U.S. patent application number 10/020549 was filed with the patent office on 2002-08-15 for 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Jacobsen, Eric Jon, Jacobsen, Susan Fox.
Application Number | 20020111483 10/020549 |
Document ID | / |
Family ID | 22509195 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020111483 |
Kind Code |
A1 |
Jacobsen, Eric Jon ; et
al. |
August 15, 2002 |
1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles containing arylsulfones
at the 9-position
Abstract
The present invention are substituted
9-arylsulfone-1,2,3,4,5,6-hexahydroa- zepino[4,5-b]indoles (X) and
unsubstituted 9-arylsulfone-1,2,3,4,5,6-hexah-
ydroazepino[4,5-b]indoles (XI) such as the compound of EXAMPLE 13 1
which are useful in treating depression, obesity and other CNS
disorders.
Inventors: |
Jacobsen, Eric Jon;
(Richland, MI) ; Jacobsen, Susan Fox; (Richland,
MI) |
Correspondence
Address: |
Bruce Stein
Pharmacia & Upjohn Company
Global Intellectual Property
301 Henrietta Street
Kalamazoo
MI
49001
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
22509195 |
Appl. No.: |
10/020549 |
Filed: |
October 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10020549 |
Oct 30, 2001 |
|
|
|
09613843 |
Jul 11, 2000 |
|
|
|
60144574 |
Jul 19, 1999 |
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Current U.S.
Class: |
540/586 |
Current CPC
Class: |
C07C 323/09 20130101;
C07D 487/04 20130101; A61P 3/04 20180101; A61P 25/22 20180101; A61P
25/18 20180101; A61P 25/24 20180101; A61P 25/00 20180101; C07C
317/34 20130101; C07C 317/36 20130101 |
Class at
Publication: |
540/586 ;
514/215 |
International
Class: |
C07D 487/04; A61K
031/55 |
Claims
1. A 9-arylsulfone of the formula (XII) 27where R.sub.3 is: (1)
--H, (2) C.sub.1-C.sub.4 alkyl, (3) C.sub.0-C.sub.4-.phi. where the
-.phi. substituent is optionally substituted with 1 or 2 (a) --F,
--Cl, --Br, --I, (b) --O--R.sub.3-1 where R.sub.3-1 is: --H,
C.sub.1-C.sub.4 alkyl, -.phi., (c) --CF.sub.3, (d)
--CO--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3 are --H and
C.sub.1-C.sub.4 alkyl, and where R.sub.3-2 and R.sub.3-3 are taken
with the attached nitrogen atom to form a ring selected from the
group consisting of 1-pyrrolidinyl, 1-piperazinyl and
1-morpholinyl, (e) --NH--SO.sub.2--R.sub.3-4 where R.sub.3-4 is --H
and C.sub.1-C.sub.4 alkyl, (f) --NR.sub.3-2R.sub.3-3 where
R.sub.3-2 and R.sub.3-3 are as defined above, (g)
--NR.sub.3-4--CO--R.sub.3-4 where R.sub.3-4 is as defined above,
(h) --SO.sub.2--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3
are as defined above, (I) --C.dbd.N, (j) --NO.sub.2, where R.sub.N
is: (1) --H, (2) C.sub.1-C.sub.4 alkyl, (3) C.sub.0-C.sub.4-.phi.
where the -.phi. substituent is optionally substituted with 1 or 2
(a) --F, --Cl, --Br, --I, (b) --O--R.sub.N-1 where R.sub.N-1 is
--H, C.sub.1-C.sub.4 alkyl, -.phi., (c) --CF.sub.3, (d)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are --H and
C.sub.1-C.sub.4 alkyl, and where R.sub.3-2 and R.sub.3-3 are taken
with the attached nitrogen atom to form a ring selected from the
group consisting of 1-pyrrolidinyl, 1-piperazinyl and
1-morpholinyl, (e) --NH--SO.sub.2--R.sub.N-4 where R.sub.N-4 is --H
and C.sub.1-C.sub.4 alkyl, (f) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, (g)
--NR.sub.N-4--CO--R.sub.N-4 where R.sub.N-4 is as defined above,
(h) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are as defined above, (I) --C.ident.N, (j) --NO.sub.2, where
R.sub.X is: (1) --H (2) --F, --Cl, --Br, --I, (3) --O--R.sub.X-1
where R.sub.X-1 is: --H, C.sub.1-C.sub.4 alkyl, -.phi., (4)
--CF.sub.3, (5) --CO--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and
R.sub.X-3 are as defined above, (6) --NH--SO.sub.2--R.sub.X-4 where
R.sub.X-4 is as defined above, (7) --NR.sub.X-2R.sub.X-3 where
R.sub.X-2 and R.sub.X-3 are as defined above, (8)
--NR.sub.X-4--CO--R.sub.X-4 where R.sub.X-4 is as defined above,
(9) --SO.sub.2--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and R.sub.X-3
are as defined above, (10) --C.ident.N, (11) --NO.sub.2; where
R.sub.9 is: (1) --H, (2) --F, --Cl, (3) C.sub.1-C.sub.4 alkyl, (4)
C.sub.1-C.sub.3 alkoxy, (5) --CF.sub.3, (6) C.sub.0-C.sub.4-.phi.
where the -.phi. substituent is optionally substituted with 1 or 2
(a) --F, --Cl, --Br, --I, (b) --O--R.sub.9-1 where R.sub.9-1 is:
--H, C.sub.1-C.sub.4 alkyl, -.phi., (c) --CF.sub.3, (d)
--CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are --H and
C.sub.1-C.sub.4 alkyl, and where R.sub.9-2 and R.sub.9-3 are taken
with the attached nitrogen atom to form a ring selected from the
group consisting of 1-pyrrolidinyl, 1-piperazinyl and
1-morpholinyl, (e) --NH--SO.sub.2--R.sub.9-4 where R.sub.9-4 is --H
and C.sub.1-C.sub.4 alkyl, (f) --NR.sub.9-2R.sub.9-3 where
R.sub.9-2 and R.sub.9-3 are as defined above, (g)
--NR.sub.9-4--CO--R.sub.9-4 where R.sub.9-4 is as defined above,
(h) --SO.sub.2--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3
are as defined above, (I) --C.ident.N, (j) --NO.sub.2 (7)
--OR.sub.9-1 where R.sub.9-1 is as defined above, (8)
--CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are as
defined above, (9) --NR.sub.9-2R.sub.9-3 where R.sub.9-2 and
R.sub.9-3 are as defined above, (10) --NH--SO.sub.2--R.sub.9-4
where R.sub.9-4 is as defined above, (11) --NH--CO.sub.2--R.sub.9-2
where R.sub.9-2 is as defined above and pharmaceutically acceptable
salts thereof.
2. A 9-arylsulfone (XII) according to claim 1 where R.sub.3 is
selected from the group consisting of --H and C.sub.1-C.sub.2
alkyl.
3. 9-arylsulfone (XII) according to claim 2 where R.sub.3 is
--H.
4. A 9-arylsulfone (XII) according to claim 1 where R.sub.N is
selected from the group consisting of --H and C.sub.1-C.sub.4
alkyl.
5. A 9-arylsulfone (XII) according to claim 4 where R.sub.N is --H,
C.sub.1 alkyl and C.sub.2 alkyl.
6. A 9-arylsulfone (XII) according to claim 1 where R.sub.X is
selected from the group consisting of --H, --F and --Cl.
7. A 9-arylsulfone (XII) according to claim 6 where R.sub.X is
--H.
8. A 9-arylsulfone (XII) according to claim 1 where R.sub.9 is
selected from the group consisting of --H, --F, --Cl,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy and --CF.sub.3.
9. A 9-arylsulfone (XII) according to claim 8 where R.sub.9 is --H,
--F, --Cl, C.sub.1 alkyl, C.sub.1 alkoxy, and --CF.sub.3.
10. A 9-arylsulfone (XII) according to claim 8 where the R.sub.9
substituent is in the 3- or 4-position.
11. A 9-atylsulfone (XII) according to claim 1 where the
pharmaceutically acceptable salt is selected from the group
consisting of salts of methanesulfonic, hydrochloric, hydrobromic,
sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric,
maleic, CH.sub.3--(CH.sub.2).sub.n--C- OOH where n is 0 thru 4,
HOOC--(CH.sub.2).sub.n--COOH where n is as defined above.
12. A 9-arylsulfone (XII) according to claim 11 where the
pharmaceutically acceptable salt is selected from the group
consisting of salts of hydrochloric, maleate and methanesulfonic
acids.
13. A 9-arylsulfone (XII) according to claim 12 where the
pharmaceutically acceptable salt is the salt of hydrochloric
acid.
14. A 9-arylsulfone (XII) according to claim 1 where the
substituted 9-arylsulfone is selected from the group consisting of:
9-(phenylsulfonyl)-1,2,3,4,5 ,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino
[4,5-b]indole,
9-[(3-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino
[4,5-b]indole,
9-[(3-methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino
[4,5-b]indole,
9-[(4-trifluoromethyphenyl)sulfonyl]1,2,3,4,5,6-hexahydroa-
zepino[4,5-b]indole,
6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepi-
no[4,5-b]indole,
6-ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydr-
oazepino[4,5-b]indole,
6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-h-
exahydroazepino[4,5-b]indole,
6-methyl-9-[(4-trifluoromethylphenyl)sulfony-
l]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
6-ethyl-9-[(4-trifluoromethy-
lphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and
6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
15. A 9-arylsulfone (XII) according to claim 14 where the
substituted 9-arylsulfone is
6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino-
[4,5-b]indole.
