0.706 mmol) was dissolved in benzene
(15 mL). 2,4-Dichlorobenzenboronic acid (0.270 g, 1.41 mmol) was
added. Bis(triphenylphosphine)palladiumdichloride (0.035 g, 0.05
mmol) and 2M aqueous Na.sub.2CO.sub.3 (1.2 mL) were added to the
reaction mixture. Ar was bubbled through the reaction mixture for
20 min. The reaction mixture was refluxed under N.sub.2 for 22 h.
The solvent was evaporated at reduced pressure to yield a dark
slurry. The crude material was partitioned between EtOAc and water.
The aqueous layer was extracted with EtOAc (2.times.) and the
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude product was chromatographed (15:1 toluene:EtOAc) and
tert-butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]-
pyridine-2(1H)-carboxylate (0.221 g) was obtained in 74% yield. MS
(ESI+) for C.sub.22H.sub.23Cl.sub.2NO.sub.3 m/z 420.0
(M+H).sup.+.
[0310] tert-Butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[-
3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved
in CH.sub.2Cl.sub.2 (7 mL). Trifluoracetic acid (0.81 mL, 20
equiv.) was added, and the reaction mixture was stirred at rt under
N.sub.2 for 2 h. The reaction mixture was cooled to -5.degree. C.
and 2N aqueous NaOH (8 mL) was added. The reaction mixture was
partitioned between CH.sub.2Cl.sub.2 and water. The water layer was
extracted with CH.sub.2Cl.sub.2 (2.times.) and with 25:1
CH.sub.2Cl.sub.2:CH.sub.3OH (2.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. Example 245 (0.16 g) was obtained in 98% yield.
MS (ESI+) for C.sub.17H.sub.15Cl.sub.2NO m/z 320.1 (M+H).sup.+.
[0311] 1,2,3,4,4a,9b-Hexahydro[1]benzofuro[3,2-c]pyridine, 246;
132
[0312] 1,2,3,4-Tetrahydro[1]benzofuro[3,2-c]pyridine hydrochlordide
(1.0 g, 4.8 mmol) was dissolved in 1:1:1 CH.sub.3COOH:EtOH:H.sub.2O
(75 mL). Pearlman's catalyst (20% Pd(OH).sub.2 on carbon, 1.718 g)
was added and the reaction mixture was stirred under H.sub.2 (1
atm) at rt. After 10 h, the starting material was consumed. The
reaction mixture was filtered through a short pad of celite. The
celite pad was rinsed with methanol and the filtrate was evaporated
under reduced pressure. The acetic acid was removed azeotropically
with toluene at reduced pressure. After drying,
1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine hydrochloride
(1.02 g) was obtained as a white amorphous solid. MS (ESI+) for
C.sub.11H.sub.13NO m/z 176.1 (M+H).sup.+.
[0313] 1,2,3,4,4a,9b-Hexahydro[1]benzofuro[3,2-c]pyridine
hydrochloride (1.02 g) was dissolved in THF (25 mL) and water (17
mL). K.sub.2CO.sub.3 (3.0 g) was added and the biphasic mixture was
stirred at rt under nitrogen. Di-tert-butyl dicarbonate (1.04 g)
was added in 3 equal portions over 1.5 h. After 2 h, the solvent
was removed in vacuo. The residue was partitioned between EtOAc and
water. The aqueous layer was extracted with EtOAc (2.times.). The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered and concentrated. tert-Butyl
3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]-2-(1H)-carboxylate (0.82 g,
63% yield) was obtained after purification by chromatography using
15% EtOAc:Hexane as the eluent. MS (ESI+) for
C.sub.16H.sub.21NO.sub.3 m/z 276.1 (M+H).sup.+.
[0314] Obtained Example 246 in 40% yield for the removal of the
protecting group according to the procedure used to prepare Example
245 making non-critical changes. MS (ESI+) for C.sub.11H.sub.13NO
m/z 176.2 (M+H).sup.+.
[0315]
8-[2-(Trifluoromethyl)phenyl]-1,2,3,4,4a,9b-hexahydro[1]benzofuro[3-
,2-c]pyridine, 247; 133
[0316] Obtained tert-butyl
8-(2-trifluoromethylphenyl)-3,4,4a,9b-tetrahydr-
o[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate in 68% and Example
247 in 98% yield according to the procedure used to prepare Example
245 making non-critical changes. MS (ESI+) for C.sub.18H.sub.16NO
m/z 320.1 (M+H).sup.+.
