Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-18
2003-05-13
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S214020, C514S249000, C514S299000, C514S306000, C540S579000, C540S593000, C544S349000, C546S112000, C546S138000, C546S183000
Reexamination Certificate
active
06562809
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to 3-bicycloindole compounds, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the treatment or diagnosis of CNS conditions.
BACKGROUND TO THE INVENTION
Through its interaction with receptors borne on neuronal and other cells, 5-hydroxytryptamine (5-HT or serotonin) exerts various physiological effects. Imbalances in this interaction are believed to be responsible for such conditions as anxiety, hallucination, migraine, chemotherapy-induced nausea and for disorders in sexual activity, cardiovascular activity and thermoregulation, among others. From an improved understanding of the 5-HT receptor population, it is apparent that these effects are mediated selectively through individual types and subtypes of the 5-HT receptors. Migraine, for example, has been treated with ergotamine, dihydroergotamine, methylsergide and, most recently, sumatriptan, all of which presumably act at 5-HT
1D
receptor subtype.
Current treatments for migraine, including sumatriptan, continue to have unwanted side effects. These include coronary vasospasm, hypertension and angina. Recent evidence suggests that sumatriptan's contraction of coronary arteries may be mediated by its stimulation of the 5-HT
1B
(formerly 5-HT
1D&bgr;
) subtype of the 5-HT receptors (Kaumann, A. J. Circulation, 1994, 90:1141-1153).
Given the physiological and clinical significance of the 5-HT
1D
receptor, and the potential side effect liability of stimulation of its 5-HT
1B
receptor, it would be desirable to provide compounds that bind with high affinity to the 5-HT
1D
receptor. Such compounds would be medically useful, for example, to treat indications such as migraine and others for which administration of a 5-HT
1D
ligand is indicated. Also they could be used diagnostically, for example, to identify these receptors and to screen drug candidates.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there are provided compositions, either for use as reagents, for example in the identification of 5-HT
1D
receptors or receptor ligands, or for pharmaceutical use to treat conditions where stimulation of the 5-HT
1D
receptor is indicated, containing the compounds of Formula I:
wherein:
R
1
is selected from the group consisting of a group of Formula II:
H, halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
1-7
cycloalkenyl, C
3-7
cycloalkoxy, C
3-7
cycloalkylthio, halo-substituted-C
1-6
alkyl, C
1-6
alkylthio, C
2-7
alkanoyl, C
2-7
alkanoyloxy, nitro, cyano, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted phenyloxy, CH
2
SO
2
NR
7
R
8
, C(O)R
9
, OC(O)R
9
, NR
14
R
15
, C(O)NR
14
R
15
, SO
2
NR
14
R
15
, CO
2
R
16
, NHC(O)R
17
, NHC(NR
16
)R
17
, C(NR
19
)NR
20
R
21
, SCF
3
, SO
2
CF
3
, formyl, CF
3
and CF
3
O;
X is selected from the group consisting of O, S, SO, SO
2
, NR
10
and CR
11
R
12
;
- - - - - , in ring A and ring B, represents a single or double bond provided that only one double bond is present in a ring at a time;
R
2
is selected from the group consisting of H, OH, C
1-6
alkyl and C
1-6
alkoxy;
R
3
is selected from the group consisting of H, OH, C
1-6
alkyl, C
1-6
alkoxy,
C
1-6
alkylthio and optionally substituted benzyloxy;
R
4
is selected from the group consisting of H and C
1-4
alkyl;
R
5
is selected from the group consisting of H, OH, C
1-6
alkyl and C
1-6
alkoxy;
R
6
is selected from the group consisting of H, OH, C
1-6
alkoxy or null, provided that when R
6
is selected from the group consisting of H, OH and C
1-6
alkoxy, - - - - - represents a single bond in ring A and when R
6
is null, - - - - - represents a double bond in ring A;
R
7
and R
3
are independently selected from the group consisting of H and C
1-6
alkyl;
R
9