16. A 9-arylsulfone (XII) according to claim 1 where the
substituted 9-arylsulfone is selected from the group consisting of:
9-[(3,4-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-
e,
9-[(3,5-difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]ind-
ole,
9-[(3,5-difluorophenyl)sulfonyl]-6methyl1,2,3,4,5,6-hexahydroazepino[-
4,5-b]indole,
9-[(4-(2-hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-
-hexahydroazepino[4,5-b]indole,
3,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole,
3-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-h-
exahydroazepino[4,5-b]indole and
9-[(4-fluorophenyl)sulfonyl]-3-isopropyl--
6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
17. A 9-arylsulfone (XII) according to claim 1 where the
substituted 9-arylsulfone is selected from the group consisting of:
1-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
2-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
4-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
5-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole,
9-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino-
[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-he-
xahydroazepino[4,5-b]indole,
1,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-h-
exahydroazepino[4,5-b]indole,
2,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6--
hexahydroazepino[4,5-b]indole,
4,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-
-hexahydroazepino[4,5-b]indole,
5,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1,6-dimethyl-
-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-2- ,6-dimethyl-1,2,3,4,5
,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydr-
oazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5-
,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-2-methy-
l-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfon-
yl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexa-
hydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-2,6-dimethyl-1-
,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-
-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepin-
o[4,5-b]indole.
18. A thio ether of formula (III) 28where R.sub.9 and R.sub.X are
as defined in claim 1.
19. A thio ether according to claim 18 where R.sub.9 is selected
from the group consisting of --H, --F, --Cl, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy and --CF.sub.3 and where R.sub.X is selected
from the group consisting of --H, --F and --Cl.
20. An amine of formula (IV) 29where R.sub.9 and R.sub.X are as
defined in claim 1.
21. An amine according to claim 20 where R.sub.9 and R.sub.X are as
defined in claim 19.
22. A hydrazine of formula (V) 30where R.sub.9 and R.sub.X are as
defined in claim 1.
23. A hydrazine according to claim 22 where R.sub.9 and R.sub.X are
as defined in claim 19.
24. A compound of formula (VII) 31where PG is selected from the
group consisting of .phi.--CH.sub.2--, .phi.--CO--,
.phi.--CH.sub.2--CO.sub.2-- and --CO--O--C(CH.sub.3).sub.3 where
R.sub.9 and R.sub.X are as defined in claim 1.
25. A compound according to claim 24 where PG is .phi.--CH.sub.2--
or .phi.--CO-- and where R.sub.9 and R.sub.X are as defined in
claim 19.
26. A protected 9-arylsulfone of formula (VII) 32where PG is as
defined in claim 24 and R.sub.9 and R.sub.X are as defined in claim
1.
27. A protected 9-arylsulfone according to claim 26 where PG is as
defined in claim 25 and where R.sub.9 and R.sub.X are as defined in
claim 19.
28. A method of treating a human who has a condition selected from
the group consisting of anxiety, depression, schizophrenia, stress
related disease, panic, a phobia, obsessive compulsive disorder,
obeisity, post-traumatic stress syndrome who is in need of such
treatment which comprises administering an effective amount of a
9-arylsulfone of the formula (XII) 33where R.sub.3 is: (1) --H, (2)
C.sub.1-C.sub.4 alkyl, (3) C.sub.0-C.sub.4-.phi. where the -.phi.
substituent is optionally substituted with 1 or 2 (a) --F, --Cl,
--Br, --I, (b) --O--R.sub.3-1 where R.sub.3-1 is: --H,
C.sub.1-C.sub.4 alkyl, -.phi., (c) --CF.sub.3, (d)
--CO--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3 are --H and
C.sub.1-C.sub.4 alkyl, and where R.sub.3-2 and R.sub.3-3 are taken
with the attached nitrogen atom to form a ring selected from the
group consisting of 1-pyrrolidinyl, 1-piperazinyl and
1-morpholinyl, (e) --NH--SO.sub.2--R.sub.3-4 where R.sub.3-4 is --H
and C.sub.1-C.sub.4 alkyl, (f) --NR.sub.3-2R.sub.3-3 where
R.sub.3-2 and R.sub.3-3 are as defined above, (g)
--NR.sub.3-4--CO--R.sub.3-4 where R.sub.3-4 is as defined above,
(h) --SO.sub.2--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3
are as defined above, (I) --C.ident.N, (j) --NO.sub.2, where
R.sub.N is: (1) --H, (2) C.sub.1-C.sub.4 alkyl, (3)
C.sub.0C.sub.4-.phi. where the -.phi. substituent is optionally
substituted with 1 or 2 (a) --F, --Cl, --Br, --I, (b)
--O--R.sub.N-1 where R.sub.N-1 is --H, C.sub.1-C.sub.4 alkyl,
-.phi., (c) --CF.sub.3, (d) --CO--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are --H and C.sub.l-C.sub.4 alkyl, and
where R.sub.3-2 and R.sub.3-3 are taken with the attached nitrogen
atom to form a ring selected from the group consisting of
1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl, (e)
--NH--SO.sub.2--R.sub.N-4 where R.sub.N-4 is --H and
C.sub.1-C.sub.4 alkyl, (f) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (g) --NR.sub.N-4--CO--R.sub.N-4
where R.sub.N-4 is as defined above, (h)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
as defined above, (I) --C.ident.N, (j) --NO.sub.2, where R.sub.X
is: (1) --H (2) --F, --Cl, --Br, --I, (3) --O--R.sub.X-1 where
R.sub.X-1 is: --H, C.sub.1-C.sub.4 alkyl, -.phi., (4) --CF.sub.3,
(5) --CO--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and R.sub.X-3 are as
defined above, (6) --NH--SO.sub.2--R.sub.X-4 where R.sub.X-4 is as
defined above, (7) --NR.sub.X-2R.sub.X-3 where R.sub.X-2 and
R.sub.X-3 are as defined above, (8) --NR.sub.X-4--CO--R.sub.X-4
where R.sub.X-4 is as defined above, (9)
--SO.sub.2--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and R.sub.X-3 are
as defined above, (10) --C.ident.N, (11) --NO.sub.2; where R.sub.9
is: (1) --H, (2) --F, --Cl, (3) C.sub.1-C.sub.4 alkyl, (4)
C.sub.1-C.sub.3 alkoxy, (5) --CF.sub.3, (6) C.sub.0C.sub.4-.phi.
where the -.phi. substituent is optionally substituted with 1 or 2
(a) --F, --Cl, --Br, --I, (b) --O--R.sub.9-1 where R.sub.9-1 is:
--H, C.sub.1-C.sub.4 alkyl, -.phi., (c) --CF.sub.3, (d)
--CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are --H and
C.sub.1-C.sub.4 alkyl, and where R.sub.9-2 and R.sub.9-3 are taken
with the attached nitrogen atom to form a ring selected from the
group consisting of 1-pyrrolidinyl, 1-piperazinyl and
1-morpholinyl, (e) --NH--SO.sub.2--R.sub.9-4 where R.sub.9-4 is --H
and C.sub.1-C.sub.4 alkyl, (f) --NR.sub.9-2R.sub.9-3 where
R.sub.9-2 and R.sub.9-3 are as defined above, (g)
--NR.sub.9-4--CO--R.sub.9-4 where R.sub.9-4 is as defined above,
(h) --SO.sub.2--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3
are as defined above, (I) --C.ident.N, (j) --NO.sub.2 (7)
--OR.sub.9-1 where R.sub.9-1 is as defined above, (8)
--CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are as
defined above, (9) --NR.sub.9-2R.sub.9-3 where R.sub.9-2 and
R.sub.9-3 are as defined above, (10) --NH-SO.sub.2--R.sub.9-4 where
R.sub.9-4 is as defined above, (11) --NH--CO.sub.2--R.sub.9-2 where
R.sub.9-2 is as defined above, and pharmaceutically acceptable
salts thereof.
29. A method of treating a human according to claim 28 where the
condition is anxiety or depression.
30. A method of treating a human according to claim 28 where the
administered is orally, sublingually, transdermally and
parenterally.
31. A method of treating a human according to claim 30 where the
administration is oral.
32. A method of treating a human according to claim 28 where the
administration is in divided doses either two, three or four times
daily.
33. A method of treating a human according to claim 28 where the
effective amount is from about 0.1 to about 50 mg/kg/day.
34. A method of treating a human according to claim 33 where the
effective amount is from about 0.1 to about 10 mg/kg/day.
35. A method of treating a human according to claim 28 where the
9-arylsulfone of the formula (XII) is selected from the group
consisting of
9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3-methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-trifluoromethyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]i-
ndole,
6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-
e,
6-ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b-
]indole,
6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepin-
o[4,5-b]indole,
6-methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-
-hexahydroazepino[4,5-b]indole,
6-ethyl-9-[(4-trifluoromethylphenyl)sulfon-
yl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
6-methyl-9-(phenylsulfonyl)-
-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,4-difluorophenyl)sulfony-
l]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfo-
nyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sul-
fonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-(2-hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroaze-
pino[4,5-b]indole,
3,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroaz-
epino[4,5-b]indole,
3-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepi-
no[4,5-b]indole and
9-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,-
3,4,5,6-hexahydroazepino[4,5-b]indole.