[0317]
8-[2-(Trifluoromethoxy)phenyl]-1,2,3,4,4a,9b-hexahydro[1]benzofuro[-
3,2-c]pyridine, 248; 134
[0318] Obtained tert-butyl
8-[2-(trifluoromethoxy)phenyl]-3,4,4a,9b-tetrah-
ydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate in 74% yield (MS
(ESI+) for C.sub.23H.sub.24O.sub.4NF.sub.3 m/z 435.9 (M+H).sup.+)
and Example 248 in 100% yield according to the procedure used to
prepare Example 245 making non-critical changes. MS (ESI+) for
C.sub.18H.sub.16NO.sub.2F.sub.- 3 m/z 336.1 (M+H).sup.+.
[0319]
6-Bromo-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro[-
3,2-c]pyridine, 249; 135
[0320] Example 249 as a racemic mixture was prepared according to
the procedure used to prepare Example 245. Example 249 was obtained
in 92% yield from tert-butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-
[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (racemic) which was
obtained in 82% yield from tert-butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[-
1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (MS (ESI+) for
C.sub.22H.sub.22BrCl.sub.2NO.sub.3 m/z 499.8 (M+H).sup.+). HRMS
(FAB) for Example 249, calcd for
C.sub.17H.sub.14BrCl.sub.2NO+H.sub.1 397.9714, found 397.9705.
[0321] (4aS, 9bR)
6-Bromo-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1-
]benzofuro[3,2-c]pyridine & (4aR, 9bS)
6-Bromo-8-(2,4-dichlorophenyl)-1,2,-
3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine:
[0322] tert-Butyl
8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[-
3,2-c]pyridine-2(1H)-carboxylate (5.360 g, 12.750 mmol) was
dissolved in 160 mL CH.sub.3COOH. N-Bromosuccinimide (4.539 g,
25.500 mmol) was added. The reaction mixture was stirred under
N.sub.2 at rt for 27 h. The reaction mixture was poured into a
mixture of 300 g ice and 100 mL water. The aqueous mixture was
extracted with EtOAc (3.times.). The combined organic layers were
washed with 5M NaOH (2.times.250 mL), 25% KOH (2.times.200 mL) and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The crude product was chromatographed (SiO.sub.2,
15% EtOAc:hexane), and tert-butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyr-
idine-2(1H)-carboxylate was obtained in 82% yield (5.250 g, 10.516
mmol). MS (ESI+) for C.sub.22H.sub.22BrCl.sub.2NO.sub.3 m/z 499.8
(M+H).sup.+.
[0323] The enantiomers of tert-butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a-
,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (253
mg) were separated using a 5.times.50 cm Chiralpak AD column
eluting with 1:1 i-PrOH:heptane at a flowrate of 70 mL/min. with UV
detection at 265 nm. The sample was dissolved in 15 mL of 3:1
i-PrOH:CHCl.sub.3 for injection into the HPLC. Each pure enantiomer
of tert-butyl 6-bromo-8-(2,4-dichloro-
phenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate
was separately converted to the respective pure enantiomer of
6-bromo-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]-
pyridine according to the procedure used to prepare
8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine-
. The faster-eluting intermediate provided Example 249(a) and the
slower-eluting enantiomer provided Example 249(b). MS for Example
249(a), (ESI+) for C.sub.17H.sub.14BrCl.sub.2NO m/z 399.8
(M+H).sup.+. MS for Example 249(b), (ESI+) for
C.sub.17H.sub.14BrCl.sub.2NO m/z 399.8 (M+H).sup.+.
