5-heteroaryl substituted indoles

Details 5-heteroaryl substituted indoles 5-heteroaryl substituted indoles

2000-09-28

2003-08-05

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S339000, C514S333000, C514S323000, C514S241000, C514S242000, C514S247000, C514S256000, C514S255050, C514S252030, C514S183000, C546S193000, C546S201000, C546S256000, C546S268400, C546S274400, C544S179000, C544S180000, C544S182000, C544S238000, C544S333000, C544S405000

Reexamination Certificate

active

06602889

ABSTRACT:

This application is a 371 of PCT/DK99/00119, filed on Mar. 9, 1999.
The present invention relates to novel 5-heteroaryl substituted indoles having high affinity for &agr;
1
-adrenoceptors. According to their activity at &agr;
1
-adrenoceptors, the compounds of the invention are considered useful for the treatment of diseases or disorders responsive to &agr;
1
-adrenoceptor antagonists. 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 in general optionally 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-alkyamino. The compounds are claimed to be potent and long-lasting dopamine antagonists, and accordingly useful for the treatment of psychoses, and additionally 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
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. The compounds of the present invention differ from the compounds disclosed therein by being substituted in position 5 with an aromatic heterocyclic ring.
The compounds disclosed in WO 92/15301 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 Benign Prostatic Hyperplacia (BPH) and 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 peripherally effects. Prazosin has also in some animal models indicated effects in the central nervous system, although prazosin is considered to have poor CNS penetration. Until now, no &agr;
1
-adrenoceptor selective antagonist with good CNS penetration to the human brain has been described.
Evidence exists indicating that blockade of &agr;
1
-adrenoceptor neurotransmission could be beneficial in the treatment of schizophrenia. Most classical antipsychotics including clozapine bind potently to &agr;
1
-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 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 arrhytrnias and for the reduction of intra ocular pressure.
THE INVENTION
Accordingly, the present invention relates to 5-substituted indole derivatives having the general formula:
wherein
Het is a five or six membered aromatic heterocyclic ring containing at least one nitrogen as a ring member, and optionally substituted with one or more substituents selected from C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio and hydroxy;n is 0, or 1;
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, C
3-8
-cycloalkyl, C
3-8
-cycloalkyl-C
1-6
-alkyl, C
1-6
-alkyl, or C
2-6
-alkenyl, optionally 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, C
1-6
-alkyl or C
2-6
-alkenyl optionally 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 another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention relates to the use of a compound of formula I as defined above or an acid addition salt thereof and optionally a second pharmaceutically active ingredient for the manufacture of a pharmaceutical preparation for the treatment of a disorder or disease responsive to antagonism of &agr;
1
-adrenoceptor.
Diseases or disorders responsive to antagonism of &agr;
1
-adrenoceptors includes psychosis, mania, benign prostatic hyperplacia, hypertension, cardiac arrhytmias and reduction of intra ocular pressure.
In still another aspect, the present invention relates to the use of a compound of formula I as above and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of psychosis.
In a further aspect, the invention 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 of formula I as above and optionally a second pharmaceutically active ingredient to said mammal.
In still another aspect, the present invention relates to a method for the treatment of psychosis in a mammal comprising administering a compound of formula I as above and optionally a second agent having antipsychotic activity to said mammal.
Finally, the present invention relates to radio-labelled compounds of formula I and the use thereof in various biological assays and PET- or SPECT studies.


REFERENCES:
patent: 5317103 (1994-05-01), Baker et al.
patent: 5322851 (1994-06-01), Perregaard
patent: 497512 (1992-08-01), None
patent: 0 497 512 (1992-08-01), None
patent: WO 92/13856 (1992-08-01), None
patent: WO 92/13856 (1992-08-01), None
patent: WO 92/15301 (1992-09-01), None
patent: WO 94/03446 (1994-02-01), None

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