2-phenylindoles as antiestrogenic pharmaceutical agents

Details 2-phenylindoles as antiestrogenic pharmaceutical agents 2-phenylindoles as antiestrogenic pharmaceutical agents

2000-05-26

2003-01-07

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S339000, C514S397000, C546S277400, C548S509000, C548S312100

Reexamination Certificate

active

06503938

ABSTRACT:

This invention relates to 2-phenylindoles, a process for their production, pharmaceutical preparations that contain the latter as well as their use for the production of pharmaceutical agents.
The new 2-phenylindoles are reproduced by general formula I
in which
R
1
means one of the radicals —(CH
2
)
n
—S(O)
m
—R
4
, —(CH
2
)
n
—NR
6
—SO
2
—R
4
, —(CH
2
)
m′
whereby n and n′ are integers from 4 to 12 and m and m′ are 0, 1 or 2, and X stands for a methylene group, an imino group ═NR
6
, an oxygen or sulfur atom,
R
2
and R
3
, independently of one another, mean a hydrogen atom, a C
1
to C
10
alkyl group, a benzyl, alkanoyl or alkanoyloxy or carbamoyl radical of formula —C(O)R
5
or —C(O)NR
6
R
7
or a tetrahydropyranyl group,
R
4
means a hydrogen atom, a C
1
to C
10
alkyl group, a completely or partially fluorinated alkyl group —(CH
2
)
o
—(CF
2
)
p
CF
3
, whereby o and p, independently of one another, are in each case an integer from 0 to 6, an (alkyl)amino or (alkyl)carbamoyl group of formula —(CH
2
)
q
—Y—NR
8
R
9
, whereby q is an integer from 0 to 6 and Y stands for a direct bond, a methylene or carbonyl group, but if Y means a carbonyl group and m is 2, q cannot be 0, an aryl, aralkyl or heteroaryl radical,
R
5
means a C
1
to C
10
alkyl or C
1
to C
10
alkyloxy group, a phenyl or benzyl radical,
R
6
, R
7
, R
8
and R
9
, independently of one another, mean a hydrogen atom, a C
1
to C
10
alkyl or benzyl group, and R
10
means a methyl group and R
11
means a hydrogen atom or R
10
and R
11
together mean a di-, tri- or tetramethylene bridge, which also can have a C—C double bond anywhere in the bridge.
As alkyl groups with 1 to 10 carbon atoms for radicals R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
, the radicals methyl, ethyl, propyl, butyl, pentyl, hexyl, hepty, octyl, nonyl and decanyl and also their branched-chain variants, for example the isopropyl, isobutyl or tert-butyl radicals, are suitable. Cycloalkyl groups with 3 to 10 carbon atoms, and among them especially the cyclopentyl or cyclohexyl radical, can also be mentioned.
A phenyl, 1- or 2-naphthyl radical can stand for an aryl radical R
4
; primarily a benzyl radical, but also a phenethyl, 1- or 2-naphthylmethyl radical can stand for an aralkyl radical R
4
; and mainly a 2-, 3- or 4-pyridinyl radical or an imidazolyl radical, which can carry a low alkyl group (C
1
-C
4
), for example a methyl group, but also a 2-pyrazine, 2-, 4- or 5-pyrimidine, 3-pyrazine as well as a 2- or 3-thiophene radical on the nitrogen atom can stand for a heteraryl radical R
4
.
If R
5
is to be a C
1
-C
10
alkoxy radical, this is primarily a methoxy, ethoxy, n- or isopropoxy, n-, iso- or tert-butoxy radical.
n or n′ preferably stands for an integer from 6 to 12, m can be 0, 1 or 2, all indicated meanings are equally possible for o and p; the combinations o=3 and p=1 as well as o=0 and p=0 are to be emphasized for the partially fluorinated alkyl radical R
4
; finally, q is preferably selected from the range of 2 to 5.
Radicals R
2
and R
3
preferably each represent a hydrogen atom.
The meanings of n, n′, m, m′, R
4
with o, p, q, Y, R
8
and R
9
and R
6
are selected together such that R
1
preferably forms one of the following side chains:
—(CH
2
)
10
—S—(CH
2
)
4
CH
3
—(CH
2
)
10
—SO—(CH
2
)
4
CH
3
—(CH
2
)
10
—SO
2
—CH
2
4
CH
3
—(CH
2
)
12
—SO—CH
2
)
2
CH
3
—(CH
2
)
12
—SO
2
CH
2
)
2
CH
3
—(CH
2
)
8
—S—(2-Pyridinyl)
—(CH