[0324]
6-Benzyl-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro-
[3,2-c]pyridine, 250; 136
[0325] B-Benzyl-9-BBN (1.3 mL 0.5 M sol in THF, 0.650 mmol) was
added to degassed DMF (3 mL), followed by sequential addition of
tert-butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyr-
idine-2(1H)-carboxylate (0.255 g, 0.511 mmol), catalyst
Cl.sub.2PdDPPF (0.018 g, 0.022 mmol) and K.sub.2CO.sub.3 (0.220 g,
1.592 mmol). The reaction mixture was stirred under N.sub.2 at
65.degree. C. for 6 h. The reaction mixture was poured into water
and extracted with EtOAc (2.times.). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude was purified by
chromatography (14% EtOAc/Hexane) and tert-butyl
6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofu-
ro[3,2-c]pyridine-2(1H)-carboxylate was obtained in 77% yield
(0.200 g, 0.392 mmol). MS (ESI+) for
C.sub.29H.sub.29Cl.sub.2NO.sub.3 m/z 510.1 (M+H).sup.+.
[0326] tert-Butyl
6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]b-
enzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.137 g, 0.270 mmol) was
dissolved in CH.sub.2Cl.sub.2 (5 mL). Trifluoracetic acid (0.44 mL,
5.670 mmol) was added and the reaction mixture was stirred at rt
under N.sub.2 for 4 h. The reaction mixture was cooled to 0.degree.
C. and 25% aqueous NaOH (15 mL) was added. The reaction mixture was
partitioned between CH.sub.2Cl.sub.2 and water. The water layer was
extracted with CH.sub.2Cl.sub.2 (2.times.). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude was purified by chromatography
(1% NH.sub.4OH, 5.95% CH.sub.3OH, 93.05% CH.sub.2Cl.sub.2), and
Example 250 was obtained in 86% yield. MS (ESI+) for
C.sub.24H.sub.21Cl.sub.2NO m/z 410.0 (M+H).sup.+.
[0327]
6-Butyl-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro[-
3,2-c]pyridine, 251; 137
[0328] Obtained tert-butyl
6-butyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrah-
ydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate in 63% yield
based on recovered starting material (MS (ESI+) for
C.sub.26H.sub.31Cl.sub.2NO.sub- .3 m/z 475.9 (M+H).sup.+) and
Example 251 in 93% yield according to the procedure used to prepare
Example 250 making non-critical changes. HRMS (FAB) calcd for
C.sub.21H.sub.23Cl.sub.2NO+H.sub.1 376.1235, found 376.1243.
[0329]
8-(2,4-Dichlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b-hexahydro[1]ben-
zofuro[3,2-c]pyridine, 252; 138
[0330] tert-Butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]be-
nzofuro[3,2-c]pyridine-(1H)-carboxylate (3.30 g, 6.62 mmol, 1
equiv.), potassium triisopropylsilanethiolate (1.51 g, 6.62 mmol, 1
equiv.) and tetrakis(triphenylphosphine)palladium (0.772 g, 0.668
mmol, 0.1 equiv.) were combined in a dry flask under N.sub.2.
Benzene (66 mL) and THF (26 mL) were added to the flask and Ar was
bubbled through the reaction mixture for 15 min. The reaction
mixture was heated to 80.degree. C. for 26.5 hr. under N.sub.2.
Upon cooling, the reaction mixture was partitioned between 4:1
toluene:EtOAc (100 mL) and H.sub.2O (100 mL). The layers were
separated and the aqueous layer was extracted with 4:1
toluene:EtOAc (100 mL). The combined organic layers were dried over
MgSO.sub.4, filtered and concentrated. The crude product (6.27 g)
was chromatographed (SiO.sub.2 250 g, eluted with 2:1
heptane:Et.sub.2O followed by 1:1 heptane:Et.sub.2O) to yield
tert-Butyl
8-(2,4-dichlorophenyl)-6-[(triisopropylsilyl)thio]-3,4,4a,9b-tetrahydro[1-
]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (2.49 g) in 62% yield.
MS (ESI+) for C.sub.26H.sub.35Cl.sub.2NOSSi m/z 508.1
(M+H).sup.+.
[0331] tert-Butyl
8-(2,4-dichlorophenyl)-6-[(triisopropylsilyl)thio]-3,4,4-
a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.111
g, 0.182 mmol) was dissolved in DMF (3 mL). 1-Iodopropane (0.2 mL)
and cesium fluoride (0.060 g) were added to the reaction mixture.
