Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-02
2002-05-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254010, C514S254020, C514S254030, C514S326000, C544S368000, C544S373000, C544S375000, C544S376000, C546S196000, C546S197000, C546S198000, C546S199000, C546S201000
Reexamination Certificate
active
06391882
ABSTRACT:
The present invention relates to novel 4, 5, 6 and 7-indole and indoline 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 SSRI's reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain, whereas sustained treatment with SSRI's 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; Invemizzi, R. et al,
Eur. J. Pharmacol
. 1994, 260, 243).
It has thus been suggested that simultaneous administration of SSRJ's 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. Phannacol
. 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).
DE patent application No. 4414113 discloses certain 4-(indol-3-yl)-1-(indol-3-yl-alkylene)-piperidines having the general formula
wherein n is 2-6 and the other substituents are as defined in the application. The compounds herein are claimed to have serotonin antagonistic and agonistic activities and to have effect on DOPA-accumulation in striatum and 5-HTP accumulation in N. Raphe. No biological data are given.
WO patent publication No. 94/21626 discloses compounds having the general formula
wherein R
2
is heteroaryl and the other substituents are as defined in the application. A compound wherein R
2
is 5-indolyl which is structurally closely related to the compounds of the invention is specifically mentioned herein. No data are given. The compounds are only said to give K
i
values of less than 1.5 &mgr;M in a test for displacement of
3
H spiperone from human dopamine D
4
receptor subtypes in clonal cell lines. WO patent publication No. 94/21627 and No. 94/21630 relate to similar compounds having affinity for human dopamine D
4
receptors.
WO patent publication No. 95/33721 relates to 1-(indanemethyl, dihydrobenzo-furanylmethyl, dihydrobenzothiophenylmethyl)piperidine,tetrahydro-pyridine, or piperazine derivatives having the general formula
wherein one of X and Y is CH
2
and the other is selected from the group consisting of CH
2
, O, or S, Ar is aryl or heteroaryl, e.g. 1-, 2-, or 3-indolyl and the other substituents is as defined in the application. The compounds interact with central 5-HT receptors, in particular with 5-HT
1A
and 5-HT
2A
receptors. Some of the compounds are said to have 5-HT reuptake inhibiting effect.
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 these compounds as active ingredients.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following alone or in combination:
A substituted 4-, 5-, 6-, or 7-indole or indoline derivative of formula (I)
wherein W is N, C, CH or COH and the dotted lines indicate optional bonds and
wherein A is a group having the formula
wherein X is CR
1A
, CHR
1A
, N, NR
1B
, O, or S, where R
1A
is as defined for R
3
to R
9
below, and where R
1B
is as defined for R
10
below;
Y is CR
2A
, CHR
2A
, N, NR
2B
, O, or S, where R
2A
is as defined for R
3
to R
9
below and where R
2B
is as defined for R
10
below, and
the dotted lines indicate optional bonds;
provided that X and Y are not both O or S;
A is a group having the formula
wherein
X is CR
1A
, CHR
1A
, N, NR
1B
, O, or S, where R
1A
is as defined for R
3
to R
9
below, and where R
1B
is as defined for R
10
below;
U is C, CH, orN; and
the dotted lines indicate optional bonds;
A is a group having the formula
wherein
U is C, CH, or N;
Y is CR
2A
, CHR
2A
, N, NR
2B
, O, or S, where R
2A
is as defined for R
3
to R
9
below and where R
2B
is as defined for R
10
below;
and the dotted lines indicate optional bonds;
n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, 4, or 5;
Z is CH
2
, O, S, CO, SO, or SO
2
, provided that if n is 0 then Z is CH
2
;
R
3
-R
9
and R
11
to R
12
are independently selected from hydrogen, halogen, cyano, nitro, C
1-6
-alk(en/yn)yl, C
1-6
alkoxy, C
1-6
-alkylthio, hydroxy, hydroxy-C
1-6
-alkyl, C
1-6
-alkoxycarbonyl, C
3-8
-cycloalk(en)yl, C
3-8
-cycloalk(en)yl-C
1-6
-alk(en/yn)yl, C
1-6
-alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, C
1-6
alkylsulfonyl, aryl and heteroaryl, and/or two adjacent groups taken from R
3
-R
9
may together form a methylenedioxy group,
and/or two adjacent groups R
7
-R
9
may together form a cyclopentyl or cyclohexyl ring which may be substituted with one or more methyl groups,
and/or one of R
3
-R
9
may alternatively be a group —NR
13
R
14
wherein R
13
is as defined for R
10
below and R
14
is hydrogen, C
1-6
-alk(en/yn)yl, C
3-8
-cycloalk(en)yl, C
3-8
-cycloalk(en)yl-C
1-6
alk(en/yn)yl, aryl, heteroaryl, aryl-C
1-6
alkyl, or hete
Korg-Jensen Christian
Mikkelsen Ivan
Moltzen Ejner Knud
Darby & Darby
H. Lundbeck A/S
Raymond Richard L.
Truong Tamthom N.
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