1,2,3,4,5,6,-hexahydroazepino [4,5-b]indoles...

Details 1,2,3,4,5,6,-hexahydroazepino [4,5-b]indoles... 1,2,3,4,5,6,-hexahydroazepino [4,5-b]indoles...

2000-07-11

2002-10-22

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S580000

Reexamination Certificate

active

06468999

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is substituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) which are useful for treating anxiety, depression and other CNS disorders in humans and animals.
2. Description of the Related Art
U.S. Pat. No. 3,652,588 discloses 6-alkyl-1,2,3,4,5,6-hexahydroazepino[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.
U.S. Pat. No. 3,839,357 discloses 6-benzyl-1,2,3,4,5,6-hexahydroazepino[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.
U.S. Pat. No. 3,676,558 discloses 6-alkyl-1,2,3,4,5,6-hexahydroazepino[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
Disclosed is a 9-arylsulfone of the formula (XII)
where R
3
is:
(1) —H,
(2) C
1
-C
4
alkyl,
(3) C
0
-C
4
-&phgr; where the −&phgr; substituent is optionally substituted with 1 or 2
(a) —F, —Cl, —Br, —I,
(b) —O—R
3-1
where R
3-1
is:
—H,
C
1
-C
4
alkyl,
—&phgr;,
(c) —CF
3
,
(d) —CO—NR
3-2
R
3-3
where R
3-2
and R
3-3
are —H and C
1
-C
4
alkyl, and where R
3-2
and R
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
2
—R
3-4
where R
3-4
is —H and C
1
-C
4
alkyl,
(f) —NR
3-2
R
3-3
where R
3-2
and R
3-3
are as defined above,
(g) —NR
3-4
—CO—R
3-4
where R
3-4
is as defined above,
(h) —SO
2
—NR
3-2
R
3-3
where R
3-2
and R
3-3
are as defined above,
(I) —C≡N,
(j) —NO
2
,
where R
N
is:
(1) —H,
(2) C
1
-C
4
alkyl,
(3) C
0
-C
4
-&phgr; where the —&phgr; substituent is optionally substituted with 1 or 2
(a) —F, —Cl, —Br, —I,
(b) —O—R
N-1
where R
N-1
is
—H,
C
1
-C
4
alkyl,
—&phgr;,
(c) —CF
3
,
(d) —CO—NR
N-2
R
N-3
where R
N-2
and R
N-3
are —H and C
1
-C
4
alkyl, and where R
3-2
and R
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
2
—R
N-4
where R
N-4
is —H and C
1
-C
4
alkyl,
(f) —NR
N-2
R
N-3
where R
N-2
and R
N-3
are as defined above,
(g) —NR
N-4
—CO—R
N-4
where R
N-4
is as defined above,
(h) —SO
2
—NR
N-2
R
N-3
where R
N-2
and R
N-3
are as defined above,
(I) —C≡N,
(j) —NO
2
,
where R
x
is:
(1) —H
(2) —F, —Cl, —Br, —I,
(3) —O—R
x−1
where R
x−1
is:
—H,
C
1
-C
4
alkyl,
—&phgr;,
(4) —CF
3
,
(5) —CO—NR
x−2
R
x−3
where R
x−2
and R
x−3
are as defined above,
(6) —NH—SO
2
—R
x−4
where R
x−4
is as defined above,
(7) —NR
x−2
R
x−3
where R
x−2
and R
x−3
are as defined above,
(8) —NR
x−4
—CO—R
x−4
where R
x−4
is as defined above,
(9) —SO
2
—NR
x−2
R
x−2
where R
x−2
and R
x−3
are as defined above,
(10) —C≡N,
(11) —NO
2
;
where R
9
is:
(1) —H,
(2) —F, —Cl,
(3) C
1
-C
4
alkyl,
(4) C
1
-C
3
alkoxy,
(5) —CF
3
,
(6) C
0
-C
4
-&phgr; where the —&phgr; substituent is optionally substituted with 1 or 2
(a) —F, —Cl, —Br, —I,
(b) —O—R
9-1
where R
9-1
is:
—H,
C
1
-C
4
alkyl,
—&phgr;,
(c) —CF
3
,
(d) —CO—NR
9-2
R
9-3
where R
9-2
and R
9-3
are —H and C
1
-C
4
alkyl, and where R
9-2
and R
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
2
—R
9-4
where R
9-4
is —H and C
1
-C
4
alkyl,
(f) —NR
9-2
R
9-3
where R
9-2
and R
9-3
are as defined above,
(g) —NR
9-4
—CO—NR
9-4
where R
9-4
is as defined above,
(h) —SO
2
—NR
9-2
R
9-3
where R
9-2
and R
9-3
are as defined above,
(I) —C≡N,
(j) —NO
2
(7) —OR
9-1
where R
9-1
is as defined above,
(8) —CO—NR
9-2
R
9-3
where R
9-2
and R
9-3
are as defined above,
(9) —NR
9-2
R
9-3
where R
9-2
and R
9-3
are as defined above,
(10) —NH—SO
2
—NR
9-4
where R
9-4
is as defined above,
(11) —NH—CO
2
—R
9-2
where R
9-2
is as defined above,
and pharmaceutically acceptable salts thereof.
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 &phgr;—CH
2
—, &phgr;—CO—, &phgr;—CH
2
—CO
2
— and —CO—O—C(CH
3
)
3
and where R
9
and R
x
are as defined above.
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
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 (XII) includes both the unsubstituted 9-arylsulfones (IX), where R
3
is —H and substituted 9-arylsulfones (X) where R
3
is ≠ 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.
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
9
substituents and R
9
includes —H, —F, —Cl, C
1
-C
3
alkyl, C
1
-C
3
alkoxy and —CF
3
; it is preferred that R
9
is —H, —F, —Cl, C
1
alkyl, C
1
alkoxy, and —CF
3
and when F- it is preferred that it be in the 4- or p-position. It is preferred that the R
9
substituent be in either the 3- or 4-position.
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
x
groups. If R
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
x
substitutent (other than —H) to the unsubstituted 9-arylsulfone (IX) once it is formed. Therefore, the R
x
group should be part of the appropriately substituted 4-chloro-1-nitrobenzene (II) when it is reacted with the thiol (I). R
x
includes of —H, —F and —Cl; it is preferred that R
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).
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 corre

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