The reaction mixture was stirred at rt under N.sub.2 for 2.5 h. The
reaction mixture was partitioned between EtOAc (30 mL) and 2:3
water:brine (25 mL). The aqueous layer was back extracted with
EtOAc (30 mL). The combined organic layers were washed with water
(20 mL), with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. tert-Butyl
8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetr-
ahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in
quantitative yield (0.090 g). MS (ESI+) for
C.sub.25H.sub.29Cl.sub.2NO.su- b.3S m/z 517.0 (M+23).sup.+.
[0332] tert-Butyl
8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetrahyd-
ro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.090 g, 0.182
mmol) was dissolved in CH.sub.2Cl.sub.2 (5 mL). Trifluoracetic acid
(0.3 mL, 0.182 mmol) was added and the reaction mixture was stirred
at rt under N.sub.2 for 2.5 h when all the starting material was
consumed. The reaction mixture was cooled to 0.degree. C. and 5M
NaOH (10 mL) was added. The reaction mixture was partitioned
between CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted
with CH.sub.2Cl.sub.2 (2.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The crude was purified by chromatography (first
eluting with 3:1 Hexane:EtOAc, and then eluting with 2:6:92 conc.
NH.sub.4OH:CH.sub.3OH:CH.sub.2Cl.sub.2 to elute the product).
Example 252 (0.070 g) was obtained in 97% yield. HRMS (FAB) calcd
for C.sub.20H.sub.21CL.sub.2NOS+H.sub.1 394.0799, found
394.0797.
[0333]
8-(2,4-Dichlorophenyl)-6-(isopropylthio)-1,2,3,4,4a,9b-hexahydro[1]-
benzofuro[3,2-c]pyridine, 253; 139
[0334] Example 253 is obtained using the procedures to obtain
Example 252, making non-critical changes. tert-Butyl
8-(2,4-dichlorophenyl)-6-(isoprop-
ylthio)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate
was obtained 90% yield from tert-Butyl
8-(2,4-dichlorophenyl)-6-[(triisop-
ropylsilyl)thio]-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-car-
boxylate using 2-iodopropane as the alkylating agent. MS (ESI+) for
C.sub.25H.sub.29Cl.sub.2NO.sub.3S m/z 493.9 (M+H).sup.+. Example
253 is obtained in 91% yield. HRMS (FAB) calcd for
C.sub.20H.sub.21Cl.sub.2NOS+H- .sub.1 394.0799, found 394.0797.
[0335]
8-(2,4-Dichlorophenyl)-6-(isobutylthio)-1,2,3,4,4a,9b-hexahydro[1]b-
enzofuro[3,2-c]pyridine, 254; 140
[0336] tert-Butyl
8-(2,4-dichlorophenyl)-6-(isopropylthio)-3,4,4a,9b-tetra-
hydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate is obtained in
93% yield (MS (ESI+) for C.sub.26H.sub.31Cl.sub.2NO.sub.3S m/z
529.8 (M+Na).sup.+) and Example 254 is obtained in 75% yield
according to the procedures used to prepare Example 252, making
non-critical changes. HRMS (FAB) calcd for
C.sub.21H.sub.23Cl.sub.2NOS+H.sub.1 408.0956, found 408.0959.
[0337]
8-(2,4-Dichlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b-hexahydro[1]ben-
zofuro[3,2-c]pyridine, 255; 141
[0338] tert-Butyl
8-(2,4-dichlorophenyl)-6-(methylthio)-3,4,4a,9b-tetrahyd-
ro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate is obtained 61%
yield (MS (ESI+) for C.sub.23H.sub.25Cl.sub.2NO.sub.3S m/z 465.8
(M+H).sup.+) and Example 255 is obtained in 99% yield according to
the procedures used to prepare Example 252, making non-critical
changes. HRMS (FAB) calcd for C.sub.18H.sub.17Cl.sub.2NOS+H.sub.1
366.0486, found 366.0483.
[0339]
6-(Cyclopentylthio)-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[-
1]benzofuro[3,2-c]pyridine, 256; 142
[0340] tert-Butyl
6-(cyclopentylthio)-8-(2,4-dichlorophenyl)-3,4,4a,9b-tet-
rahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate is obtained in
92% yield (MS (ESI+) 464.1
(C.sub.27H.sub.31Cl.sub.2NO.sub.3S+H-C.sub.4H.sub.- 8, rel.
intensity 16%), 446.1 (16), 420.1 (44), 396.1 (100), 378.1 (78),
352.1 (44)) and Example 256 is obtained according to Example 252,
making non-critical changes. MS (ESI+) 420.2; HRMS (FAB) calcd for
C.sub.22H.sub.23CL.sub.2NOS+H.sub.1 420.0956, found 420.0953.
