5-HT1F agonists

Details 5-HT1F agonists 5-HT1F agonists

2001-08-01

2004-02-24

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S233800, C514S252180, C514S302000, C544S061000, C544S127000, C544S362000, C546S115000

Reexamination Certificate

active

06696439

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 seven receptor classes, the most heterogeneous of which appears to be 5-HT
1
. A human gene which expresses one of these 5-HT
1
receptor subtypes, 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.
This invention relates to novel 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.
The present invention relates to a compound of formula I:
and pharmaceutical acid addition salts thereof, where;
R is
E—D is C═CH or CH—CH
2
;
R
1
is hydrogen or C
1
-C
4
alkyl;
R
2
is hydrogen, halo, hydroxy, —NR
3
R
4
, —SR
3
, —C(O)R
3
, —C(O)NR
3
R
4
, —NR
3
SO
2
R
5
, —NHC(Q)NR
3
R
4
, —NHC(O)OR
3
, or —NR
3
C(O)R
5
;
R
3
, R
4
, and R
5
are independently hydrogen, C
1
-C
4
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, or —(CH
2
)
n
aryl; or R
3
and R
4
combine, together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine, or thiomorpholine ring;
n is 0, 1, 2, 3, 4, 5, or 6; and
Q is O or S.
This invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier, diluent, or excipient.
In addition, the present invention relates to a method for activating 5-HT
1F
receptors in mammals comprising administering to a mammal in need of such activation an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
Moreover, the current invention relates to a method for inhibiting neuronal protein extravasation comprising administering to a mammal in need of such inhibition an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
One 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, 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.
The use of a compound of formula I for the activation of the 5-HT
1F
receptor, for the inhibition of peptide extravasation in general or due to stimulation of the trigeminal ganglia specifically, and for the treatment of any of the disorders described above, are all embodiments of the present invention.
The general chemical terms used throughout have their usual meanings. For example, the term “C
1
-C
4
alkyd” refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term “C
1
-C
6
” alkyl includes those groups listed for C
1
-C
4
alkyl and also refers to saturated, straight, or branched hydrocarbon chains of 5 to 6 carbon atoms. Such groups include, but are not limited to, pentyl, pant-2-yl, pent-3-yl, neopentyl, hexyl, and the like. The term “C
3
-C
8
cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term “C
2
-C
6
alkenyl” refers to mono-unsaturated straight or branched hydrocarbon chains containing from 2 to 6 carbon atoms and includes, but is not limited to, vinyl, allyl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like.
The term “C
2
-C
6
alkynyl” refers to straight or branched hydrocarbon chains containing 1 triple bond and from 2 to 6 carbon atoms and includes, but is not limited to, acetylenyl, propynyl, 2-butyn-4-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the like.
The terms “C
1
-C
6
alkoxy” and “C
1
-C
4
alkoxy” refer respectively to a C
1
-C
6
alkyl and C
1
-C
4
alkyl group bonded through an oxygen atom. The term “heteroaryloxy” refers to a heteroaryl or substituted heteroaryl group bonded through an oxygen atom. The term “aryloxy” refers to a phenyl or substituted phenyl group bonded through an oxygen atom. The term “C
1
-C
4
acyl” refers to a formyl group or a C
1
-C
3
alkyl group bonded through a carbonyl moiety. The term “C
1
-C
4
alkoxycarbonyl” refers to a C
1
-C
4
alkoxy group bonded through a carbonyl moiety.
The term “aryl” refers to an optionally substituted phenyl.
The term “aryl” refers to an optionally substituted phenyl or optionally substituted heterocyclic ring.
The term “heterocyclic” is taken to mean an unsaturated 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from: nitrogen, oxygen and sulfur, said ring optionally being benzofused. Heterocyclic rings include furanyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl, and the like.
The terms “substituted phenyl” and “substituted heterocycle” are taken to mean that the cyclic moiety in either case is substituted once with halo, cyano, nitro, C
1
-C
4
acyl, trifluoromethane, trifluoromethoxy, C
1
-C
4
alkoxycarbonyl, C
1
-C
6
alkoxy, or C
1
-C
4
alkyl, or two to five substituents independently selected from the halo group.
The term “amino protecting group” as used in this specification refers to a substituents commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl

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