Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-06
2004-05-18
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S217000, C548S224000
Reexamination Certificate
active
06737431
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention pertains to novel benzoxazole derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. In mammals, melatonin levels show a cyclical, circadian pattern, with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology.
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [
125
I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In the mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [
125
I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al.,
J. Biol. Rythms,
1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al.,
Br. Med. J.
292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487 published on Apr. 14, 1994.
Melatonin binding sites have been found in diverse tissues of the body—i.e., in the retina, superchiasmatic nucleus, spleen, etc. This means that melatonin exerts multiple physiological effects and is not highly selective. The potential for side effects with melatonin use is large. Melatonin agonists should be more selective than melatonin and have fewer side effects. Suitable melatonin agonists could overcome melatonin's drawbacks, resulting in products having more predictable and, possibly, sustained activity.
Melatonin agonists should be particularly useful for the treatment of chronobiological disorders. They would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, periondontitis, immune disorders, neuroendocrine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as:
wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application No. EP 527 687 A disclose, as melatonin ligands, ethylamines having cyclic substituents:
wherein Ar′ is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R
1
is, inter alia, an alkyl or cycloalkyl group; and R
2
is hydrogen or lower alkyl.
Matsuda, et al. in International Patent Application No. WO 95/22521 disclose 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as N-methyl-D-aspartate (NMDA) receptor antagonists, wherein R
1
represents, inter alia, a C
1
-C
5
linear saturated aliphatic, a C
1
-C
5
linear unsaturated aliphatic, a branched aliphatic, or a phenyl group which may be substituted with one to three substituents selected independently from the group consisting of halogen, C
1
-C
4
alkyl, nitro, amino, hydroxy, and C
1
-C
4
alkoxy as shown below:
The 1,2-diarylcyclopropane derivatives disclosed in NE 6701256 have CNS stimulant properties:
wherein Ar
1
and Ar
2
are independently and optionally substituted phenyl; R
1
is inter alia hydrogen, lower alkyl or acyl; R
2
is inter alia alkyl, cycloalkyl or aralkyl.
Keavy et al. In U.S. Pat. No. 5,753,709 issued on May 19, 1998, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure:
wherein X represents halogen, hydrogen, cyano, aryl, C
1-4
alkyl or OR
5
wherein, inter alia, R
5
is hydrogen, C
1-20
alkyl or C
4-20
alkylcycloalkyl; Y is hydrogen or halogen; R is hydrogen, halogen or C
1-4
alkyl; R
1
is hydrogen, C
1-4
alkyl or benzyl; and R
2
is C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, C
2-4
alkoxyalkyl, C
1-4
trifluoromethylalkyl or C
2-8
alkylthioalkyl.
Catt et al. in U.S. Pat. No. 5,856,529 issued on Jan. 5, 1999, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure:
wherein Q
1
and Q
2
represent hydrogen or halogen; X is CH
2
, CH or oxygen; Y is CR
3
, C
3
R
4
or (CH
2
)
n
whereby n is 1 to 4; Z is CH
2
, CH or oxygen; R is hydrogen, halogen or C
1-4
alkyl; m is 1 or 2; R
2
is hydrogen or C
1-4
alkyl; and R
1
is C
1-6
alkyl, C
3-6
cycloalkyl, C
1-3
haloalkyl, C
1-6
alkylamino, C
2-6
alkenyl, C
1-4
alkoxy(C
1-4
)alkyl, C
1-4
alkylthio(C
1-4
)alkyl or C
1-4
trifluoromethylalkyl.
Takaki et al. in U.S. Pat. No. 6,211,225 issued on Apr. 3, 2001, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure:
wherein the wavy bond~~represents the racemate, the (R)-enantiomer or the (S)-enantiomer; R
1
and R
2
each are independently hydrogen or halogen; W is CR
5
, CR
5
R
6
or (CH
2
)
n
with n being 1 to 2; Z is CH
2
, CH or oxygen; R
3
is hydrogen or C
1-4
alkyl; R
4
is C
1-6
alkyl, C
3-6
cycloalkyl, C
1-3
haloalkyl, C
1-6
alkylamino, C
2-6
alkenyl, C
1-4
alkoxy(C
1-4
)alkyl, C
1-4
alkylthio(C
1-4
)alkyl or C
1-4
trifluoromethylalkyl; R
5
and R
6
are each independently hydrogen or C
1-4
alkyl.
The foregoing disclosures do not teach or suggest the novel melatonergic benzoxazole derivatives of the present invention. The novel compounds of the present invention display melatonergic agonist activity.
SUMMARY OF THE INVENTION
The present invention is directed to, in a first aspect, a compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof wherein
A is C
1-4
alkylene or 1,2 disubstituted cyclopropyl;
B is C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy, or C
1-4
alkylamino;
X is hydrogen, halogen, C
2-4
alkenyl, C
1-6
alkyl, furyl, or phenyl optionally substituted with halogen, C
1-6
alkoxy, or haloalkyl; and
Y is hydrogen, phenyl, or C
1-6
alkyl optionally substituted with phenyl.
In another aspect, the present invention is directed to a method of treating a circadian rhythm-related disorder in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
In yet another aspect, the present invention is directed to a pharmaceutical composition for treating circadian rhythm-related disorders comprising a therapeutically effective amount of a compound as defined by Formula I and a pharmaceutically
Bertenshaw Stephen R.
Chen Jie
Denhart Derek
Johnson Graham
Sun Li-Qiang
Algieri Aldo A.
Bristol--Myers Squibb Company
Ramsuer Robert W.
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