36. A method of treating a human according to claim 35 where the
9-arylsulfone of the formula (XII) is
6-methyl-9-(phenylsulfonyl)-1,2,3,4-
,5,6-hexahydroazepino[4,5-b]indole.
37. A method of treating a human according to claim 28 where the
9-arylsulfone of the formula (XII) is selected from the group
consisting of
1-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
2-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
4-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
5-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole,
9-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino-
[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-he-
xahydroazepino[4,5-b]indole,
1,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-h-
exahydroazepino[4,5-b]indole,
2,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6--
hexahydroazepino[4,5-b]indole,
4,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-
-hexahydroazepino[4,5-b]indole,
5,6-dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-1,6-dimethyl-
-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-2-
,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole,
9-[(4-fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydr-
oazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-1-methyl-1,2,3
,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-2--
methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)s-
ulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexa-
hydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-2,6-dimethyl-1-
,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-
-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
9-[(3,5-difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepin-
o[4,5-b]indole.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the following
provisional application: U.S. Ser. No. 60/144574, filed Jul. 19,
1999, under 35 USC 119(e)(i).
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is substituted
9-arylsulfone-1,2,3,4,5,6-hexa- hydroazepino[4,5-b]indoles (X)
which are useful for treating anxiety, depression and other CNS
disorders in humans and animals.
[0004] 2. Description of the Related Art
[0005] U.S. Pat. No. 3,652,588 discloses
6-alkyl-1,2,3,4,5,6-hexahydroazep- ino[4,5-b]indoles which were
useful for tranquilizing and sedating mammals to suppress hunger in
mammals. This document discloses that there can be substitution at
the 9-position. However, those substituents are limited to
hydrogen, alkyl, alkoxy and halogen.
[0006] U.S. Pat. No. 3,839,357 discloses
6-benzyl-1,2,3,4,5,6-hexahydroaze- pino[4,5-b]indoles which were
useful for tranquilizing mammals. This document discloses that
there can be substitution at the 9-position. However, those
substituents are limited to hydrogen, alkyl, alkoxy and
halogen.
[0007] U.S. Pat. No. 3,676,558 discloses
6-alkyl-1,2,3,4,5,6-hexahydroazep- ino[4,5-b]indoles which were
useful to suppress hunger in mammals. This document discloses that
there can be substitution at the 9-position. However, it is limited
to hydrogen, alkyl, alkoxy and halogen.
SUMMARY OF INVENTION
[0008] Disclosed is a 9-arylsulfone of the formula (XII) 2
[0009] where R.sub.3 is:
[0010] (1) --H,
[0011] (2) C.sub.1-C.sub.4 alkyl,
[0012] (3) C.sub.0-C.sub.4-.phi. where the -.phi. substituent is
optionally substituted with 1 or 2
[0013] (a) --F, --Cl, --Br, --I,
[0014] (b) --O--R.sub.3-1 where R.sub.3-1 is:
[0015] --H,
[0016] C.sub.1-C.sub.4 alkyl,
[0017] -.phi.,
[0018] (c) --CF.sub.3,
[0019] (d) --CO--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3
are --H and C.sub.1-C.sub.4 alkyl, and where R.sub.3-2 and
R.sub.3-3 are taken with the attached nitrogen atom to form a ring
selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl
and 1-morpholinyl,
[0020] (e) --NH--SO.sub.2--R.sub.3-4 where R.sub.3-4 is --H and
C.sub.1-C.sub.4 alkyl,
[0021] (f) --NR.sub.3-2R.sub.3-3 where R.sub.3-2 and R.sub.3-3 are
as defined above,
[0022] (g) --NR.sub.3-4--CO--R.sub.3-4 where R.sub.3-4 is as
defined above,
[0023] (h) --SO.sub.2--NR.sub.3-2R.sub.3-3 where R.sub.3-2 and
R.sub.3-3 are as defined above,
[0024] (I) --C.ident.N,
[0025] (j) --NO.sub.2,
[0026] where R.sub.N is:
[0027] (1) --H,
[0028] (2) C.sub.1-C.sub.4 alkyl,
[0029] (3) C.sub.0-C.sub.4-.phi. where the -.phi. substituent is
optionally substituted with 1 or 2
[0030] (a) --F, --Cl, --Br, --I,
[0031] (b) --O--R.sub.N-1 where R.sub.N-1 is
[0032] --H,
[0033] C.sub.1-C.sub.4 alkyl,
[0034] -.phi.,
[0035] (c) --CF.sub.3,
[0036] (d) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are --H and C.sub.1-C.sub.4 alkyl, and where R.sub.3-2 and
R.sub.3-3 are taken with the attached nitrogen atom to form a ring
selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl
and 1-morpholinyl,
[0037] (e) --NH--SO.sub.2--R.sub.N-4 where R.sub.N-4 is --H and
C.sub.1-C.sub.4 alkyl,
[0038] (f) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
as defined above,
[0039] (g) --NR.sub.N-4--CO--R.sub.N-4 where R.sub.N-4 is as
defined above,
[0040] (h) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined above,
[0041] (I) --C.ident.N,
[0042] (j) --NO.sub.2,
[0043] where R.sub.X is:
[0044] (1) --H
[0045] (2) --F, --Cl, --Br, --I,
[0046] (3) --O--R.sub.X-1 where R.sub.X-1 is:
[0047] --H,
[0048] C.sub.1-C.sub.4 alkyl,
[0049] -.phi.,
[0050] (4) --CF.sub.3,
[0051] (5) --CO--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and R.sub.X-3
are as defined above,
[0052] (6) --NH--SO.sub.2--R.sub.X-4 where R.sub.X-4 is as defined
above,
[0053] (7) --NR.sub.X-2R.sub.X-3 where R.sub.X-2 and R.sub.X-3 are
as defined above,
[0054] (8) --NR.sub.X-4--CO--R.sub.X-4 where R.sub.X-4 is as
defined above,
[0055] (9) --SO.sub.2--NR.sub.X-2R.sub.X-3 where R.sub.X-2 and
R.sub.X-3 are as defined above,
[0056] (10) --C.ident.N,
[0057] (11) --NO.sub.2;
[0058] where R.sub.9 is:
[0059] (1) --H,
[0060] (2) --F, --Cl,
[0061] (3) C.sub.1-C.sub.4 alkyl,
[0062] (4) C.sub.1-C.sub.3 alkoxy,
[0063] (5) --CF.sub.3,
[0064] (6) C.sub.0-C.sub.4-.phi. where the -.phi. substituent is
optionally substituted with 1 or 2
[0065] (a) --F, --Cl, --Br, --I,
[0066] (b) --O--R.sub.9-1 where R.sub.9-1 is:
[0067] --H,
[0068] C.sub.1-C.sub.4 alkyl,
[0069] -.phi.,
[0070] (c) --CF.sub.3,
[0071] (d) --CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3
are --H and C.sub.1-C.sub.4 alkyl, and where R.sub.9-2 and
R.sub.9-3 are taken with the attached nitrogen atom to form a ring
selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl
and 1-morpholinyl,
[0072] (e) --NH--SO.sub.2--R.sub.9-4 where R.sub.9-4 is --H and
C.sub.1-C.sub.4 alkyl,
[0073] (f) --NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are
as defined above,
[0074] (g) --NR.sub.9-4--CO--R.sub.9-4 where R.sub.9-4 is as
defined above,
[0075] (h) --SO.sub.2--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and
R.sub.9-3 are as defined above,
[0076] (I) --C.ident.N,
[0077] (j) --NO.sub.2
[0078] (7) --OR.sub.9-1 where R.sub.9-1 is as defined above,
[0079] (8) --CO--NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3
are as defined above,
[0080] (9) --NR.sub.9-2R.sub.9-3 where R.sub.9-2 and R.sub.9-3 are
as defined above,
[0081] (10) --NH--SO.sub.2--R.sub.9-4 where R.sub.9-4 is as defined
above,
[0082] (11) --NH--CO.sub.2--R.sub.9-2 where R.sub.9-2 is as defined
above, and pharmaceutically acceptable salts thereof.
[0083] Also disclosed are compounds which are intermediates in the
production of the 9-arylsulfones (XII), the thio ethers of formula
(III), the amines of formula (IV), the hydrazines of formula (V),
the compounds of formula (VII) and the protected 9-arylsulfones of
formula (VIII) where PG is selected from the group consisting of
.phi.--CH.sub.2--, .phi.--CO--, .phi.--CH.sub.2--CO.sub.2-- and
--CO--O--C(CH.sub.3).sub.3 and where R.sub.9 and R.sub.X are as
defined above.
[0084] Further disclosed is a method of treating a human who has a
condition selected from the group consisting of anxiety,
depression, schizophrenia, stress related disease, panic, a phobia,
obsessive compulsive disorder, obeisity, post-traumatic stress
syndrome who is in need of such treatment which comprises
administering an effective amount of a 9-arylsulfone of the formula
(XII).
DETAILED DESCRIPTION OF THE INVENTION
[0085] The unsubstituted 9-arylsulfones (IX) and substituted
9-arylsulfones (X) are both prepared by means known to those
skilled in the art. The term 9-arylsulfones (XI) includes both the
unsubstituted 9-arylsulfones (IX), where R.sub.3 is --H and
substituted 9-arylsulfones (X) where R.sub.3 is .noteq. to --H. The
process of preparation can be viewed as being in two parts. The
first part is the production of the appropriately substituted
hydrazone (V), see CHART A. The second part is the coupling and
reaction of the appropriately substituted hydrazone (V) with the
1-protected hexahydro-4H-azepine-4-one (VI) to give the
intermediate (VII) and its transformation to the unsubstituted
9-arylsulfone (IX), see CHART B.
