Indole and 2,3-dihydroindole derivatives, their preparation...

Details Indole and 2,3-dihydroindole derivatives, their preparation... Indole and 2,3-dihydroindole derivatives, their preparation...

2002-08-16

2004-04-27

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S323000, C514S338000, C514S339000, C546S197000, C546S201000, C546S277400, C546S277700, C546S278100

Reexamination Certificate

active

06727263

ABSTRACT:

The present invention relates to novel indole and 2,3-dihydroindole derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake. The compounds of the invention also possess antagonistic activity at 5-HT
1A
receptors and are considered to be particularly useful for the treatment of depression.
BACKGROUND
Selective serotonin (or 5-HT) reuptake inhibitors (SSRI's) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors). The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
SSRI's and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment is necessary to produce the therapeutic effect. The late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential. Further, one in three patients are not responsive to SSRI's.
Electrophysiological experiments in rats have shown that acute administration of SSRIs reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain, whereas sustained treatment with SSRIs leads to normalization of the firing activity of the 5-HT neurons (Arborelius, L. et al,
Naunyn-Schmiedeberg's Arch. Pharmacol.
1995, 352, 157; Gartside, S. E. et al,
Br. J. Pharmacol.
1995, 115, 1064; Chaput, Y. et al,
Naunyn
-
Schmiedeberg's Arch. Pharmacol.
1986, 33, 342).
Further, it has been shown that the recovery of the firing activity of 5-HT neurons is linked to desensitization of somatodendritic 5-HT
1A
autoreceptors (Le Poul, E. et al,
Naunyn
-
Schmiedeberg's Arch. Pharmacol.
1995, 352, 141; Invernizzi, RE. et al,
Eur. J. Pharmacol.
1994, 260, 243).
It has thus been suggested that simultaneous administration of SSRIs and an agent causing rapid desensitization or inhibition of the 5-HT
1A
receptor mediated feed back mechanism would lead to rapid onset of antidepressive effect (Artigas, F. et al,
Trends Neurosci.
1996, 19, 378; De Vry, J., et al,
Drug News Perspec.
1996, 9, 270)
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT
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 inhibit the decrease in firing caused by acute administration of serotonin reuptake inhibitors.
Further, treatment with a combination of pindolol (a well known 5-HT
1A
receptor and &bgr;-adrenoceptor antagonist) and SSRI's has been evaluated in clinical trials. A remarkable improvement of the mood of patients was reported within one week. In addition, combined administration of pindolol and a SSRI was shown to have a good effect on patients who were non-responsive to treatment with currently available antidepressants (Artigas F. et al.,
Arch. Gen. Psychiatry,
1994, 51, p 248-251 and Blier, P. et al.,
J. Clin. Psychopharmacol.
1995, 15, p 217-222).
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-A2-714 663).
In EP-A1-529 462 certain 1,4-benzodioxan derivatives having the general formula
wherein B is an optionally substituted indol-3-yl group and Q is C
n
H
2n
wherein n is 1, 2, 3, 4, 5, or 6 are disclosed. These compounds are said to have serotonin agonistic and serotonin antagonistic activity as well as serotonin reuptake inhibiting activity and to be useful as anxiolytics, antidepressants, antipsychotics, antihypertensives, and cerebroprotective agents.
In U.S. Pat. No. 5,200,948, Perregaard et al., disclose related indoles, indazoles, 2-indolones and 2,3-dihydro derivatives thereof having the formula
wherein X is —CH—, —CH
2
—, —NH—, or —CO—; and Ar is
wherein Y is O, or S, Z is O, S, or —CH
2
—, and n is 1, 2, or 3.
These compounds are valuable 5-HT
1A
receptor ligands.
OBJECT OF THE INVENTION
It is the object of the present invention to provide compounds with potent serotonin reuptake inhibiting activity as well as antagonistic properties at 5-HT
1A
receptors. Such compounds may be useful as fast onset of action medicaments for the treatment of affective disorders, such as depression.
A further object of the present invention is to provide a pharmaceutical composition comprising the above compounds as active ingredients.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following alone or in combination:
An indole or 2,3-dihydro-indole derivative having the formula
any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein
X is —O—, —S—, or —CR
4
R
5
—; and
Y is —CR
6
R
7
—, —CR
6
R
7
—CR
8
R
9
—, or —CR
6
═CR
7
—; or
X and Y together form a group —CR
4
═CR
5
—, or —CR
4
═CR
5
—CR
6
R
7
—;
Z is —O—, or —S—;
W is N, C, or CH;
A is a group selected from a group of formula (II), (III) and (IV)
wherein the dotted lines mean an optional bond;
R
1
, R
2
, R
3
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
are each independently selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro, cyano, and aryl or arylalkyl wherein aryl may be substituted with halogen, trifluoromethyl, alkoxy, hydroxy, amino, alkylamino, nitro and cyano;
R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are each independently selected from hydrogen and alkyl; and
R
11
is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl and formyl.
In one embodiment of the invention Z is —O—, and the other substituents are as defined above.
In another embodiment of the invention Z is —S—and the other substituents are as defined above.
In a third embodiment of the invention A is a group of formula (II) and the other substituents are as defined above.
In a fourth embodiment of the invention A is a group of formula (III) and the other substituents are as defined above.
In a fifth embodiment of the invention A is a group of formula (IV) and the other substituents are as defined above.
Thus, in a special embodiment of the invention A is a group of formula (II) and Z is —O, A is a group of formula (III) and Z is —O—, A is a group of formula (IV) and Z is —O—, A is a group of formula (II) and Z is —S—, A is a group of formula (III) and Z is —S—or A is a group of formula (IV) and Z is —S—.
In a further embodiment of the invention R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are selected from hydrogen or methyl.
Examples of compounds according to the invention are
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indole,
6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole,
6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole,
6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3,-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-&ls

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