2
)
10
—S—[2-(N-Methyl)imidazolyl]
—(CH
2
)
11
—N(—CH
3
)—SO
2
—(CH
2
)
2
CH
3
—(CH
2
)
11
—N(—CH
3
)—SO
2
—CH
2
-Phenyl
—(CH
2
)
10
—SO
2
—N(—CH
3
)—(CH
2
)
3
CH
3
—(CH
2
)
9
—SO—(CH
2
)
3
C
2
F
5
—(CH
2
)
9
—SO
2
—CH
2
)
3
C
2
F
5
—(CH
2
)
10
—S—CH
2
—CO—N(—CH
3
)—CH(CH
3
)
2
—CH
2
—p—C
6
H
4
—O—(CH
2
)
4
—SO
2
—C
5
H
11
—(CH
2
)
6
—S—(CH
2
)—CO—N(—CH
3
)—(CH
2
)
3
CH
3
Radical —OR
2
can be present in the 4-, 5-, 6- or 7-position of the bicyclic compound of the phenylindole (benzo[a]carbazole).
Especially preferred are those compounds of general formula I in which radical —OR
2
is bound to carbon atom 5.
The compounds that are mentioned below are preferred within the scope of this invention:
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylthio)-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylsulfonyl)-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-(propylsulfonyl)-dodecyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfonyl)-nonyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[8-(2-pyridinylthio)-octyl]-indole
1-[10-(n-butyl-methylsulfamoyl)-decyl]-5-hydroxy-(4-hydroxyphenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[11-(N-methyl-propylsulfonamido)-undecyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[11-(N-methyl-phenylmethanesulfonamido)-undecyl]-indole
1-{6-[3′-(n-butyl-methylcarbamoyl)-propylthio]-hexyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylsulfinyl)-decyl)-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-indole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylthio)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylsulfonyl)-decyl]benzo[a]carbazole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[10-(pentylthio)-decyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[10-(pentylsulfonyl)-decyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[12-(propylsulfonyl)-dodecyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-indole
1-[10-(n-butyl-methylsulfamoyl)-decyl]-5-methoxy-2-(4-methoxyphenyl)-3-methylindole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[8-(2-pyridinylthio)-octyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[11-(N-methyl-propylsulfonamido)-undecyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[11-(N-methyl-phenylmethanesulfonamido)-undecyl]-indole
1-(6-mercaptohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methylindole
1-{6-[3′-(n-butyl-methylcarbamoyl)-propylthio]-hexyl}-5-methoxy-2-(4-methoxy-phenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-(propylsulfinyl)-dodecyl]-indole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylthio)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylsulfonyl)-decyl]benzo[a]carbazole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-[2-(N-methyl-imidazolyl)thio]-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-[(methyl-iso-propylcarbamoyl)-methylthio]-decyl]-indole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylsulfinyl]-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[9-(4,4,5,5,5-pentafluoropentylsulfonyl)-nonyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylmethylsulfamoyl)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-[2-(N-methyl-imidazolyl)thio]-decyl]benzo[a]carbazole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butoxy]-phenyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butoxy]-benzyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butyl]methylamino]-phenyl]-indole
Especially to be emphasized within the scope of this invention are those compounds of general formula I, in which R
10
together with R
11
stand for an ethano or etheno bridge. For these compounds, the radicals R
1
that are already mentioned above also are regarded as preferred.
It h

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