5-aminoalkyl and 5-aminocarbonyl substituted indoles

Details 5-aminoalkyl and 5-aminocarbonyl substituted indoles 5-aminoalkyl and 5-aminocarbonyl substituted indoles

2002-03-08

2004-12-21

Chang, Celia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S201000

Reexamination Certificate

active

06833376

ABSTRACT:

The present invention relates to novel 5-aminoalkyl and 5-aminocarbonyl substituted indoles having high affinity for &agr;
1
-adrenoceptors. The compounds of the invention are considered useful for the treatment of diseases or disorders responsive to antagonism of the &agr;
1
-adrenoceptor. Further, as the compounds are selective &agr;
1
-adrenoceptor ligands they may be particularly useful as PET or SPECT ligands.
BACKGROUND
U.S. Pat. No. 4.710.500 discloses 5-substituted indole derivatives having the general formula:
The compounds may be substituted in position
5
with a substituent selected from halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, CF
3
, lower alkylsulphonyl, amino, lower alkylamino and lower di-alkylamino. The compounds are claimed to be potent and long-lasting dopamine antagonists, and accordingly useful for the treatment of psychoses. The compounds are also claimed to be strong 5-HT antagonists indicating effects in the treatment of negative symptoms of schizophrenia and depression and for the treatment of cardiovascular diseases.
The use of sertindole having the formula
as an antipsychotic is specifically claimed in EP-A2-0 392 959.
This type of compounds has also been shown to be useful for the treatment of a range of other disorders including anxiety (WO 92/00070), cognitive disorders (WO 92/15303), abuse (WO 92/15302) and hypertension (WO 92/15301).
WO 92/15301 discloses compounds having affinity for the &agr;
1
-adrenoceptor. However, the compounds disclosed therein are not selective for the &agr;
1
-adrenoceptor.
Interest in the development of &agr;
1
-adrenoceptor antagonists has primarily focused on therapeutics for the treatment of cardiovascular diseases (Hieble et al.,
Exp. Opin. Invest. Drugs,
1997, 6, 3657). Prazosin is the prototype of an &agr;
1
-adrenoceptor antagonist which has very potent peripheral effects. Prazosin is considered to have poor CNS penetration although it in some animal models have shown effects indicating potency in the central nervous system. Until now, no &agr;
1
-adrenoceptor selective antagonists with good CNS penetration to the human brain have been available.
Evidence exists indicating that blockade of &agr;
1
-adrenoceptor neurotranstission could be beneficial i the treatment of schizophrenia. Most classical antipsychotics including clozapine b potently to a,-adrenoceptors labelled with [
3
H]prazosin or [
3
H]WB-4101. Some studies seem to indicate a central role of the &agr;
1
-component for the atypical profile of clozapine. ( Baldessarini, et al.,
Br. J. Psychiatry,
1992, 160, 12-16 and Prinssen, et al.,
Eur. J. PharmacoL,
1994, 262, 167-170). Further, repeated co-administration of prazosin and haloperidol was found to reduce the effect of haloperidol on the firing of dopamine neurons in nigrostriatal areas, suggesting that the combination would be effective as antipsychotic treatment without producing extrapyramidal side effects (EPS) (Chiodo, et al.,
J Neurosci.
1985, 3, 2539-2544).
It has also been suggested that centrally acting &agr;
1
-adrenoceptor antagonists will have antimanic effects while corresponding agonists would be beneficial for the treatment of depression (Lipinsky, et al.,
Life Sciences,
1987, 40, 1947-1963).
Labelled compounds of the present invention are considered to be valuable PET (positron emission tomography) ligands and SPECT (single photon emission computed tomography) ligands due to their selectivity for &agr;
1
-adrenoceptors.
Finally, it is well established that &agr;
1