[0341]
6-(Cyclobutylthio)-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1-
]benzofuro[3,2-c]pyridine, 257; 143
[0342] tert-Butyl
6-(cyclobutylthio)-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetr-
ahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate is obtained in
42% yield (MS (ESI+) 450.1
(C.sub.26H.sub.29Cl.sub.2NO.sub.3S+H-C.sub.4H.sub.- 8, rel.
intensity 100%), 432 (55), 406.1 (70), 396 (49), 378.1 (31), 352
(16)) and Example 257 is obtained according to Example 252. OAMS
supporting ions at: ESI+ 406.2; HRMS (FAB) calcd for
C.sub.21H.sub.21CL.sub.2NOS+H.sub.1 406.0799, found 406.0797.
[0343]
8-(2,4-Dichlorophenyl)-6-morpholin-4-yl-1,2,3,4,4a,9b-hexahydro[1]b-
enzofuro[3,2-c]pyridine, 258; 144
[0344] A 7 mL vial with a Teflon lined cap was charged with
Pd(OAc).sub.2 (3.4 mg, 0.015 mmol), 2-(di-t-butylphosphino)biphenyl
(17.9 mg, 0.06 mmol), and NaOtBu (67.2 mg (0.7 mmol) under an argon
blanket. A solution of the bromide (250 mg, 0.5 mmol) in toluene (1
mL) was added followed by the morpholine (0.052 mL, 0.6 mmol). The
reaction was placed on an orbital shaker and heated to 50.degree.
C. for 18 hours. The reaction was cooled to RT and diluted with
ethyl ether (25 mL), filtered through a pad of celite and
concentrated to give 308 mg of a crude orange oil. The crude was
purified on silica gel using 25% EtOAc in heptane as the eluent to
give 181 mg (72%) of tert-butyl
8-(2,4-dichlorophenyl)-6-morpholin-4-y-
l-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate
as a pale yellow oil. OAMS supporting ions at: ESI+ 504.9.
[0345] The carboxylate was diluted in a solution of
CH.sub.2Cl.sub.2 (5 mL) cooled to 0.degree. C. TFA (5 mL) was added
to the cooled solution and the ice bath was removed. The reaction
turned from pale yellow to pale green within 10 minutes. After
stirring at ambient temperature for 1.5 hours, the reaction was
concentrated in vacuo, partioned between 5N NaOH and EtOAc (2
times). The organics were combined, dried with MgSO.sub.4, filtered
and concentrated to 160 mg of a crude clear oil. The crude was
purified on silica gel using 5% methanol in CH.sub.2Cl.sub.2 as the
eluent to give 124 mg (87%) of
8-(2,4-dichlorophenyl)-6-morpholin-4-y-
l-1,2,3,4,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine as a yellow
oil. OAMS supporting ions at: ESI+ 404.8. HRMS (FAB) calcd for
C.sub.21H.sub.22CL.sub.2N.sub.2O.sub.2+H.sub.1 405.1136, found
405.1122.
[0346]
N-Benzyl-8-(2,4-dichlorophenyl)-1,2,3,4,4a,9b-hexahydro[1]benzofuro-
[3,2-c]pyridin-6-amine, 259; 145
[0347] Following the general procedure of Example 258, making
non-critical variations (substituting morpholine with benzylamine),
gave 230 mg of a crude solid. This material was purified by eluting
with 5% methanol in CH.sub.2Cl.sub.2 to afford 90 mg (40%) of
Example 259 as a yellow oil. HRMS (FAB) calcd for
C.sub.24H.sub.22CL.sub.2N.sub.2O+H.sub.1 425.1187, found
425.1199.
[0348]
8-(2,4-Dichlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-hexahydro[1]-
benzofuro[3,2-c]pyridine, 260; 146
[0349] Prepared using the general procedure for Example 258, making
non-critical variations (substituting morpholine with pyrrolidine)
to give 85 mg off white foam (44%).