[0086] The appropriately substituted thiols (I) are either known to
those skilled in the art or can be readily prepared from known
starting materials by means well known to those skilled in the art.
There can be either one or two R.sub.9 substituents and R.sub.9
includes --H, --F, --Cl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy and --CF.sub.3; it is preferred that R.sub.9 is --H, --F,
--Cl, C.sub.1 alkyl, C.sub.1 alkoxy, and --CF.sub.3 and when F-- it
is preferred that it be in the 4- or p-position. It is preferred
that the R.sub.9 substituent be in either the 3- or 4-position.
[0087] The appropriately substituted thiol (I) is coupled with the
appropriately substituted 4-chloro-1-nitrobenzene (II) by known
means to produce the thioether (III). There can be either one or
two R.sub.X groups. If R.sub.X is other than --H, it should be part
of the 4-chloro-1-nitrobenzene (II) so that it will become part of
the final unsubstituted 9-arylsulfone (IX) when it is formed. It is
most difficult to add the R.sub.X substitutent (other than --H) to
the unsubstituted 9-arylsulfone (IX) once it is formed. Therefore,
the R.sub.X group should be part of the appropriately substituted
4-chloro-1-nitrobenzene (II) when it is reacted with the thiol (I).
R.sub.X includes of --H, --F and --Cl; it is preferred that R.sub.X
is --H. The thioether (III) is then oxidized with hydrogen peroxide
(30%) followed by reduction with rhodium on carbon (5%), all of
which is known to those skilled in the art, to produce the amine
(IV). The amine (IV) is then diazotized by (sodium) nitrite and
(hydrochloric) acid followed by reduction with tin chloride/water
to give the corresponding hydrazine (V).
[0088] The second part of the reaction, is well known to those
skilled in the art, see U.S. Pat. Nos. 3,652,588, 3,676,558 and
3,839,357. The only difference between the process in those patents
and that here is the arylsulfone substituent at the 9-position.
That substituent is already in place in the hydrazine (V) prior to
the reaction of the 9-arylsulfone hydrazine (V) with the
1-protected hexahydro-4H-azepine-4-one (VI) to produce the
correspondingly substituted intermediate (VII). Suitable protecting
groups (PG) include .phi.--CH.sub.2--, .phi.--CO--,
.phi.--CH.sub.2--CO.sub.2-- and --CO--O--C(CH.sub.3).sub.3; it is
preferred that the protecting group be .phi.--CH.sub.2-- or
.phi.--CO--. The cyclization of the intermediate (VII) to the
corresponding protected arylsulfone (VIII) and then the
deprotection to the unsubstituted 9-arylsulfone (IX) all follow
known methods. The protecting groups (PG) are readily removed by
means well known to those skilled in the art. The unsubstituted
9-arylsulfone (IX) can then be substituted at the C3-position
(R.sub.3, ring nitrogen atom) as well as on the indole nitrogen
(R.sub.N) as is known to those skilled in the art. Alternatively,
arylsulfone (VIII) can be alkylated with the desired R.sub.N--X
substituent to give the protected indole (XI) which then is
deprotected to give the desired substituted 9-arylsulfone (X).
Useful R.sub.3 groups include of --H and C.sub.1-C.sub.2 alkyl; it
is preferred that R.sub.3 be --H. Useful R.sub.N groups include of
--H and C.sub.1-C.sub.4 alkyl; it is preferred that R.sub.N is --H,
C.sub.1 alkyl and C.sub.2 alkyl. The invention here is not the
process chemistry but rather the novel products produced.
[0089] The preferred protecting group for the intermediates (VI),
(VII) and (VIII) are benzyl and benzamide though other groups are
operable as is known to those skilled in the art.
[0090] The 9-arylsulfones (XI) are amines, and as such form acid
addition salts when reacted with acids of sufficient strength.
Pharmaceutically acceptable salts include salts of both inorganic
and organic acids. The pharmaceutically acceptable salts are
preferred over the corresponding free amines since they produce
compounds which are more water soluble and more crystalline. The
preferred pharmaceutically acceptable salts include salts of the
following acids methanesulfonic, hydrochloric, hydrobromic,
sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric,
maleic, CH.sub.3--(CH.sub.2).sub.n--COOH where n is 0 thru 4,
HOOC--(CH.sub.2).sub.N--COOH where n is as defined above. aa
[0091] The 9-arylsulfones (XI) of the present invention are useful
to treat anxiety, depression, schizophrenia, stress related
disease, panic, a phobia, obsessive compulsive disorder, obeisity,
post-traumatic stress syndrome and other CNS disorders. It is
preferred that the 9-aryl sulfones (XI) be used to treat anxiety
for depression. To treat these diseases the 9-arylsulfones (XI) are
administered orally, sublingually, transdermally or parenterally to
provide a dosage of about 0.1 to about 50 mg/kg/day. It is
preferred that the dosage range be from about 0.1 to about 10
mg/kg/day. The 9-arylsulfones (XI) can be administered in divided
doses either two, three or four times daily. It is preferred that
the 9-arylsulfones (XI) be administered orally.
[0092] The exact dosage and frequency of administration depends on
the particular 9-arylsulfone(s) used, the particular disease being
treated, the severity of the disease being treated, the age,
weight, general physical condition of the particular patient, other
medication the individual may be taking as is well known to those
skilled in the art and can be more accurately determined by
measuring the blood level or concentration of the 9-arylsulfone
(XI) in the patient's blood and/or the patient's response to the
particular condition being treated.
Definitions and Conventions
[0093] The definitions and explanations below are for the terms as
used throughout this entire document including both the
specification and the claims.
[0094] I. Conventions for Formulas and Definitions of Variables
[0095] The chemical formulas representing various compounds or
molecular fragments in the specification and claims may contain
variable substituents in addition to expressly defined structural
features. These variable substituents are identified by a letter or
a letter followed by a numerical subscript, for example, "Z.sub.1"
or "R.sub.i" where "i" is an integer. These variable substituents
are either monovalent or bivalent, that is, they represent a group
attached to the formula by one or two chemical bonds. For example,
a group Z.sub.1 would represent a bivalent variable if attached to
the formula CH.sub.3--C(.dbd.Z.sub.1)H. Groups R.sub.i and R.sub.j
would represent monovalent variable substituents if attached to the
formula CH.sub.3--CH.sub.2-- --C(R.sub.i)(R.sub.j)--H. When
chemical formulas are drawn in a linear fashion, such as those
above, variable substituents contained in parentheses are bonded to
the atom immediately to the left of the variable substituent
enclosed in parenthesis. When two or more consecutive variable
substituents are enclosed in parentheses, each of the consecutive
variable substituents is bonded to the immediately preceding atom
to the left which is not enclosed in parentheses. Thus, in the
formula above, both R.sub.i and R.sub.j are bonded to the preceding
carbon atom. Also, for any molecule with an established system of
carbon atom numbering, such as steroids, these carbon atoms are
designated as C.sub.i, where "i" is the integer corresponding to
the carbon atom number. For example, C.sub.6 represents the 6
position or carbon atom number in the steroid nucleus as
traditionally designated by those skilled in the art of steroid
chemistry. Likewise the term "R.sub.6" represents a variable
substituent (either monovalent or bivalent) at the C.sub.6
position.
[0096] Chemical formulas or portions thereof drawn in a linear
fashion represent atoms in a linear chain. The symbol "--" in
general represents a bond between two atoms in the chain. Thus
CH.sub.3--O--CH.sub.2--CH(R.s- ub.i)--CH.sub.3 represents a
2-substituted-1-methoxypropane compound. In a similar fashion, the
symbol ".dbd." represents a double bond, e.g.,
CH.sub.2.dbd.C(R.sub.i)--O--CH.sub.3, and the symbol ".degree."
represents a triple bond, e.g.,
HC.degree.C--CH(R.sub.i)--CH.sub.2--CH.su- b.3. Carbonyl groups are
represented in either one of two ways: --CO-- or --C(.dbd.O)--,
with the former being preferred for simplicity.
[0097] Chemical formulas of cyclic (ring) compounds or molecular
fragments can be represented in a linear fashion. Thus, the
compound 4-chloro-2-methylpyridine can be represented in linear
fashion by N*.dbd.C(CH.sub.3)--CH.dbd.CCl--CH.dbd.C*H with the
convention that the atoms marked with an asterisk (*) are bonded to
each other resulting in the formation of a ring. Likewise, the
cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be
represented by --N*--(CH.sub.2).sub.2--N(C-
.sub.2H.sub.5)--CH.sub.2--C*H.sub.2.
[0098] A rigid cyclic (ring) structure for any compounds herein
defines an orientation with respect to the plane of the ring for
substituents attached to each carbon atom of the rigid cyclic
compound. For saturated compounds which have two substituents
attached to a carbon atom which is part of a cyclic system,
--C(X.sub.1)(X.sub.2)-- the two substituents may be in either an
axial or equatorial position relative to the ring and may change
between axial/equatorial. However, the position of the two
substituents relative to the ring and each other remains fixed.
