Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-04-20
2001-06-12
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S665000, C514S670000, C564S501000, C564S508000
Reexamination Certificate
active
06245817
ABSTRACT:
BACKGROUND OF THE INVENTION
1) Field of the Invention
This invention is a method for inhibiting the neuropeptide Y (“NPY”) Y5 receptor using a class of substituted &agr;-alkoxy and &agr;-thioalkoxyamide compositions. As antagonists of the Y5 receptor, the compositions are useful in treating obese mammals, mammals with bulimia, for treating mammals with obesity related disorders including, but not limited to type II diabetes, insulin resistance, hyperlipidemia, hypertension, polycystic ovarian disease, pulmonary disease, sleep apnea, and for treating mammals suffering from NPY Y5 receptor inhibition related disorders such as memory disorders, epilepsy, dyslipidemia, and depression.
(2) Description of the Art
NPY is a 36 amino acid peptide that is a member of a larger peptide family which includes peptide YY (PYY), and pancreatic peptide (PP). NPY is highly conserved in a variety of animal, reptile and fish species and is found mainly in the central and peripheral sympathetic neurons. Furthermore, NPY is the most prevalent peptide in the mammalian brain where it is found primarily in the limbic regions. NPY has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and regulation of coronary tone.
NPY is believed to stimulate food intake by activating a hypothalamic eating receptor. Hu et al., J. Bio. Chem., Vol. 271, No. 42 pp.26315-319 (1996) discloses the isolation and identification and the expression cloning of a novel Y-type receptor from rat hypothalamus which the authors designated Y5. According to Hu et al., the localization of Y5 mRNA in critical areas of the brain hypothalamus and other brain regions known to regulate food intake together with an in vitro pharmacological profile consistent with the in vivo feeding data leads those skilled in the art to believe that the Y5 receptor is a primary mediator of NPY-induced feeding. A human homologue of the Y5 receptor has also been identified by Gerald et al., Nature, 382:168-171 (1996) which discloses the isolation, expression and analysis of an NPY Y5 receptor from the rat hypothalamus.
Antagonists of NPY receptors other than the Y5 receptors have been identified. For example, U.S. Pat. No. 5,554,621 discloses NPY antagonists that act on the Y1, Y2, Y3 and other Y1-like or Y4-type receptors. The reported antagonists are dihydropyridine based substituents.
U.S. Pat. No. 5,506,248 also discloses NPY receptor antagonists. The compositions disclosed each include sulphamadyl and amidino radicals. The disclosed compositions do not include sulfur or oxygen in the backbone structure.
WO 96/16542 discloses genetically modified NPY receptors.
There is evidence that the Y5 receptor of NPY has a pharmacological feeding profile that is unique in comparison to other NPY receptors, namely, Y1, Y2, Y3 and Y4/PP1 because the Y5 receptor response correlates well with in vivo potencies of the standard peptides in the stimulation of feeding. Furthermore, antagonists of other NPY receptors such as Y1 do not necessarily exhibit an inhibitory response when assayed against Y5. In view of the knowledge that NPY plays an important role in eating and other disorders and in view of the knowledge that the Y5 receptor plays an important and unique role in the mechanism of such disorders, there is, therefore, a great need for antagonists of the NPY Y5 receptor. Furthermore, there is a need for antagonists of NPY that specifically target the Y5 receptor.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a method for treating obesity, obesity related disorders and eating disorders in mammals using a therapeutically effective amount of a composition heretofore unknown for its NPY Y5 inhibitory properties.
It is another object of this invention to provide a method for the effective treatment of diseases in mammals that include the NPY Y5 receptor in their mechanism.
It is still another object of this invention to provide a method for the treatment of obesity and bulimia in humans using a class of substituted &agr;-alkoxy and &agr;-thioalkoxyamide compositions.
Another object of this invention are novel &agr;-alkoxy and &agr;-thioalkoxyamide compositions that are useful as NPY Y5 receptor antagonists and therapeutic compositions containing the same.
In one embodiment, this invention is a method for treating mammalian disorders mediated by the NPY Y5 receptor comprising the administration to a mammal of a therapeutically effective amount of at least one compound having the formula:
or pharmaceutically acceptable salts thereof wherein R
1
-R
5
are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, phenyl, substituted phenyl, benzothiophene, furan, fluoride, cyano, naphthyl, substituted naphthyl, fluorene, substituted fluorene and dibenzofuran and X is oxygen or sulfur.
In another embodiment, this invention is a class of novel &agr;-alkoxy and &agr;-thioalkoxyamide compositions. The novel compositions have the same general formula disclosed above except for compounds 137-188 identified in Table 4 as prior art compositions.
In yet another embodiment, this invention is a pharmaceutical dosage form comprising the novel &agr;-alkoxy and &agr;-thioalkoxyamide compositions described above and at least one pharmaceutical additive.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods for using &agr;-alkoxy and &agr;-thioalkoxyamide compositions that are NPY Y5 receptor antagonists to treat NPY mediated disorders including eating disorders such as bulimia and obesity. The present invention also includes novel &agr;-alkoxy and &agr;-thioalkoxyamide compositions. The &agr;-alkoxy and &agr;-thioalkoxyamide compositions described immediately below, except for compounds 137-188 disclosed in Table 4 are novel, while the compounds described below, including compounds 137-188 disclosed in Table 4 are useful in the methods disclosed herein.
Compositions that fall within the scope of this invention have the general formula:
wherein R
1
-R
5
are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, phenyl, substituted phenyl, benzothiophene, furan, fluoride, nitro, cyano, naphthyl, substituted naphthyl, fluorene, substituted fluorene and dibenzofuran and wherein and X is sulfur, or oxygen.
In the novel compositions of this invention, R
1
may be any substituent other than those R
1
substituents used in compounds 137-188 as disclosed in Table 4. More preferably, in the novel compounds of this invention, R
1
will be selected from the group of substituents including lower alkyl, substituted lower alkyl, substituted phenyl, phenyl, benzothiophene, furan, naphthyl, substituted naphthyl, fluorene, substituted fluorene, dibenzofuran and fluorine. When R
1
is a substituted phenyl, then the substituted phenyl may be substituted with one or more substituents including phenyl, cyanophenyl, halogens including fluoride, chloride, iodide and bromide, a branched or straight chain alkyl group having from 1 to 6 carbon atoms.
It is preferred that R
2
is hydrogen, or an unsubstitued or substituted alkyl group having from 1 to 6 carbon atoms.
R
1
and R
2
can together with an adjacent nitrogen atom form a 3 atom to 7 atom heterocycle.
It is preferred that R
3
and R
4
are individually selected from the group hydrogen, lower alkyl, substituted lower alkyl, or substituted or un
Connell Richard D.
Ladouceur Gaetan H.
Lease Timothy G.
Osterhout Martin H.
Bayer Corporation
Jones Dwayne C.
McDonnell & Boehnen Hulbert & Berghoff
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