[0350]
8-(2,4-Dichlorophenyl)-6-methoxy-1,2,3,4,4a,9b-hexahydro[1]benzofur-
o[3,2-c]pyridine, 261; 147
[0351] In a 7 mL vial, copper (I) bromide (0.15 mmol, 22 mg) was
diluted with 0.1 mL EtOAc and 0.6 mL of sodium methoxide in
methanol (25 wt%). tert-Butyl
6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofur-
o[3,2-c]pyridine-2(1H)-carboxylate (0.5 mmol, 250 mg) was added to
the thick slurry and heated to 85.degree. C. on the orbit shaker.
An additional 0.1 mL of EtOAc was added. After 4.5 hr, the solvent
was removed in vacuo. The resulting material was diluted with water
and extracted three times with EtOAc. The combined organics were
washed with brine, dried over NaSO.sub.4, decanted and concentrated
to give crude yellow-brown oil. This material was diluted with 4 mL
CH.sub.2Cl.sub.2 and cooled to 0.degree. C. with an ice bath. After
15 min, 4 ml trifluoroacetic acid was added and the reaction was
stirred at rt. After 2 hr the solvent was removed in vacuo to give
crude oil-after a NaOH workup. The crude material was purified by
column chromatography (0.5/3.5/96
NH.sub.4OH/CH.sub.3OH/CH.sub.2Cl.sub.2) to give 105 mg colorless
oil (60%).
[0352] Using synthetic procedures similar to those described
herein, the following compounds of formula (II) can also be
prepared: 148
[0353]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridin-6-amine, 121; 149
[0354]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]pyridin-6-amine, 122; 150
[0355]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-N-cyclohexyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridin-6-amine, 123; 151
[0356]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridin-6-amine, 124; 152
[0357]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 125; 153
[0358]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-N-phenyl-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridin-6-amine, 126; 154
[0359]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridin-6-amine, 127; 155
[0360]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]pyridin-6-amine, 128; 156
[0361]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-N,N-dimethyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridin-6-amine, 129; 157
[0362]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridin-6-amine, 130; 158
[0363]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b,-hexa-
hydro[1]benzofuro[3,2-c]-pyridin-6-amine, 131; 159
[0364]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-N,N-diethyl-1,2,3,4,4a,9b-
,-hexahydro[1]benzofuro[3,2-c]-pyridin-6-amine, 132; 160
[0365]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-methyl-N-ethyl-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridin-6-amine, 133; 161
[0366]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-methyl-N-propyl-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridin-6-amine, 134; 162
[0367]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-methyl-N-cyclohexyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridin-6-amine, 135; 163
[0368]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-ethyl-N-propyl-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridin-6-amine, 136; 164
[0369]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-ethyl-N-cyclohexyl-1,2,3,4,4a,9b-
,-hexahydro[1]benzofuro[3,2-c]pyridin-6-amine, 137; 165
[0370]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridin-6-amine, 138; 166
[0371]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N-propyl-N-cyclohexyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridin-6-amine, 139; 167
[0372]
(4aS,9bR)-8-(2,4-dichlorophenyl)-N,N-dicyclohexyl-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridin-6-amine, 140; 168
[0373]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-methyl-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 141; 169
[0374]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 142; 170
[0375]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-propyl-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 143; 171
[0376]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(isopropyl)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 144; 172
[0377]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-butyl-1,2,3,4,4a,9b,-hexahydro[1-
]benzofuro[3,2-c]pyridine, 145; 173
[0378]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(1-ethylpropyl)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 146; 174
[0379]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 147; 175
[0380]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 148; 176
[0381]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 149; 177
[0382]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-methyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 150; 178
[0383]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 151; 179
[0384]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-propyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 152; 180
[0385]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(isopropyl)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 153; 181
[0386]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-butyl-1,2,3,4,4a,9b,-hexahydr-
o[1]benzofuro[3,2-c]pyridine, 154; 182
[0387]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(1-ethylpropyl)-1,2,3,4,4a,9b-
,-hexahydro[1]benzofuro[3,2-c]pyridine, 155; 183
[0388]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 156; 184
[0389]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 157; 185
[0390]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 159; 186