While either substituent at times may lie in the plane of the ring
(equatorial) rather than above or below the plane (axial), one
substituent is always above the other. In chemical structural
formulas depicting such compounds, a substituent (X.sub.1) which is
"below" another substituent (X.sub.2) will be identified as being
in the alpha (.alpha.) configuration and is identified by a broken,
dashed or dotted line attachment to the carbon atom, i.e., by the
symbol " - - - " or " . . . ". The corresponding substituent
attached "above" (X.sub.2) the other (X.sub.1) is identified as
being in the beta (.beta.) configuration and is indicated by an
unbroken or solid line attachment to the carbon atom.
[0099] When a variable substituent is bivalent, the valences may be
taken together or separately or both in the definition of the
variable. For example, a variable R.sub.i attached to a carbon atom
as --C(.dbd.R.sub.i)-- might be bivalent and be defined as oxo or
keto (thus forming a carbonyl group (--CO--) or as two separately
attached monovalent variable substituents a-R.sub.i-j and
.beta.-R.sub.i-k. When a bivalent variable, R.sub.i, is defined to
consist of two monovalent variable substituents, the convention
used to define the bivalent variable is of the form
"a-R.sub.i-j:.beta.-R.sub.i-k" or some variant thereof. In such a
case both a-R.sub.i-j and .beta.-R.sub.i-k are attached to the
carbon atom to give --C(a-R.sub.i-j)(.beta.-R.sub.i-k)--. For
example, when the bivalent variable R.sub.6, --C(.dbd.R.sub.6)--is
defined to consist of two monovalent variable substituents, the two
monovalent variable substituents are a-R.sub.6-1:.beta.-R.sub.6-2,
. . . a-R.sub.6-9:.beta.-R.sub.6-10, etc, giving
--C(a-R.sub.6-1)(.beta.-R.sub.- 6-2)--, . . .
--C(a-R.sub.6-9)(.beta.-R.sub.6-10)--, etc. Likewise, for the
bivalent variable R.sub.11, --C(.dbd.R.sub.11)--, two monovalent
variable substituents are a-R.sub.11-1:.beta.-R.sub.11-2. For a
ring substituent for which separate a and .beta. orientations do
not exist (e.g. due to the presence of a carbon carbon double bond
in the ring), and for a substituent bonded to a carbon atom which
is not part of a ring the above convention is still used, but the a
and .beta. designations are omitted.
[0100] Just as a bivalent variable may be defined as two separate
monovalent variable substituents, two separate monovalent variable
substituents may be defined to be taken together to form a bivalent
variable. For example, in the formula
--C.sub.1(R.sub.i)H--C.sub.2(R.sub.- j)H--(C.sub.1 and C.sub.2
define arbitrarily a first and second carbon atom, respectively)
R.sub.i and R.sub.j may be defined to be taken together to form (1)
a second bond between C.sub.1 and C.sub.2 or (2) a bivalent group
such as oxa (--O--) and the formula thereby describes an epoxide.
When R.sub.i and R.sub.j are taken together to form a more complex
entity, such as the group --X--Y--, then the orientation of the
entity is such that C.sub.1 in the above formula is bonded to X and
C.sub.2 is bonded to Y. Thus, by convention the designation " . . .
R.sub.i and R.sub.j are taken together to form
--CH.sub.2--CH.sub.2--O--C- O-- . . . " means a lactone in which
the carbonyl is bonded to C.sub.2. However, when designated " . . .
R.sub.j and R.sub.i are taken together to form
--CO--O--CH.sub.2--CH.sub.2-- the convention means a lactone in
which the carbonyl is bonded to C.sub.1.
[0101] The carbon atom content of variable substituents is
indicated in one of two ways. The first method uses a prefix to the
entire name of the variable such as "C.sub.1-C.sub.4", where both
"1" and "4" are integers representing the minimum and maximum
number of carbon atoms in the variable. The prefix is separated
from the variable by a space. For example, "C.sub.1-C.sub.4 alkyl"
represents alkyl of 1 through 4 carbon atoms, (including isomeric
forms thereof unless an express indication to the contrary is
given). Whenever this single prefix is given, the prefix indicates
the entire carbon atom content of the variable being defined. Thus
C.sub.2-C.sub.4 alkoxycarbonyl describes a group
CH.sub.3--(CH.sub.2).sub.n--O--CO-- where n is zero, one or two. By
the second method the carbon atom content of only each portion of
the definition is indicated separately by enclosing the
"C.sub.i-C.sub.j" designation in parentheses and placing it
immediately (no intervening space) before the portion of the
definition being defined. By this optional convention
(C.sub.1-C.sub.3)alkoxycarbonyl has the same meaning as
C.sub.2-C.sub.4 alkoxy-carbonyl because the "C.sub.1-C.sub.3"
refers only to the carbon atom content of the alkoxy group.
Similarly while both C.sub.2-C.sub.6 alkoxyalkyl and
(C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)a- lkyl define alkoxyalkyl
groups containing from 2 to 6 carbon atoms, the two definitions
differ since the former definition allows either the alkoxy or
alkyl portion alone to contain 4 or 5 carbon atoms while the latter
definition limits either of these groups to 3 carbon atoms.
[0102] When the claims contain a fairly complex (cyclic)
substituent, at the end of the phrase naming/designating that
particular substituent will be a notation in (parentheses) which
will correspond to the same name/designation in one of the CHARTS
which will also set forth the chemical structural formula of that
particular substituent.
II. Definitions
[0103] All temperatures are in degrees Centigrade.
[0104] HPLC refers to high pressure liquid chromatography.
[0105] DMSO refers to dimethylsulfoxide.
[0106] DMF refers to dimethylfornamide.
[0107] Saline refers to an aqueous saturated sodium chloride
solution.
[0108] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[0109] IR refers to infrared spectroscopy.
[0110] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (d) downfield
from tetramethylsilane.
[0111] -.phi. refers to phenyl (C.sub.6H.sub.5).
[0112] MS refers to mass spectrometry expressed as m/e, m/z or
mass/charge unit. [M+H].sup.+ refers to the positive ion of a
parent plus a hydrogen atom. CI refers to electron impact. CI
refers to chemical ionization. FAB refers to fast atom
bombardment.
[0113] HRMS refers to high resolution mass spectrometry.
[0114] Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[0115] When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
[0116] When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v).
EXAMPLES
[0117] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. The following detailed
examples describe how to prepare the various compounds and/or
perform the various processes of the invention and are to be
construed as merely illustrative, and not limitations of the
preceding disclosure in any way whatsoever. Those skilled in the
art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
Preparation 1 1-[4-(Phenylsulfonyl)phenyl]hydrazine (V)
[0118] 3
[0119] A mixture of 4-chlorophenyl phenyl sulfone (10.1 g, 40.0
mmol), hydrazine mono-hydrate (30 mL), and triethylamine (4 drops)
in ethylene glycol (20 mL) is heated at 150.degree. for 15 hr. Upon
cooling, the mixture is diluted with H.sub.2O and filtered. The
residual solid is washed with H.sub.2O until the washings are
neural (pH=6). This material is then triturated with methylene
chloride and dried under reduced pressure at 50.degree. to give the
title compound, IR (drift) 3282, 1586, 1514, 1306, 1291, 1158,
1145, 1104, 996, 813, 756, 730, 717, 688 and 678 cm.sup.-1; NMR
(300 MHz, CDCl.sub.3) 7.70-7.85, 7.45-7.65, 6.79 and 4.22 .delta.;
MS (EI) m/z 248 (M.sup.+), 125, 123, 108, 107, 90, 80, 77, 63 and
51.
Preparation 2 1-[4-[(4-Fluorophenyl)sulfonyl]phenyl]hydrazine
(V)
[0120] 4
[0121] Step I: 4-Fluorophenyl-4-nitrophenyl sulfide (III)
[0122] A mixture of 4-fluorothiophenol (I, 2.08 g, 19.5 mmol),
1-chloro-4-nitrobenzene (II, 3.39 g, 21.5 mmol), and potassium
carbonate (5.40 g, 39.0 mmol) in acetonitrile (75 mL) is stirred at
20-25.degree. under nitrogen for 16 hr. The mixture is diluted with
H.sub.2O (100 mL) and extracted into methylene chloride
(3.times.100 mL). The extracts are dried over anhydrous magnesium
sulfate, filtered, and concentrated under reduced pressure to
provide a quantitative yield of the desired thioether,
mp=84-90.degree.; NMR (300 MHz, CDCl.sub.3) 8.07, 7.45-7.60 and,
7.05-7.25 .delta..
[0123] Step II: 4-[(4-Fluorophenyl)sulfonyl]phenylamine (IV)
[0124] A hot mixture (100.degree.) of 4-fluorophenyl 4-nitrophenyl
sulfide (III, Step I, 1.91 g, 7.66 mmol) in glacial acetic acid (50
mL) is treated with hydrogen peroxide (30%, 2.60 mL), followed 20
min later by a second portion of hydrogen peroxide (30%, 1.70 mL).
The mixture continued to heat for an additional 30 min, and is then
allowed to cool to 20-25.degree.. The mixture is concentrated to
near dryness and filtered, rinsing the solid with H.sub.2O. The
solid is dried in a vacuum oven at 50.degree. to give the
intermediate sulfone, IR (drift) 1590, 1534, 1356, 1307, 1294,
1242, 1166, 1156, 1109, 1101, 858, 839, 742, 687 and 665 cm.sup.-1;
NMR (300 MHz, CDCl.sub.3) 8.35, 8.12, 7.95-8.05 and 7.15-7.30
.delta.; MS (EI) m/z 281 (M.sup.+), 159, 143, 111, 95, 95, 83, 76,
74 and 51.