is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furanyl and optionally substituted naphthyl;
R
10
is selected from the group consisting of H, C
1-6
alkyl, optionally substituted benzyl, C(O)NHR
13
, SO
2
NHR
13
and C(S)NHR
13
;
One of R
11
and R
12
is selected from the group consisting of H, C
1-6
alkyl and optionally substituted benzyl and the other is H;
R
13
is selected from the group consisting of H, C
1-6
alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl;
R
14
, R
15
and R
16
are independently selected from the group consisting of H,
C
1-6
alkyl and phenyl or R
14
and R
15
may form an alkylene bridge, —(CH
2
)
n
—,
where n=3-6, to form, together with the nitrogen to which they are attached a 4- to 7- membered ring;
R
17
is selected from the group consisting of H, C
1-6
alkyl, C
1-6
alkoxy, phenyl, phenoxy, NH
2
, alkylamino, dialkylamino, benzyl and benzyloxy;
R
18
is selected from the group consisting of H and C
1-6
alkyl;
R
19
is selected from the group consisting of H and C
1-6
alkyl;
R
20
and R
21
are independently selected from the group consisting of H and C
1-6
alkyl or one of R
20
and R
21
, together with R
19
, forms an alkylene bridge, —(CH
2
)
n
—, where n=2 or 3, connecting the nitrogen atoms to which they are attached;
n is selected from the group consisting of an integer of from 1-3; and
Z is selected from the group consisting of C and N, provided that when Z is N, - - - - - represents a single bond in ring B.
It is another aspect of the present invention to provide a method effective to treat medical conditions for which stimulation of the 5-HT
1D
receptor is indicated, such as to treat migraine.
According to another aspect of the invention, there are provided compounds of Formula III and a salt, solvate or hydrate thereof:
wherein:
R
1
is a group of Formula II:
X is selected from the group consisting of O, S, SO, SO
2
, NR
10
and CR
11
R
12
;
- - - - - , in ring A and ring B, represents a single or double bond provided that only one double bond is present in a ring at a time;
R
2
is selected from the group consisting of H, OH, C
1-6
alkyl and C
1-6
alkoxy;
R
3
is selected from the group consisting of H, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio and optionally substituted benzyloxy;
R
4
is selected from the group consisting of H and C
1-4
alkyl;
R
5
is selected from the group consisting of H, OH, C
1-6
alkyl and C
1-6
alkoxy;
R
6
is selected from the group consisting of H, OH, C
1-6
alkoxy or null, provided that when R
6
is selected from the group consisting of H, OH and C
1-6
alkoxy, - - - - - represents a single bond in ring A and when R
6
is null, - - - - - represents a double bond in ring A;
R
10
is selected from the group consisting of H, C
1-6
alkyl, optionally substituted benzyl, C(O)NHR
13
, SO
2
NHR
13
and C(S)NHR
13
;
One of R
11
and R
12
is selected from the group consisting of H, C
1-6
alkyl and optionally substituted benzyl and the other is H;
R
13
is selected from the group consisting of H, C
1-6
alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl;
n is selected from the group consisting of an integer of from 1-3;
Z is selected from the group consisting of C and N, provided that when Z is N, represents a single bond in ring B.
It is an aspect of the present invention to provide a compound that binds to the 5-HT
1D
receptor.
It is another aspect of the present invention to provide compounds which bind selectively to the 5-HT
1D
receptor, relative particularly to the 5-HT
1B
receptor.
These and other aspects of the present invention are described in greater detail hereinbelow.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The term “C
1-6
alkyl” as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term “C
1-6
alkoxy” as used herein means straight and branched chain alkoxy radicals containing from one to six carbon a
Edwards Louise
Slassi Abdelmalik
Tehim Ashok
Xin Tao
Coleman Brenda
NPS Allelix Corp.
Rothwell Figg Ernst & Manbeck
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