Carboxamides useful as 5-HT1F agonists

Details Carboxamides useful as 5-HT1F agonists Carboxamides useful as 5-HT1F agonists

1999-12-21

2001-04-24

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S411000, C546S276700, C548S448000

Reexamination Certificate

active

06221884

ABSTRACT:

Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff (
Arch. Neurol. Psychiatry
, 39, 737-63 (1938)). They proposed that the cause of migraine headache was vasodilatation of extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT
1
agonist which does not cross the blood-brain barrier, contract cephalic vascular smooth muscle and are effective in the treatment of migraine. (Humphrey, et al.,
Ann. NY Acad. Sci
., 600, 587-600 (1990)). Recent work by Moskowitz has shown, however, that the occurrence of migraine headaches is independent of changes in vessel diameter (
Cephalalgia
, 12, 5-7, (1992)).
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT
1D
subtype, located on the trigeminovascular fibers (
Neurology
, 43(suppl. 3), S16-S20 (1993)).
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least four receptor classes, the most heterogeneous of which appears to be 5-HT
1
. A human gene which expresses a fifth 5-HT
1
subtype, named 5-HT
1F
, was isolated by Kao and coworkers (
Proc. Natl. Acad. Sci. USA
, 90, 408-412 (1993)). This 5-HT
1F
receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. The high affinity of sumatriptan at this subtype, K
i
=23 nM, suggests a role of the 5-HT
1F
receptor in migraine.
A series of N-aryl-3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides have been described by Porter, et al., (WO 94/14773, Jul. 7, 1994) as 5-HT
1
-like agonists, which exhibited vasoactive effects. The amides of the present invention are 5-HT
1F
agonists which inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders without the vasoconstrictive liability of structurally similar compounds.
The present invention provides novel 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and 4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides of Formula I:
wherein:
R
1
and R
2
are independently hydrogen, C
1
-C
4
alkyl, or —CH
2
CH
2
-Aryl where Aryl is phenyl, phenyl monosubstituted with halo, or 1-(C
1
-C
6
alkyl)pyrazol-4-yl;
R
3
is C
3
-C
6
cycloalkyl, or a heterocycle;
n is 1 or 2; and pharmaceutically acceptable salts and hydrates thereof.
A further embodiment of this invention is a method for increasing activation of the 5-HT
1F
receptor by administering a compound of Formula I.
A further embodiment of this invention is a method for increasing activation of the 5-HT
1F
receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, dysphoric disorder, alcoholism, tobacco abuse, panic disorder, anxiety, general pain, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism, trichotillomania, trigeminal neuralgia, dental pain or temperomandibular joint dysfunction pain. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employ a compound of Formula I.
In addition, this invention provides pharmaceutical formulations comprising an effective amount for activation of the 5-HT
1F
receptor of a compound of Formula I, in combination with a suitable pharmaceutical carrier, diluent, or excipient.
The general chemical terms used in the formulae above have their usual meanings. For example, the term “alkyl” includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term “cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “alkoxy” includes such groups as methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. The term “halo” includes fluoro, chloro, bromo, and iodo.
The term “heterocycle” is taken to mean fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-3-yl, N-methylpyrrol-3-yl, oxazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, pyrazol-4-yl, pyrimidin-5-yl, or pyrazin-4-yl. These heterocycles contain unsubstituted carbon atoms. Up to three available carbon atoms within any heterocyclic system may optionally be substituted with substituents independently selected from the group consisting of halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or C
1
-C
4
alkoxycarbonyl.
The compounds of the present invention possess an asymmetric carbon. This carbon is labelled with an asterisk in the following formula:
As such, each of the compounds of the present invention exists not only as the racemate but as individual R- and S-enantiomers as well:
The compounds of the present invention include not only the racemates, but also their respective optically active R- and S-enantiomers and any mixture thereof. While all racemates, mixtures, and individual enantiomers are useful 5-HT
1F
agonists, it is preferred that the compound exist as a single enantiomer.
While all of the compounds of this invention are useful as 5-HT
1F
agonists, certain classes are preferred. The following paragraphs describe such preferred classes.
aa) R
1
is hydrogen;
ab) R
1
is C
1
-C
6
alkyl;
ac) R
1
is ethyl;
ad) R
1
is methyl;
ae) R
1
is —CH
2
CH
2
-Ar where Ar is 1-(C
1
-C
6
alkyl)-pyrazol-4-yl;
af) R
1
is —CH
2
CH
2
-Ar where Ar is 1-methylpyrazol-4-yl;
ag) R
1
is —CH
2
CH
2
-Ar where Ar is 1-isopropylpyrazol-4-yl;
ah) R
2
is hydrogen;
ai) R
2
is C
1
-C
6
alkyl;
aj) R
2
is ethyl;
ak) R
2
is methyl;
al) R
2
is —CH
2
CH
2
-Ar where Ar is 1-(C
1
-C
6
alkyl)-pyrazol-4-yl;
am) R
2
is —CH
2
CH
2
-Ar where Ar is 1-methylpyrazol-4-yl;
an) R
2
is —CH
2
CH
2
-Ar where Ar is 1-isopropylpyrazol-4-yl;
ao) R
3
is a heterocycle;
ap) R
3
is pyridin-3-yl;
aq) R
3
is pyridin-4-yl;
ar) R
3
is pyridin-3-yl or pyridin-4-yl monosubstituted with halo;
as) R
3
is pyridin-3-yl or pyridin-4-yl monosubstituted with chloro;
at) R
3
is pyridin-3-yl or pyridin-4-yl monosubstituted with fluoro;
au) R
3
is fur-2-yl or fur-3-yl;
av) R
3
is thien-2-yl or thien-3-yl;
aw) R
3
is pyrrol-3-yl;
ax) R
3
is oxazol-5-yl;
ay) R
3
is isoxazol-4-yl or isoxazol-5-yl;
az) R
3
is pyrazol-4-yl;
ba) R
3
is pyrimidin-5-yl;
bb) R
3
is pyrazin-4-yl;
bc) R
3
is fur-2-yl or fur-3-yl optionally substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or halo;
bd) R
3
is fur-2-yl;
be) R
3
is fur-3-yl;
bf) R
3
is thien-2-yl or thien-3-yl optionally substituted with C
1
-C
4
alkyl or C
1
-C
4
alkoxy;
bg) R
3
is thien-2-yl;
bh) R
3
is thien-3-yl;
bi) R
3
is pyridin-3-yl or pyridin-4-yl optionally substituted with halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy;
bj) R
3
is 6-halopyridin-3-yl;
bk) R
3
is C
3
-C
6
cycloalkyl;
bl) R
3
is cyclopropyl;
bm) n is 1;
bn) n is 2;
bo) The compound is a racemate;
bp) The compound is the R-enantiomer;
bq) The compound is the S-enantiomer;
br) The compound is a free base;
bs) The compound is a salt;
bt) The compound is the hydrochloride salt;
bu) The compound is the fumarate salt;
bv) The compound is the oxalate salt.
It will be understood that the above classes may be combined to form additional preferred classes.
The compounds of this invention are useful in a method for increasing activation of the 5-HT
1F
receptor for treating

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