[0125] A mixture of 4-fluorophenyl 4-nitrophenyl sulfone (1.89 g,
6.72 mmol) in methanol (80 ml) is treated with Rhodium on carbon
(5%, 95 mg) and hydrogenated at 20 psi for 24 hr. The mixture is
filtered, rinsing with methylene chloride (2.times.100 mL) and
methanol (100 mL). The filtrate is concentrated to near dryness and
refiltered, rinsing with minimal methanol. The solid is dried in
the vacuum oven at 50.degree. to give the desired amine,
mp=204-205.degree.: IR(drift)3473, 3373, 1638, 1592, 1489, 1303,
1294, 1285, 1231, 1159, 1144, 1107, 834, 713 and 689 cm.sup.-1; NMR
(300 MHz, CDCl3) 7.80-7.95, 7.60-7.75, 7.13, 6.60-6.75 and 4.17
.delta.; MS (EI) m/z 251 (M.sup.+), 140, 108, 95, 92, 80, 65, 65,
63 and 51.
[0126] Step III: 1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine
(V)
[0127] A mixture of 4-[(4-fluorophenyl)sulfonyl]phenylamine (IV,
Step II, 3.10 g, 12.3 mmol) in concentrated hydrochloric acid (30
mL) at 0.degree. is treated with sodium nitrite (934 mg, 13.5 mmol)
in H.sub.2O (15 mL). After 30 min, the mixture is treated with
stannous chloride (5.57 g, 24.7 mmol) in concentrated hydrochloric
acid (15 mL). The mixture is stirred at 0.degree. for 1 hr, and
then at 20-25.degree. for 1 hr. The precipitate is collected and
slurried in H.sub.2O. The mixture is made basic (sodium hydroxide,
50%) and the solid isolated. The material is partitioned between
methylene chloride and saline. The organic layer is dried,
filtered, and concentrated under reduced pressure to give the title
compound, NMR (300 MHz, CDCl.sub.3) 7.85-7.95, 7.74, 7.13, 6.85,
5.64 and 3.65 .delta..
Example 1
9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0128] 5
[0129] Step I: 1-Benzyl-4-azepanone
N-[4-(phenylsulfonyl)phenyl]hydrazone (VII)
[0130] A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (V,
PREPARATION 1, 7.06 g, 28.4 mmol) and 4-benzylazapanone (VI, 5.78
g, 28.4 mmol) in ethanol (130 mL) is treated with glacial acetic
acid (8 drops) and heated at reflux for 1 hr. Upon cooling, the
precipitate is collected, washed with ethanol and dried in the
vacuum oven at 50.degree. to give the desired compound,
mp=142-146.degree.. The filtrate is concentrated and purified via
flash chromatography (ethyl acetate/heptane; 65/35) to provide
additional product as two regioisomers. Analytical data for one
isomer: IR (drift) 1593, 1511, 1323, 1301, 1261, 1148, 1106, 1069,
833, 758, 748, 735, 709, 689 and 600 cm.sup.-1; NMR (300 MHz,
CDCl.sub.3) 7.85-7.95, 7.77, 7.40-7.65, 7.15-7.35, 7.06, 3.65,
2.65-2.85, 2.55-2.65, 2.35-2.45 and, 1.70-1.85; MS (EI) m/z 433
(M.sup.+), 186, 120, 108, 97, 96, 91, 82, 77, 65 and 51. Analytical
data for the slower eluting isomer: IR (drift) 1593, 1509, 1324,
1296, 1285, 1264, 1148, 1106, 1085, 1069, 834, 735, 710, 688 and
605 cm.sup.-1; NMR (300 MHz, CDCl.sub.3) 7.85-7.95, 7.70-7.85,
7.35-7.55, 7.15-7.35, 7.06, 3.60, 2.55-2.75, 3.32-2.45 and
1.85-2.00; MS (EI) m/z 433 (M.sup.+), 187, 186, 120, 108, 97, 91,
82, 77, 65 and 51.
[0131] Step II:
3-Benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4-
,5-b]indole (VIII)
[0132] A mixture of 1-benzyl-4-azepanone
N-[4-(phenylsulfonyl)phenyl]hydra- zone (VII, Step I, 3.41 g, 7.86
mmol) and polyphosporic acid (4.78 g) in o-xylene (550 mL) is
heated at 100.degree. under nitrogen for 3 hr. Upon cooling, the
xylene is decanted and the residual material partitioned between
methylene chloride/methanol and sodium hydroxide (0.5 M). The
phases are separated and the aqueous layer is further extracted
with more methylene chloride/methanol (2.times.). The organic
phases are combined and dried over anhydrous magnesium sulfate,
filtered, and concentrated under reduced pressure to give an oil.
The oil is purified by flash chromatography (Biotage 40M; ethyl
acetate/heptane, 7/3) to give the desired indole, mp=86-88.degree.,
dec; IR (drift) 3343, 2910, 1475, 1449, 1337, 1301, 1146, 1131,
1090, 748, 731, 719, 698, 688 and 627 cm.sup.-1; NMR (300 MHz,
CDCl.sub.3) 8.10-8.20, 8.06, 7.96, 7.66, 7.25-7.55, 3.85 and
2.90-3.05 .delta.; MS (EI) m/z 416 (M.sup.+), 296, 154, 146, 134,
134, 132, 120, 91 and 65.
[0133] Step III:
9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]ind- ole
(IX)
[0134] A mixture of
3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepi-
no[4,5-b]indole (VIII, Step II, 453 mg, 1.09 mmol) in methanol (50
mL) is treated with palladium hydroxide (118 mg) and hydrogenated
at 30 psi for 5 days. The mixture is filtered, rinsing with
methanol and methylene chloride, and the filtrate concentrated
under reduced pressure to give an amorphous solid. The material is
purified by flash chromatography (Biotage 40M; methanol/methylene
chloride, 5/95; methanol/methylene chloride/ammonium hydroxide,
20/79/1) to give the title compound. Analytical data for the
hydrochloride salt, mp=290-291.5.degree.; IR (drift) 3382, 2751,
2698, 2689, 2646, 2438, 1297, 1150, 1131, 1095, 801, 759, 722, 684
and 616 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 11.65, 7.35,
8.05-8.15, 7.85-7.95, 7.40-7.65, 3.20-3.40 and 3.10-3.25 8; MS (EI)
m/z 326 (M.sup.+), 298, 297, 286, 285, 284, 143 and 77; HRMS (FAB)
calculated for C.sub.18H.sub.19N.sub.2O.sub.2S=327.1167, found
327.1165.
Example 2
9-[(4-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0135] 6
[0136] Following the general procedure of EXAMPLE 1 (Steps I-III)
and making non-critical variations,
1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hyd- razine (V, PREPARATION
2) is converted to the title compound, mp=168.degree., dec.; IR
(drift) 2923, 1590, 1491, 1475, 1336, 1308, 1287, 1236, 1147, 1131,
1089, 837, 816, 749 and 683 cm.sup.-1; NMR (300 MHz, CDCl.sub.3)
8.05-8.15, 8.05, 7.90-8.00, 7.55-7.65, 7.30-7.35, 7.12, 3.05-3.15
and 2.90-3.00 .delta.; HRMS (FAB) calculated for
C.sub.18H.sub.18FN.sub.2O.sub.2S=345.1073, found 345.1087.
Example 3
9-[(4-Methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0137] 7
[0138] Following the general procedure of EXAMPLE 1 (Steps I-III)
and making non-critical variations,
1-[4-[(4-methylphenyl)sulfonyl]phenyl]hyd- razine (V, PREPARATION
2) is converted to the title compound, mp=125.degree., dec; IR
(drift) 3027, 2921, 2830, 1475, 1453, 1336, 1298, 1287, 1150, 1130,
1090, 812, 747, 682 and 658 cm.sup.-1; NMR (300 MHz, CDCl.sub.3)
8.12, 7.83, 7.55-7.65, 7.20-7.35, 3.05-3.20, 2.90-3.05 and 2.36
.delta.; MS (EI) m/z 340 (M.sup.+), 311, 298, 154, 144, 143, 115,
91, 91 and 65; HRMS (FAB) calculated for
C.sub.19H.sub.21N.sub.2O.sub.2S=- 341.1324, found 341.1311.
Example 4
9-[(4-Methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0139] 8
[0140] Following the general procedure of EXAMPLE 1, and making
non-critical variations,
1-[4-[(4-methylphenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)
is converted to the title compound, mp=139.degree., dec.; IR
(drift) 2927, 2837, 1593, 1496, 1335, 1312, 1293, 1260, 1142, 1130,
1092, 834, 802, 748 and 683 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6)
11.30, 7.90-8.00, 7.75-7.85, 7.40-7.50, 7.30-7.40, 7.00-7.10, 3.77
and 2.75-3.05; MS (EI) m/z 356 (M.sup.+), 327, 314, 155, 154, 143,
143, 115, 77 and 57; HRMS (FAB) calculated for
C.sub.19H.sub.21N.sub.2O.sub.3S=357.- 1273, found 357.1275.
