5-HT1F agonists

Details 5-HT1F agonists 5-HT1F agonists

2000-12-05

2002-03-19

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S113000

Reexamination Certificate

active

06358972

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
against 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:
or a pharmaceutical acid addition salt thereof; where:
A is nitrogen or carbon;
D is oxygen, sulfur, or NH;
E is carbon or nitrogen;
G—J is CH
2
—CH or CH═C;
R is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl;
R
1
is hydrogen or C
1
-C
6
alkyl;
R
2
is hydrogen or C
1
-C
6
alkyl;
R
3
is hydrogen or R
2
and R
3
combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring; with the proviso that
1) A may be nitrogen only when D is NH and E is carbon;
2) E may be nitrogen only when D is NH and A is carbon;
3) when E is nitrogen, R
1
is not a substituent; or a pharmaceutical acid addition salt thereof.
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 “6:5, 6:6, or 6:7 fused bicyclic ring” refers to moieties of the formula:
respectively.
The compounds of formula I where R
2
and R
3
combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring (indolizinyl, quinolizinyl, or 1-azabicyclo[5.4.0]undecanyl ring respectively) contain a chiral center located in that bicyclic ring. This chiral center is located at the bridghead carbon ring system. Furthermore, when R
2
and R
3
combine and G—J is CH
2
—CH, the CH group of G—J is a chiral center as well. Such centers are designated “R” or “S”. For the purposes of the present application, the numbering system for naming the substituents around the 1H-indole, benzofuran, benzothiophene, indazole, and 4-aza-1H-indole rings and the R,R and S,S enantiomers are illustrated below where n is 0, 1, or 2 and A, D, E, R, and R
1
are as defined above.
All enantiomers (S,R; R,S; S,S; R,R), diastereomers, and mixtures thereof, are included within the scope of the present invention.
The term “C
1
-C
4
alkyl” includes such groups as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl. The term “C
1
-C
6
alkyl” includes those groups listed for C
1
-C
4
alkyl and also refers to saturated straight, branched, or cyclic hydrocarbon chains of 5 to 6 carbon atoms. Such groups include, but are not limited to, pentyl, pent-2-yl, pent-3-yl, neopentyl, cyclopentyl, hexyl, cyclohexyl, and the like.
The term “halo” includes fluoro, chloro, bromo and iodo.
The term “C
1
-C
6
alkoxy” refers to a C
1
-C
6
alkyl group bonded through an oxygen atom. The term “C
1
-C
4
alkoxy” refers to a C
1
-C
4
alkyl group bonded through an oxygen atom. The term “C
1
-C
4
alkylthio” refers to a C
1
-C
4
alkyl group bonded through a sulfur atom. The term “(C
1
-C
4
alkyl)sulfonyl” refers to a C
1
-C
4
alkyl group bonded through a sulfonyl moiety. 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 terms “substituted phenyl” and “substituted naphthyl” refer to a phenyl and naphthyl moiety, respectively, substituted once with halo, C
1
-C
4
alkyl, C
1
-C
6
alkoxy, C
1
-C
4
alkylthio, nitro, cyano, amino, (C
1
-C
4
alkyl)
2
amino, NH—(C
1
-C
4
acyl), NHC(O)-heteroaryl, NHC(O)-phenyl, NHC(O)-substituted phenyl, carboxamido, trifluoromethyl, trifluoromethoxy, phenyl, C
1
-C
4
acyl, benzoyl or (C
1
-C
4
alkyl)sulfonyl, or two to three substituents independently selected from: halo, nitro, C
1
-C
4
alkyl, trifluoromethyl, and C
1
-C
4
alkoxy.
The term “heteroaryl” is taken to mean an aromatic 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from: nitrogen, oxygen and sulfur, said ring optionally being benzofused. Aromatic rings include furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused aromatic rings include isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl, benzothiophen

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