[0391]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-methyl-1,2,3,4,4a,9b,-h-
exahydro[1]-benzofuro[3,2-c]pyridine, 160; 187
[0392]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-ethyl-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 161; 188
[0393]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-propyl-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 162; 189
[0394]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(isopropyl)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 163; 190
[0395]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-butyl-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 164; 191
[0396]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(1-ethylpropyl)-1,2,3,4-
,4a,9b,-hexahydro[1]benzofuro[3,2-c]-pyridine, 165; 192
[0397]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-cyclohexyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridine, 166; 193
[0398]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-phenyl-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 167; 194
[0399]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-benzyl-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 168; 195
[0400]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b,-hexa-
hydro[1]benzofuro[3,2-c]pyridine, 169; 196
[0401]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(ethylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 170; 197
[0402]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b,-hexa-
hydro[1]benzofuro[3,2-c]pyridine, 171; 198
[0403]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(2-propylthio)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 172; 199
[0404]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(butylthio)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 173; 200
[0405]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-[(1-ethylpropyl)thio]-1,2,3,4,4a-
,9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 174; 201
[0406]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(cyclohexylthio)-1,2,3,4,4a,9b,--
hexahydro[1]benzofuro[3,2-c]pyridine, 175; 202
[0407]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(phenylthio)-1,2,3,4,4a,9b,-hexa-
hydro[1]benzofuro[3,2-c]pyridine, 176; 203
[0408]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(benzylthio)-1,2,3,4,4a,9b,-hexa-
hydro[1]benzofuro[3,2-c]pyridine, 177; 204
[0409]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(methylthio)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 178; 205
[0410]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(ethylthio)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 179; 206
[0411]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(propylthio)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 180; 207
[0412]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(2-propylthio)-1,2,3,4,4a,9b,-
-hexahydro[1]benzofuro[3,2-c]pyridine, 181; 208
[0413]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(butylthio)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 182; 209
[0414]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-[(1-ethylpropyl)thio]-1,2,3,4-
,4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 183; 210
[0415]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(cyclohexylthio)-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]pyridine, 184; 211
[0416]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(phenylthio)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 185; 212
[0417]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(benzylthio)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 186; 213
[0418]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(methylthio)-1,2,3,4,4a-
,9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 187; 214
[0419]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(ethylthio)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 188; 215
[0420]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(propylthio)-1,2,3,4,4a-
,9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 189; 216
[0421]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(isopropyl)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 190; 217
[0422]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(butylthio)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 191; 218
[0423]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-[(1-ethylpropyl)thio]-1-
,2,3,4,4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 192; 219
[0424]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(cyclohexylthio)-1,2,3,-
4,4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 193; 220
[0425]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(phenylthio)-1,2,3,4,4a-
,9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 194; 221
[0426]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(benzylthio)-1,2,3,4,4a-
,9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 195; 222
[0427]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-methoxy-1,2,3,4,4a,9b,-hexahydro-
[1]benzofuro[3,2-c]pyridine, 196; 223
[0428]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 197; 224
[0429]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-propoxy-1,2,3,4,4a,9b,-hexahydro-
[1]benzofuro[3,2-c]pyridine, 198; 225
[0430]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-isopropoxy-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 199; 226
[0431]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-hexahydro[-
1]benzofuro[3,2-c]pyridine, 200; 227
[0432]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-[(1-ethylpropyl)oxy]-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 201; 228