Example 5
9-[(3-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0141] 9
[0142] Following the general procedure of EXAMPLE 1, and making
non-critical variations,
1-[4-[(3-fluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)
is converted to the title compound, mp=153-156.degree.: IR (drift)
2926, 2867, 2855, 1474, 1311, 1296, 1225, 1151, 1129, 1082, 773,
742, 698, 677 and 629 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 11.37,
8.00-8.10, 7.70-7.80, 7.30-7.75 and 2.75-2.95 .delta.; MS (EI) m/z
344 (M.sup.+), 315, 302, 154, 144, 143, 128, 128, 115 and 73; HRMS
(FAB) calculated for C.sub.18H.sub.18FN.sub.2O.sub.2S=34- 5.1073,
found 345.1075.
Example 6
9-[(3-Methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
hydrochloride (IX)
[0143] 10
[0144] Following the general procedure of EXAMPLE 1, and making
non-critical variations,
1-[4-[(3-methoxyphenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)
is converted to the title compound, mp=232-235.degree., dec.; IR
(drift) 2976, 2963, 2832, 2805, 2770, 2739, 1475, 1303, 1248, 1151,
1141, 746, 694, 682 and 629 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6)
11.63, 9.31, 8.10-8.15, 7.35-7.60, 7.10-7.20, 3.79, 3.20-3.40 and
3.05-3.40 .delta.; MS (EI) m/z 356 (M.sup.+), 327, 314, 107, 74,
73, 59, 57, 57 and 56; MS (FAB) m/z 357 (MH.sup.+), 356, 328, 177,
155, 121, 103, 89; HRMS (FAB) calculated for
C.sub.19H.sub.21N.sub.2- O.sub.3S=357.1273, found 357.1277.
Example 7
9-[(4-Trifluoromethyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]in-
dole hydrochloride (IX)
[0145] 11
[0146] Following the general procedure of EXAMPLE 1, and making
non-critical variations,
1-[4-[(4-trifluoromethylphenyl)sulfonyl]phenyl]h- ydrazine (V,
PREPARATION 2) is converted to the title compound,
mp=278-279.degree., dec.; IR (drift) 2773, 2756, 2732, 1321, 1306,
1178, 1156, 1133, 1122, 1108, 1061, 844, 716, 623 and 618
cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 8.05-8.20, 7.90-8.00,
7.55-7.45, 7.45-7.55 and 3.05-3.40 .delta.; MS (EI) m/z 394
(M.sup.+), 365, 352, 154, 143, 73, 71, 59, 58 and 57.
Example 8
6-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0147] 12
[0148] Step I:
3-Benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroaz- epino
[4,5-b]indole
[0149] A 0.degree. mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3
,4,5,6-hexahydroazepino [4,5-b]indole (EXAMPLE 1, Step II, 301 mg,
0.723 mmol) in dry DMF (5 mL) is treated with sodium hydride (60%
in oil, 32 mg, 0.795 mmol), and allowed to warm to 20-25.degree.
over 1.5 hr. The mixture is then cooled (0.degree.), treated with
iodoethane (64 .mu.L, 0.795 mmol) and allowed to slowly warm to
20-25.degree. under nitrogen over 72 hr. The resultant mixture is
diluted with ethyl acetate (50 mL) and washed with H.sub.2O
(3.times.25 mL) and saline (25 mL). The organic layer is dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to give a solid. The solid is purified via
chromatography (20 g SG; ethyl acetate/heptane, 65/35) to give the
indole as a solid, mp=188-191.degree.; IR (drift) 1477, 1373, 1300,
1289, 1157, 1148, 1094, 766, 756, 738, 728, 701, 694, 645 and 621
cm.sup.-1; NMR (300 MHz, CDCl.sub.3) 8.10-8.20, 7.90-8.05,
7.65-7.75, 7.20-7.50, 4.11, 3.82, 2.85-3.05 and 1.27 .delta.; MS
(EI) m/z 444 (M.sup.+), 326, 324, 312, 167, 154, 132, 118, 96, 91
and 64.
[0150] Step II: 6-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5
,6-hexahydroazepino[4,5-b]indole (X)
[0151] A mixture of
3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahy-
droazepino[4,5-b]indole (Step I, 107 mg, 0.241 mmol) in methanol
(20 mL, 1 drop concentrated hydrochloric acid) is treated with
palladium on carbon (10%, 32 mg) and hydrogenated at 25 psi for 48
hr. The resulting mixture is filtered, rinsing with methanol and
methylene chloride, and the filtrate is concentrated to a solid.
The solid is purified via chromatography (10 g SG;
methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give
the title compound, mp=224.degree., dec.; IR (drift) 2982, 2935,
2743, 1473, 1449, 1312, 1300, 1151, 1091, 819, 768, 728, 691, 647
and 623 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 8.09, 7.85-7.95,
7.45-7.65, 4.20, 2.95-3.25 and 1.15 .delta.; MS (EI) m/z 354
(M.sup.+), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS (FAB)
calculated for C.sub.20H.sub.23N.sub.2O.sub.2S=355.1480, found
355.1488.
Example 9
6-Ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]in-
dole hydrochloride (IX)
[0152] 13
[0153] Following the general procedure of EXAMPLE 8, and making
non-critical variations,
3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole (EXAMPLE 2) is converted to the
title compound, mp=227-233.degree., dec.; IR (drift) 2972, 2834,
2755, 2713, 2679, 1589, 1490, 1471, 1312, 1293, 1223, 1148, 1094,
715 and 693 cm.sup.-1; MS (EI) m/z 372 (M.sup.+), 331, 330, 171,
171, 154, 143, 143, 91 and 57; NMR (300 MHz, DMSO-d.sub.6) 9.30,
8.18, 8.02, 7.55-7.70, 7.41, 4.24, 3.10-3.40 and 1.19 .delta.; MS
(FAB) m/z 373 (MH.sup.+), 372, 371, 344 and 330; HRMS (FAB)
calculated for C.sub.20H.sub.22FN.sub.2O.sub.2S=3- 73.1386, found
373.1371.
Example 10
6-Methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]i-
ndole hydrochloride (IX)
[0154] Following the general procedure of EXAMPLE 8, and making
non-critical variations,
3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole (EXAMPLE 2) is converted to the
title compound, mp>300.degree.; IR (drift) 2775, 1589, 1489,
1310, 1288, 1237, 1149, 1091, 841, 836, 805, 718, 667, 639 and 605
cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 9.51, 8.17, 8.01, 7.63,
7.41, 3.72 and 3.10-3.45 .delta..
Example 11
6-Methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepin-
o[4,5-b]indole hydrochloride (IX)
[0155] 14
[0156] Following the general procedure of EXAMPLE 8, and making
non-critical variations,
3-benzyl-9-[(4-trifluoromethyl)phenyl]sulfonyl-1-
,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 7) is converted
to the title compound, mp=286.degree., dec.; IR (drift) 2740, 2716,
1321, 1309, 1187, 1172, 1155, 1132, 1109, 1098, 1063, 845, 719, 648
and 625 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 9.31, 8.19, 8.13,
7.93, 7.64, 3.71 and 3.10-3.40 .delta..
Example 12
6-Ethyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino-
[4,5-b]indole hydrochloride (IX)
[0157] 15
[0158] Following the general procedure of EXAMPLE 8, and making
non-critical variations,
3-benzyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1-
,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 7) is converted
to the title compound, mp=170-179.degree., dec.; IR (drift) 2762,
1326, 1302, 1294, 1190, 1184, 1171, 1153, 1138, 1109, 1095, 1064,
830, 716 and 618 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 9.40, 8.20,
8.14, 7.93, 7.65, 4.15-4.30, 3.10-3.45 and 1.10-1.20 .delta..
Example 13
6-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
hydrochloride (IX)
[0159] 16
[0160] Step I: 1-Benzoyl-4-azepanone
N-[4-(phenylsulfonyl)phenyl]hydrazone
[0161] A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (2.05 g,
8.26 mmol) and 4-benzoylazapanone (1.97 g, 9.09 mmol) in ethanol
(40 mL) is treated with glacial acetic acid (8 drops) and heated at
reflux for 1 hr. Upon cooling, the precipitate is collected, washed
with ethanol and dried in the vacuum oven (50.degree.) to give the
desired hydrazone, mp=202-204.degree..
[0162] Step II:
3-Benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[-
4,5-b]indole
[0163] A mixture of 1-benzoyl-4-azepanone
N-[4-(phenylsulfonyl)phenyl]hydr- azone (Step I, 2.00 g, 4.47 mmol)
in dichloroethane/phosphoric acid 84% (1/1, 40 mL) is heated at
reflux for 16 hr. Upon cooling, the product is diluted with saline
and extracted into methylene chloride (3.times.). The extracts are
dried, filtered, and concentrated under reduced pressure to give a
solid. The solid is purified via silica gel chromatography (Biotage
40M; ethyl acetate/heptane, 75/25) to give the desired indole.
[0164] Step III:
3-Benzoyl-6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahyd-
roazepino[4,5-b]indole
[0165] A 0.degree. mixture of
3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hex-
ahydroazepino[4,5-b]indole (Step II, 1.61 g, 3.74 mmol) in dry DMF
(18 mL) is treated with sodium hydride (60% in oil, 165 mg, 4.11
mmol). After 30 min, the mixture is treated with iodomethane (256
.mu.L, 4.11 mmol) and allowed to slowly warm to 20-25.degree. under
nitrogen over 16 hr. The resultant mixture is diluted with H.sub.2O
and filtered. The residual solid is triturated with refluxing
methanol, isolated, and dried in the vacuum oven at 50.degree. to
give the desired indole, mp=254-255.degree..
