Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-04
2001-04-03
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S266400, C548S255000, C546S268400, C514S339000
Reexamination Certificate
active
06211219
ABSTRACT:
The present invention relates to a class of substituted aminocyclohexane derivatives which act on 5-hydroxytryptamine (5-HT) receptors, being selective agonists of so-called “5-HT
1
-like” receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated.
It has been known for some time that 5-HT
1
-like receptor agonists which exhibit selective vasoconstrictor activity are of use in the treatment of migraine (see, for example, A. Doenicke et al.,
The Lancet,
1988. Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey,
Drug Development Research,
1992, 26, 235-240).
The human 5-HT
1
-like or 5-HT
1D
receptor has recently been shown by molecular cloning techniques to exist in two distinct subtypes. These subtypes have been termed 5-HT
1D
&agr;
(or 5-HT
1D−1
) and 5-HT
1D
&bgr;
(or 5-HT
1D−2
), and their amino acid sequences are disclosed and claimed in WO-A-91/17174.
The 5-HT
1D
&agr;
receptor subtype in humans is believed to reside on sensory terminals in the dura mater. Stimulation of the 5-HT
1D
&agr;
subtype inhibits the release of inflammatory neuropeptides which are thought to contribute to the headache pain of migraine. The human 5-HT
1D
&bgr;
receptor subtype, meanwhile, is located predominantly on the blood vessels and in the brain, and hence may play a part in mediating constriction of cerebral and coronary arteries, as well as CNS effects.
Administration of the prototypical 5-HT
1D
agonist sumatriptan (GR43175) to humans is known to give rise at therapeutic doses to certain adverse cardiovascular events (see, for example, F. Willett et al.,
Br. Med. J.,
1992, 304, 1415; J. P. Ottervanger et al.,
The Lancet,
1993, 341, 861-2; and D. N. Bateman,
The Lancet,
1993, 341, 221-4). Since sumatriptan barely discriminates between the human 5-HT
1D
&agr;
and 5-HT
1D
&bgr;
receptor subtypes (cf. WO-A-91/17174, Table 1), and since it is the blood vessels with which the 5-HT
1D
&bgr;
subtype is most closely associated, it is believed that the cardiovascular side-effects observed with sumatriptan can be attributed to stimulation of the 5-HT
1D
&bgr;
receptor subtype. It is accordingly considered (cf G. W. Rebeck et al.,
Proc. Natl. Acad. Sci. USA,
1994, 91, 3666-9) that compounds which can interact selectively with the 5-HT
1D
&agr;
receptor subtype, whilst having a less pronounced action at the 5-HT
1D
&bgr;
subtype, might be free from, or at any rate less prone to, the undesirable cardiovascular and other side-effects associated with non-subtype-selective 5-HT
1D
receptor agonists, whilst at the same time maintaining a beneficial level of anti-migraine activity.
The compounds of the present invention, being selective 5-HT
1
-like receptor agonists, are accordingly of benefit in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine. In particular, the compounds according to this invention are potent agonists of the human 5-HT
1D
&agr;
receptor subtype. Moreover, the compounds in accordance with this invention have been found to possess at least a 10-fold selective affinity for the 5-HT
1D
&agr;
receptor subtype relative to the 5-HT
1D
&bgr;
subtype, and they can therefore be expected to manifest fewer side-effects than those associated with non-subtype-selective 5-HT
1D
receptor agonists.
Several distinct classes of substituted five-membered heteroaromatic compounds are described in published European patent applications 0438230, 0494774 and 0497512, and published International patent applications 93/18029, 94/02477 and 94/03446. The compounds described therein are stated to be agonists of 5-HT
1
-like receptors, and accordingly to be of particular use in the treatment of migraine and associated conditions. None of these publications, however, discloses nor even suggests the substituted aminocyclohexane derivatives provided by the present invention.
