Benzofuran derivatives, their preparation and use

Details Benzofuran derivatives, their preparation and use Benzofuran derivatives, their preparation and use

2001-06-04

2002-12-10

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S466000, C548S467000, C544S376000, C546S196000, C546S201000, C546S277100, C546S284400, C546S283400, C514S469000, C514S470000, C514S337000, C514S339000, C514S326000

Reexamination Certificate

active

06492374

ABSTRACT:

The present invention relates to novel benzofuran derivatives potently binding to the 5-HT
1A
receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and are considered to be particularly useful for the treatment of depression.
BACKGROUND ART
Clinical studies of known 5-HT
1A
partial agonists such as e.g. buspirone, ipsapirone and gepirone have shown that 5-HT
1A
partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R.,
Drugs
1991, 41, 11). Preclinical studies indicate that full agonists also are useful in the treatment of the above mentioned anxiety related disorders (Schipper,
Human Psychopharm.,
1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of a beneficial effect of 5-HT
1A
partial agonists in the treatment of depression as well as impulse control disorders and alcohol abuse (van Hest,
Psychopharm.,
1992, 107, 474; Schipper et al,
Human Psychopharm.,
1991, 6, S53; Cervo et al,
Eur. J. Pharm.,
1988, 158, 53; Glitz, D. A., Pohl, R.,
Drugs
1991, 41, 11; Grof et al.,
Int. Clin. Psychopharmacol.
1993, 8, 167-172; Ansseau et al.,
Human Psychopharmacol.
1993, 8, 279-283).
5-HT
1A
agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchéz et al,
Psychopharmacology,
1993, 110, 53-59).
Furthermore, 5-HT
1A
agonists have been reported to show activity in animal models predictive for antipsychotic effects (Wadenberg and Ahlenius,
J. Neural. Transm.,
1991, 83,43; Ahlenius,
Pharmacol. & Toxicol.,
1989, 64, 3; Lowe et al.,
J. Med. Chem.,
1991, 34, 1860; New et al.,
J. Med. Chem.,
1989, 32, 1147; and Martin et al.,
J. Med Chem.,
1989, 32, 1052) and may therefore be useful in the treatment of psychotic disorders such as schizophrenia. Recent studies also indicate that 5-HT
1A
receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks,
Life Science
1990, 47, 1609) suggesting that 5-HT
1A
agonists are useful in the treatment of the side effects induced by conventional antipsychotic agents such as e.g. haloperidol.
5-HT
1A
agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn ,
Eur. J. Pharm.
1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT
1A
antagonists are useful in the treatment of senile dementia (Bowen et al., Trends Neur. Sci. 1992, 15, 84).
An overview of 5-HT
1A
antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al.,
Serotonin,
1997, Vol.2, Issue 7. It is stated that 5-HT
1A
antagonists may be useful in the treatment of schizophrenia, dementia associated with Alzheimer's disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
Both in animal models and in clinical trials it has been shown that 5-HT
1A
agonists exert antihypertensive effects via a central mechanism (Saxena and Villalón,
Trends Pharm. Sci.
1990, 11, 95; Gillis et al,
J. Pharm. Exp. Ther.
1989, 248, 851). 5-HT
1A
ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
5-HT reuptake inhibitors are well known antidepressant drugs and useful for the treatment of panic disorders and social phobia
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5HT
1A
receptor antagonist has been evaluated in several studies (Innis, R. B. et al.,
Eur. J. Pharmacol.,
1987, 143, p 195-204 and Gartside, S. E.,
Br. J. Pharmacol.
1995, 115, p 1064-1070, Blier, P. et al,
Trends Pharmacol. Sci.
1994, 15, 220). In these studies it was found that 5-HT
1A
receptor antagonists would abolish the initial brake on 5-HT neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a more rapid onset of therapeutic action.
Several patent applications have been filed which cover the use of a combination of a 5-HT
1A
antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A-714 663).
Accordingly, agents acting on the 5-HT
1A
receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity may be useful for the treatment of depression.
SUMMARY OF THE INVENTION
It has now been found that compounds of a certain class of benzofuran derivatives bind to the 5-HT
1A
receptor with high affinities. Furthermore, it has been found that many of these compounds have potent serotonin reuptake inhibition activity.
Accordingly, the present invention relates to novel compounds of the general Formula I:
wherein
R
1
is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalkyl, C
1-6
alkoxy, hydroxy, formyl, acyl, amino, C
1-6
alkylamino, C
2-12
dialkylamino, acylamino, C
1-6
alkoxycarbonylamino, aminocarbonylamino, C
1-6
alkylaminocarbonylamino, C
2-12
dialkylaminocarbonylamino, nitro, cyano, COOH, or COO—C
1-6
alkyl;
R
2
and R
3
are each independently selected from hydrogen, tifluoromethyl, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalkyl and C
1-6
alkoxy;
n is 1, 2, 3, 4 or 5;
m is 0 or 1;
A is selected from the following groups:
wherein
Z is O or S;
s is 0 or 1;
q is 0 or 1;
R
4
is hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
alkynyl, C
1-6
alkyl-Aryl, or C
1-6
-alkyl-O-Aryl,
D is a spacer group selected from branched or straight chain C
1-6
-alkylene, C
2-6
-alkenylene and C
2-6
-alkynylene;
B is a group selected from a group of formula (II), (III), and (IV)
wherein R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are each independently selected among the R
1
substituents;
or R
8
and R
9
together form a fused 5- or 6-membered ring optionally containing further heteroatoms;
or two of the groups of R
5
, R
6
and R
7
are linked together thereby forming a —o—(CH
2
)
p
—o—-bridge wherein p is 1 or 2;
Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, indol-2-on-1-yl, indol-2-on-3-yl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, hydroxy, C
1-6
alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C
3-8
cycloalkyl, C
3-8
cycloalkyl-C
1-6
alkyl, nitro, amino, C
1-6
alkylamino, C
2-12
dialkylamino, acylamino or alkylenedioxy;
its enantiomers, and pharmaceutically acceptable acid addition salt thereof.
In one embodiment of the invention A is a group of formula (1) and the other substituents are as defined above.
In another embodiment of the invention A is a group of formula (2) and the other substituents are as defined above.
In a third embodiment of the invention A is a group of formula (3) and the other substituents are as defined above.
In a fourth embodiment of the invention A is a group of formula (4) and the other substituents are as defined above.
Thus in a preferred embodiment of the invention A is a group of formula (1) and R
4
is methyl, ethyl, propyl, prop-2-en-1-yl, 2-furylmethyl, or 2-phenoxyethyl; q=0; or A is a group of formula (1) and Z is O and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (II), preferably a alkoxysubstituted phenyl, a benzodiox

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