[0433]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(cyclohexyloxy)-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 202; 229
[0434]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,-hexahydro-
[1]benzofuro[3,2-c]pyridine, 203; 230
[0435]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,9b,-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 204; 231
[0436]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-methoxy-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 205; 232
[0437]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 206; 233
[0438]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-propoxy-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 207; 234
[0439]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-isopropoxy-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 208; 235
[0440]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-hexahyd-
ro[1]benzofuro[3,2-c]pyridine, 209; 236
[0441]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-[(1-ethylpropyl)oxy]-1,2,3,4,-
4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 210; 237
[0442]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(cyclohexyloxy)-1,2,3,4,4a,9b-
,-hexahydro[1]benzofuro[3,2-c]pyridine, 211; 238
[0443]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,-hexahy-
dro[1]benzofuro[3,2-c]pyridine, 212; 239
[0444]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,9b,-he-
xahydro[1]benzofuro[3,2-c]pyridine, 213; 240
[0445]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-methoxy-1,2,3,4,4a,9b,--
hexahydro[1]benzofuro[3,2-c]pyridine, 214; 241
[0446]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-ethoxy-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 215; 242
[0447]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-propoxy-1,2,3,4,4a,9b,--
hexahydro[1]benzofuro[3,2-c]pyridine, 216; 243
[0448]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(2-propoxy)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 217; 244
[0449]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-butoxy-1,2,3,4,4a,9b,-h-
exahydro[1]benzofuro[3,2-c]pyridine, 218; 245
[0450]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-[(1-ethylpropyl)oxy]-1,-
2,3,4,4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 219; 246
[0451]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(cyclohexyloxy)-1,2,3,4-
,4a,9b,-hexahydro[1]benzofuro-[3,2-c]pyridine, 220; 247
[0452]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-phenoxy-1,2,3,4,4a,9b,--
hexahydro[1]benzofuro[3,2-c]pyridine, 221; 248
[0453]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-(benzyloxy)-1,2,3,4,4a,-
9b,-hexahydro[1]benzofuro[3,2-c]pyridine, 222; 249
[0454]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-piperidin-1-yl-1,2,3,4,4a,9b-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 223; 250
[0455]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-piperidin-1-yl-1,2,3,4,4a,9b--
hexahydro[1]benzofuro[3,2-c]pyridine, 224; 251
[0456]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-piperidin-1-yl-1,2,3,4,-
4a,9b-hexahydro[1]benzofuro-[3,2-c]pyridine, 225; 252
[0457]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-azepano-1-yl-1,2,3,4,4a,9b-hexah-
ydro[1]benzofuro[3,2-c]pyridine, 226; 253
[0458]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-azepano-1-yl-1,2,3,4,4a,9b-he-
xahydro[1]benzofuro[3,2-c]pyridine, 227; 254
[0459]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-azepano-1-yl-1,2,3,4,4a-
,9b-hexahydro[1]benzofuro[3,2-c]pyridine, 228; 255
[0460]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-he-
xahydro[1]benzofuro[3,2-c]pyridine, 229; 256
[0461]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4,4a,9b-
-hexahydro[1]benzofuro[3,2-c]pyridine, 230; 257
[0462]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-pyrrolidin-1-yl-1,2,3,4-
,4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine, 231; 258
[0463]
(4aS,9bR)-8-(2,4-dichlorophenyl)-5-morpholin-4-yl-1,2,3,4,4a,9b-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 232; 259
[0464]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-5-morpholin-4-yl-1,2,3,4,4a,9b--
hexahydro[1]benzofuro[3,2-c]pyridine, 233; 260
[0465]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-5-morpholin-4-yl-1,2,3,4,-
4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine, 234; 261
[0466]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-thiomorpholin-4-yl-1,2,3,4,4a,9b-
-hexahydro[1]benzofuro[3,2-c]pyridine, 235; 262
[0467]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-thiomorpholin-4-yl-1,2,3,4,4a-
,9b-hexahydro[1]benzofuro[3,2-c]pyridine, 236; 263
[0468]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-thiomorpholin-4-yl-1,2,-
3,4,4a,9b-hexahydro[1]benzofuro-[3,2-c]pyridine, 237; 264
[0469]
(4aS,9bR)-8-(2,4-dichlorophenyl)-6-piperazin-1-yl-1,2,3,4,4a,9b-hex-
ahydro[1]benzofuro[3,2-c]pyridine, 238; 265
[0470]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-6-piperazin-1-yl-1,2,3,4,4a,9b--
hexahydro[1]benzofuro[3,2-c]pyridine, 239; 266
[0471]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-6-piperazin-1-yl-1,2,3,4,-
4a,9b-hexahydro[1]benzofuro[3,2-c]pyridine, 240. 267
[0472]
(4aS,9bR)-8-(2,4,6-trichlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9b,-hex-
ahydro[1]benzofuro[3,2-c]-pyridin-6-amine, 243; and 268
[0473]
(4aS,9bR)-8-(2,6-difluoro-4-chlorophenyl)-N,N-dipropyl-1,2,3,4,4a,9-
b,-hexahydro[1]benzofuro[3,2-c]-pyridin-6-amine, 244.
[0474] 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.
* * * * *