Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-04
2004-08-17
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S330000, C546S189000, C546S208000, C546S225000, C544S060000, C544S130000, C544S365000
Reexamination Certificate
active
06777428
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 compounds of formula I:
or a pharmaceutical acid addition salt thereof, where;
A is hydrogen, halo, —OR
4
, NH
2
, or —CF
3
;
R is hydrogen, C
1
-C
4
alkyl, C
3
-C
6
alkenyl, C
3
-C
6
alkynyl, or (C
1
-C
6
alkyl)-Ar
1
;
R
1
is —NH—R
2
—R
3
, hydroxy, —OSO
2
Ar
2
, or NH
2
;
Ar, Ar
1
, Ar
2
, Ar
3
, and Ar
4
are independently an optionally substituted phenyl or optionally substituted heteroaryl;
R
2
is —CO—, —CS—, or —SO
2
—;
R
3
is hydrogen, optionally substituted C
1
-C
6
alkyl, Ar
3
, —NR
5
R
6
, or OR
5
; provided R
3
is not hydrogen if R
2
is either —CS— or —SO
2
—;
R
4
is hydrogen, optionally substituted C
1
-C
6
alkyl, or Ar; and
R
5
and R
6
are independently hydrogen, optionally substituted C
1
-C
8
alkyl, or Ar
4
; or R
6
and R
5
combine, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring.
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.
In addition, the present invention relates to a process for preparing the compounds of formula I(a):
wherein R
3
is hydrogen, optionally substituted C
1
-C
6
alkyl, Ar
3
, —NR
5
R
6
, or OR
5
;
R
5
and R
6
are independently hydrogen, optionally substituted C
1
-C
8
alkyl, or Ar
4
; or R
6
and R
5
combine, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring; and
Ar
3
and Ar
4
are independently an optionally substituted phenyl or optionally substituted heteroaryl, comprising:
(a) protecting 4-benzoylpiperidine hydrochloride to form an N-protected 4-benzoylpiperidine hydrochloride;
(b) nitrating the N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4-(mononitrobenzoyl)piperidines;
(c) deprotecting the N-protected 4-(mononitrobenzoyl)piperidine mixture to form a mixture of 4-(mononitrobenzoyl)piperidines;
(d) separating the 4-(3-nitrobenzoyl)piperidine from the mixture of 4-(mononitrobenz-oyl)piperidines;
(e) reducing the 4-(3-nitrobenzoyl)piperidine to form 4-(3-aminobenzoyl)piperidine; and
(f) acylating the 4-(3-aminobenzoyl)piperidine.
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, chronic pain, 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, allergic rhinitis, insect stings, 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
alkyl” refers to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl. The term “C
1
-C
8
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 8 carbon atoms. Such groups include, but are not limited to, pentyl, pent-2-yl, pent-3-yl, neopentyl, 2,3,4-trimethylpentyl, hexyl, hex-2-yl, hex-3-yl, hex-4-yl, 2,3-dimethylhexyl, 2-ethylhexyl, heptyl, hept-2-yl, hept-3-yl, hept-4-yl, octyl, oct-2-yl, oct-3-yl, oct-4-yl, oct-5-yl, and the like. The term “C
3
-C
8
cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term “C
3
-C
6
alkenyl” refers to mono-unsaturated straight or branched hydrocarbon chains containing from 3 to 6 carbon atoms and, includes, but is not limited to, 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
3
-C
6
alkynyl” refers to straight or branched hydrocarbon chains containing 1 triple bond and from 3 to 6 carbon atoms and includes, but is not limited to, 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 grou
Krushinski, Jr. Joseph Herman
Mancuso Vincent
Napora Freddy Andre
Schaus John Mehnert
Berch Mark L.
Eli Lilly and Company
Tucker Robert Craig
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