-adrenoceptor antagonists acting peripherally are useful for the treatment of benign prostatic hyperplacia, hypertension and cardiac arrhyttnias and for the reduction of intra ocular pressure.
THE INVENTION
Accordingly, the present invention relates to 5-aminoalkyl and 5-aminocarbonyl substituted indole derivatives having the general formula:
wherein
R
1
is —(CH
2
)
n-1
,—CONR
10
R
11
, —(CH
2
)
n
-NR
10
R
11
or
wherein R
10
and R
11
independently are selected from hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl C
3-8
-cycloalkyl, C
3-8
-cycloalkyl-C
1-6
-alkyl, aryl-C
1-6
-alkyl, aryl, acyl, amino-C
1-6
-alkyl and mono- or di-C
1-6
-alkylamino-C
1-6
-alkyl, R
12
is hydrogen or C
1-6
-alkyl, n is 1 to 3 and q is 2 to 5;
G is N, C, or CH; the dotted line meaning a bond when G is C, and the dotted line meaning no bond when G is CH, or N;
Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C
1-6
-alkyl, C
1-6
-alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
R
2
, R
3
, R
4
and R
5
are independently selected from hydrogen, C
1-6
-alkyl, C
1-6
-alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, C
1-6
-alkylamino and C
1-6
-dialkylamino;
R
6
is hydrogen, or C
3-8
-cycloalkyl, C
3-8
-cycloalkyl-C
1-6
-alkyl, C
1-6
-alkyl, C
2-6
-alkenyl or C
2-6
-alkenyl, which may optionally be substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive, or R
6
is a group of the Formula II or III:
wherein m is an integer from 2-6;
W is O, or S;
U is N or CH;
Z is —(CH
2
)
p
-, p being 2 or 3, or Z is —CH═CH—or 1,2-phenylene optionally substituted with halogen or trifluoromethyl, or Z is —COCH
2
- or —CSCH
2
-;
V is O, S, CH
2
, or NR
9
, wherein R
9
is hydrogen, or C
1-6
-alkyl, C
2-6
-alkenyl or C
2-6
-alkenyl which may optionally be substituted with one or two hydroxy groups, or a C
3-8
-cycloalkyl or C
3-8
-cycloalkyl-C
1-6
-alkyl group; X is N, C, or CH; Y is N, C, or CH; provided at least one of X and Y is N; and R
7
is hydrogen, or C
1-6
-alkyl;
or a pharmaceutically acceptable acid addition salt thereof
In a particular embodiment, the present invention relates to compounds wherein R
1
is —CONR
10 R
11
or —(CH
2
)
n
-NR
10
R
11
wherein R
10
and R
11
are independently selected from hydrogen, C
1-6
alkyl and acyl.
In another particular embodiment, R
6
is a group of formula II, in particular a 2-imidazolidinon ring.
Such compounds include in particular the compounds:
1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-N-methyl-1H-indole-5-carboxamide;
N,N-Dimethyl-1-(4fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-1H-indole-5-carboxamide;
1-[2[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl ]ethyl]2-imidazolidinon;
1-[2[4[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-2-imidazolidinon;
1-[2[4-[1-(4fluorophenyl)-5-methylaminomethyl-1H-indol-3-yl]-1-piperidinyl]ethyl ]-2-imidazolidinon; or
1-[2[4-[5-aminomethyl-1-(4fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl ]-2-irnidazolidinon;
or a pharmaceutically acceptable acid addition salt thereof.
The present invention also relates to a pharmaceutical composition comprising at least one compound as above or a pharmaceutically acceptable acid addition salt thereof and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carrier or diluents.
The present application relates to the use of a compound as above and optionally a second pharmaceutically active ingredient for the preparation of a medicament for the treatment of a disorder or disease responsive to antagonism of &agr;
1
-adrenoceptors.
The present invention also relates to a method for the treatment of a disorder or disease responsive to antagonism of &agr;
1
-adrenoceptors in a mammal comprising administering a compound as above or an acid addition salt thereof and optionally a second pharmaceutically active ingredient to said mammal.
In a particular embodiment, the second pharmaceutically active ingredient is a

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