WO-A-94/08993 and WO-A-95/28400 describe substituted pyridinyl-benzofuran derivatives, and analogues thereof. These compounds are stated therein to be selective agonists at 5-HT
1
-like receptors and thus useful in treating conditions associated with cephalic pain, including migraine. Neither of these publications, however, discloses or even suggests the substituted aminocyclohexane derivatives provided by the present invention.
In EP-A-0548813 is described a series of alkoxypyridin-4-yl and alkoxypyrimidin-4-yl derivatives of indol-3-ylalkylpiperazines which are alleged to provide treatment of vascular or vascular-related headaches, including migraine. There is, however, no disclosure nor any suggestion in EP-A-0548813 of replacing the substituted piperazine moiety with a differently substituted cyclohexane moiety.
WO-A-91/18897 describes a class of tryptamine derivatives substituted by various five-membered rings, which are stated to be specific to a particular type of “5-HT
1
-like” receptor and thus to be effective agents for the treatment of clinical conditions, particularly migraine, requiring this activity. A further class of tryptamine derivatives with alleged anti-migraine activity is disclosed in WO-A-94/02460. However, neither WO-A-91/18897 nor WO-A-94/02460 discloses or suggests the substituted aminocyclohexane derivatives provided by the present invention.
Moreover, nowhere in the prior art mentioned above is there any disclosure of a subtype-selective 5-HT
1D
receptor agonist having a 5-HT
1D
&agr;
receptor binding affinity (IC
50
) below 50 nM and at least a 10-fold selective affinity for the 5-HT
1D
&agr;
receptor subtype relative to the 5-HT
1D
&bgr;
subtype.
WO-A-95/32196, WO-A-96/04269, WO-A-96/04274, WO-A-96/16056 and WO-A-96/17842 describe various classes of heterocyclic compounds as alpha subtype-selective agonists of the human 5-HT
1D
receptor. However, there is no disclosure nor any suggestion in any of these publications of the substituted aminocyclohexane derivatives provided by the present invention.
The compounds according to the present invention are subtype-selective 5-HT
1D
receptor agonists having a human 5-HT
1D
&agr;
receptor binding affinity (IC
50
) below 100 nM, typically below 50 nM, suitably below 10 nM and preferably below 1 nM; and at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity and preferably at least a 100-fold selective affinity, for the human 5-HT
1D
&agr;
receptor subtype relative to the 5-HT
1D
&bgr;
subtype. Moreover, the compounds in accordance with this invention possess interesting properties in terms of their efficacy and/or bioavailability.
The present invention provides a compound of formula I, or a salt or prodrug thereof:
wherein
Z represents hydrogen, halogen, cyano, nitro, trifluoromethly. —OR
5
, —OCOR
5
, —OCONR
5
R
6
, —OCH
2
CN, —OCH
2
CONR
5
R
6
, —SR
5
, —SOR
5
, —SO
2
R
5
, —SO
2
NR
5
R
6
, —NR
5
R
6
, —NR
5
COR
6
, —NR
5
CO
6
, —NR
5
SO
2
R
6
, —COR
5
, —CO
2
R
5
, —CONR
5
R
6
, or a group of formula (Za), (Zb), (Zc) or (Zd):
in which the asterisk * denotes a chiral centre; or
Z represents an optionally substituted five-membered herteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole; or
Z represents an optionally substituted six-membered heteroaromatic ring selected from pyridine, pyrazine, pyrimidine and pyridazine;
X represents oxygen, sulphur, —NH— or methylene;
Y represents oxygen or sulphur;
E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;
Q represents a straight or branched alkylene chain containing from 1 to 6 carbon atoms, optionally substituted in any position by one or more substituents selected from fluoro and hydroxy;
T represents nitrogen or CH;
U represents nitrogen or C—R
2
;
V represents oxygen, sulphur or N—R
3
;
R
1
represents aryl(C
MacLeod Angus Murray
Showell Graham Andrew
Street Leslie Joseph
Durette Philippe L.
Fan Jane
McGinnis James L.
Merck Sharp & Dohme Ltd.
Rose David L.
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