[0166] Step IV:
6-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4-
,5-b]indole hydrochloride
[0167] A mixture of
3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole (Step III, 1.25 g, 2.81 mmol) and potassium
hydroxide (1.58 g, 28.1 mmol) in ethylene glycol (30 mL) is heated
at 130.degree. under nitrogen for 92 hr. Upon cooling, the mixture
is diluted with H.sub.2O and extracted into ethyl acetate
(3.times.). The combined extracts are washed with H.sub.2O
(2.times.) and saline, dried over anhydrous magnesium sulfate,
filtered, and concentrated under reduced pressure to give a solid.
The solid is dissolved in hot methylene chloride/methanol and
treated with methanolic hydrochloric acid. The resultant mixture is
concentrated and crystallized from ethyl acetate/methanol to give
the title compound, mp>300.degree.; IR (drift) 2820, 2792, 2747,
2717, 2704, 2665, 2651, 1299, 1147, 1096, 803, 729, 687, 643 and
621 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) 9.41, 8.13, 7.85-7.95,
7.50-7.65, 3.70 and 3.10-3.40 .delta.; MS (EI) m/z 340 (M.sup.+),
298, 157, 156, 128, 78, 74, 73, 58 and 57; HRMS (FAB) calculated
for C.sub.19H.sub.21N.sub.2O.sub.2S=341.1324, found=341.1319.
Example 14
9-[(3,4-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0168] 17
[0169] Following the general procedure of EXAMPLE 1 (steps I-III)
and making non-critical variations,
1-[4-[(3,4-difluorophenyl)sulfonyl]phenyl- ]hydrazine (V,
PREPARATION 2) is converted to the title compound, mp=320.degree.,
dec; IR (drift) 2732, 1507, 1310, 1293, 1277, 1147, 1128, 1116,
1072, 800, 751, 686, 627, 622 and 610 cm.sup.-1; NMR (300 MHz,
DMSO-d.sub.6) .delta.11.75, 9.50, 8.10-8.20, 7.75-7.85, 7.55-7.70,
7.40-7.50, 3.25-3.40 and 3.10-3.25; OAMS (supporting ions at):
ESI+363.1, ESI-361.0.
Example 15
9-[(3,5-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(IX)
[0170] 18
[0171] Following the general procedure of EXAMPLE 1 (steps I-III)
and making non-critical variations,
1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl- ]hydrazine (V,
PREPARATION 2) is converted to the title compound,
mp=313-315.degree., dec; IR (drift) 3256, 1606, 1591, 1307, 1285,
1269, 1153, 1138, 1122, 983, 850, 795, 678, 666 and 618 cm.sup.-1;
NMR (300 MHz, DMSO-d.sub.6) .delta.11.70, 9.35, 8.15-8.25,
7.40-7.85 and 3.10-3.40; MS (EI) m/z 362 (M.sup.+), 333, 320, 154,
142, 127, 115, 113, 92 and 63.
Example 16
9-[(3,5-Difluorophenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-
-b]indole hydrochloride (IX)
[0172] 19
[0173] Following the general procedure of EXAMPLE 13 (steps I-IV)
and making non-critical variations,
1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl- ]hydrazine (V,
PREPARATION 2) (EXAMPLE 2) is converted to the title compound,
mp=337-340.degree., dec; IR (drift) 2767, 2750, 1603, 1437, 1308,
1295, 1144, 1129, 988, 807, 709, 681, 675, 650 and 627 cm.sup.-1;
NMR (300 MHz, DMSO-d.sub.6) .delta.9.35, 8.20-8.30, 7.60-7.80, 3.71
and 3.15-3.45; MS (EI) m/z 376 (M.sup.+), 334, 334, 156, 114, 113,
64, 63, 57, 52 and 51; HRMS (FAB) calculated for
C.sub.19H.sub.19F.sub.2N.sub.2O.- sub.2S=377.1135,
found=377.1125.
Example 17
9-[(4-(2-Hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole hydrochloride (IX)
[0174] 20
[0175] Following the general procedure of EXAMPLE 13 (steps I-IV)
and making non-critical variations,
1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hyd- razine (V, PREPARATION
2) is converted to the title compound, mp=285-287.degree., dec; IR
(drift) 2957, 2835, 2811, 2760, 1592, 1492, 1458, 1309, 1293, 1261,
1142, 1092, 721, 637 and 618 cm.sup.-1; NMR (300MHz, DMSO-d.sub.6)
.delta.9.43, 8.09, 7.81, 7.57, 7.06, 4.85-4.95, 3.95-4.05, 3.69 and
3.00-3.45; MS (EI) m/z 400 (M.sup.+), 86, 84, 77, 73, 72, 71, 58,
57, 56 and 51; HRMS (FAB) calculated for
C.sub.21H.sub.25N.sub.2O.sub.4S=401.1535, found=401.1540.
Example 18
3,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(X)
[0176] 21
[0177] A mixture of
6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepi-
no[4,5-b]indole (EXAMPLE 13, 341 mg, 1.00 mmol) in acetonitrile (5
mL) is treated with formaldehyde (37%, 0.400 mL, 5.00 mmol), sodium
cyanoborohydride (101 mg, 1.60 mmol) and glacial acetic acid (1
drop). After 5 hr, the mixture is diluted with ethyl acetate and
then washed with water and saline. The organic layer is dried,
filtered, and concentrated. The concentrate is dissolved in
methylene chloride/methanol and treated with methanolic
hydrochloric acid. The solvent is then removed and the residual
solid crystallized from hot ethyl acetate/methanol to give the
title compound, mp=283-286.degree.; IR (drift) 2523, 2477, 2453,
2428, 1479, 1311, 1304, 1283, 1150, 1094, 756, 730, 694, 644 and
623 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) .delta.11.00, 8.16,
7.85-7.95, 7.50-7.65, 3.70, 3.15-3.45 and 2.89; MS (FAB) m/z 355
(MH.sup.+), 354, 353, 58 and 44; HRMS (FAB) calculated for
C.sub.20H.sub.23N.sub.2O.sub.2S=355.1480, found=355.1488.
Example 19
3-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole
(X)
[0178] 22
[0179] Following the general procedure of EXAMPLE 18, and making
non-critical variations,
9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[- 4,5-b]indole
(EXAMPLE 1) is converted to the title compound, mp=150.degree.,
dec; IR (drift) 2623, 1474, 1447, 1338, 1301, 1173, 1152, 1129,
1090, 755, 741, 719, 689, 673 and 615 cm.sup.-1; NMR (300 MHz,
DMSO-d.sub.6) .delta.11.68, 8.14, 7.85-7.95, 7.40-7.65, 3.10-3.45
and 2.88; MS (EI) m/z 340 (M.sup.+), 296, 77, 74, 73, 72, 71, 58,
57, 56 and 51; HRMS (FAB) calculated for
C.sub.19H.sub.21N.sub.2O.sub.2S=341.1324, found=341.1331.
Example 20
9-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroaze-
pino[4,5-b]indole (X)
[0180] 23
[0181] Following the general procedure of EXAMPLE 18, and making
non-critical variations,
6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,-
6-hexahydroazepino[4,5-b]indole (EXAMPLE 10) ) is converted to the
title compound, mp=282-283.degree., dec; IR (drift) 2479, 2437,
1589, 1490, 1310, 1284, 1239, 1161, 1144, 1092, 838, 809, 718, 677
and 667 cm.sup.-1; NMR (300 MHz, DMSO-d.sub.6) .delta.10.60, 8.17,
7.99, 7.62, 7.39, 3.71, 3.10-3.75 and 1.31; MS (EI) m/z 400
(M.sup.+), 385, 328, 315, 169, 167, 127, 85, 71, 70 and 56; HRMS
(FAB) calculated for C.sub.22H.sub.26FN.sub.- 2O.sub.2S=401.1699,
found=401.1709.
Examples 21-44
[0182] Following the general procedure of the above EXAMPLEs,
making non-critical variations and starting with the corresponding
appropriate starting materials, the following compounds are
obtained:
[0183] 21.
1-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole
[0184] 22.
2-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole
[0185] 23.
4-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole
[0186] 24.
5-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]-
indole
[0187] 25.
9-[(4-Fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole
[0188] 26.
9-[(4-Fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole
[0189] 27.
9-[(4-Fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole
[0190] 28.
9-[(4-Fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazep-
ino[4,5-b]indole
[0191] 29.
1,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole
[0192] 30.
2,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole
[0193] 31.
4,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole
[0194] 32.
5,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,-
5-b]indole
[0195] 33.
9-[(4-Fluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0196] 34.
9-[(4-Fluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0197] 35.
9-[(4-Fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0198] 36.
9-[(4-Fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0199] 37.
9-[(3,5-Difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0200] 38.
9-[(3,5-Difluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0201] 39.
9-[(3,5-Difluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0202] 40.
9-[(3,5-Difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydro-
azepino[4,5-b]indole
[0203] 41.
9-[(3,5-Difluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexah-
ydroazepino[4,5-b]indole
[0204] 42.
9-[(3,5-Difluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexah-
ydroazepino[4,5-b]indole
[0205] 43.
9-[(3,5-Difluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexah-
ydroazepino[4,5-b]indole
[0206] 44.
9-[(3,5-Difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexah-
ydroazepino[4,5-b]indole 24 25 26
* * * * *